CN107028907B - Divalproex sodium sustained-release tablet - Google Patents

Abstract

The invention discloses a divalproex sodium sustained release tablet, which comprises a first step of preparing an auxiliary material soft material, a second step of preparing a medicine-containing soft material and preparing granules, wherein the obtained granules are uniform in appearance, free of adhesive glue cluster formation, moderate in particle size, good in flowability and compressibility, uniform in content of active ingredients and capable of ensuring stable and controllable medicine quality. The divalproex sodium sustained-release tablets prepared from the obtained granules have good in-vitro release, the similarity of a release curve and a drug product on the market is high, and the sustained-release tablets can effectively control the drug to be slowly released within 24 hours.

Description

Divalproex sodium sustained-release tablet

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a divalproex sodium sustained-release tablet.

Background

Epilepsy is a chronic brain disease, is intrinsically abnormal in electrical discharge, and has recurrent seizures. According to WHO statistics, 5000 million epileptics exist in the world, Chinese epileptics are over 800 million patients, the lifetime prevalence rate is 0.7%, and about 40 million new cases occur every year. Divalproex sodium can regulate balance nerve excitation and inhibition by increasing gamma-aminobutyric acid (GABA) level and other mechanisms, thereby effectively controlling epileptic seizure, having broad-spectrum antiepileptic effect and treating various neurological diseases, and being applicable to various epileptic patients. Because of its lower gastrointestinal side effects and less drug interactions, it has become the first line of choice for the treatment of most primary and symptomatic generalized seizures.

Divalproex sodium was developed by Abbott, Inc. USA, and approved for the treatment of epilepsy in 1983, and subsequently approved for the treatment of bipolar disorder and the prevention of migraine in 1995 and 1996, respectively, at a specification of 250mg and 500 mg. The product can also prevent migraine in children and adults, has remarkable curative effect on acute manic episode of bilateral affective disorder (BPD), has small side effect, and has become a first-line medicament for treating bilateral affective disorder in North America.

Compared with other commonly used antiepileptic drugs, divalproex sodium has shorter elimination half-life, thereby causing great fluctuation of plasma concentration of the drug and particularly influencing the clinical application of the drug when the drug is taken for a long time. Frequent administration is required to maintain reasonably stable plasma concentrations, thereby causing inconvenience to the patient. In order to overcome the defects, the divalproex sodium can be prepared into sustained-release tablets so as to reduce the administration times.

When divalproex sodium is prepared into sustained-release tablets, the blocky divalproex sodium is generally required to be crushed, but the flowability and compressibility of the crushed divalproex sodium are poor, and ideal flowability and compressibility are difficult to obtain by adopting a direct tabletting process, so that a wet granulation process is required to improve the flowability of powder and reduce the content difference among tablets.

Wet granulation is a process in which a binder is added to a pharmaceutical powder and the powder is agglomerated together by the bridging or binding action of the binder to produce granules. The wet-process prepared granules have the advantages of good quality, attractive appearance, good compression formability and the like after surface wetting, can obviously improve the fluidity and the dispersibility of materials, is favorable for accurate metering, and ensures the attractive appearance of tabletting.

Although wet granulation can be adopted, sodium valproate and divalproex sodium can generate physical and chemical changes after moisture absorption, and are difficult to dry for further tabletting, for example, patent CN99814629.3 and patent US6713086 mix the crushed divalproex sodium with lactose, microcrystalline cellulose and hydroxypropyl methyl cellulose, then add a wetting agent to prepare soft materials and granules, then dry with a fluidized bed to obtain powder granules, then mix the powder granules with silicon dioxide and tabletting to obtain the divalproex sodium sustained release tablets. However, the applicant actually examines and finds that the process has large-area bonding when molding and drying after preparing a soft material, and if a subsequent tabletting process is carried out, the large-area bonded particles need to be crushed again, which also causes the problems of poor uniformity of the content of the drug in the prepared sustained-release tablet and the like. In order to solve the problem of moisture absorption of divalproex sodium in the process of wet granulation of divalproex sodium, a patent of ' a divalproex sodium sustained-release tablet and a preparation method thereof ' (application number is CN201110075637.3, Sun Weidong) ' adopts various auxiliary materials such as a retardant, a diluent, a disintegrant, a binder, a pH regulator, a lubricant, an anti-sticking agent and the like when preparing the divalproex sodium sustained-release tablet, but the problems of difficult tablet weight control, increased impurity introduction opportunities and the like are caused.

Disclosure of Invention

In order to solve the problems of granule adhesion, content uniformity in tablets and the like caused by the moisture absorption problem of the divalproex sodium in the wet granulation process and simultaneously avoid the problems of a series of tablet weights, increase of related substances and the like caused by using a large amount of different auxiliary materials, the applicant obtains a sustained-release tablet capable of solving the problems through a large amount of experimental researches, and the sustained-release tablet is prepared by preparing a soft material by using a hydrophilic framework material and a diluent through a wetting agent, preparing the divalproex sodium and the soft material into a medicine-containing soft material, granulating, drying, mixing with a flow aid, and tabletting. The method avoids excessive contact of divalproex sodium and a wetting agent, so that a liquid bridge frame and a bonding effect formed by active ingredients among auxiliary materials are small, the prepared divalproex sodium-containing granules are attractive in appearance, good in flowability and compressibility and uniform in granule content, and the quality of the preparation is controllable and stable.

The invention provides a divalproex sodium sustained-release tablet, which contains divalproex sodium, a hydrophilic gel skeleton sustained-release material, a diluent and a wetting agent, and the preparation method of the sustained-release tablet comprises the following steps:

(1) uniformly mixing the hydrophilic gel framework material and the diluent, and adding a wetting agent to prepare a soft material;

(2) adding divalproex sodium into the soft material prepared in the step (1), uniformly stirring and mixing to prepare a medicine-containing soft material, sieving the prepared medicine-containing soft material with a 20-24-mesh sieve for granulation, drying, and grading with a 20-24-mesh sieve;

(3) and (3) adding 1-5 wt% of glidant into the granules obtained in the step (2), uniformly mixing, and tabletting to obtain the finished product.

The weight percentage content of the divalproex sodium is preferably 41.4-55%, the weight percentage content of the hydrophilic gel framework material is preferably 20-36%, and the weight percentage content of the diluent is preferably 10-35%.

The hydrophilic gel framework material is preferably one or more of hydroxypropyl methyl cellulose, polyoxyethylene, Arabic gum, sodium alginate and carrageenan; most preferred is hydroxypropyl methylcellulose.

The diluent is preferably one or more of lactose, microcrystalline cellulose, starch and mannitol; lactose and microcrystalline cellulose are preferred; more preferably, the mass ratio of the lactose to the microcrystalline cellulose is 0.3-2.

The wetting agent is preferably one or both of ethanol and water; ethanol is most preferred.

The glidant is silicon dioxide or magnesium stearate, preferably silicon dioxide.

The invention can adopt conventional stirring equipment and granulating equipment in the stirring, mixing and wet granulating processes, and the invention discloses a wet mixing granulator with the stirring speed of 300-400 rpm and the shearing speed of 3000-4000 rpm.

The divalproex sodium used in the invention can be commercially available or prepared by a conventional process and then crushed by various conventional methods; preferably, the medicine is obtained by crushing and then sieving with a sieve of 80-100 meshes.

The invention further provides a sustained-release tablet, which comprises the following components in percentage by weight:

the preparation method of the sustained-release tablet comprises the following steps:

a) crushing divalproex sodium and sieving with a 100-mesh sieve;

b) mixing hydroxypropyl methyl cellulose, microcrystalline cellulose and lactose to obtain a uniformly dispersed mixed material;

c) under the condition of stirring, adding a proper amount of ethanol into the uniformly mixed material prepared in the step b), wherein the adding amount of the ethanol is 150-300 mL per 1kg of the material, so as to prepare a wet soft material;

d) adding 41.4-55 wt% of divalproex sodium prepared in the step a) into the soft material prepared in the step c) under stirring conditions, and continuously mixing the materials by using a wet mixing granulator to prepare the soft material, wherein the stirring speed is 300-400 rpm, and the shearing speed is 3000-4000 rpm;

e) sieving the soft material prepared in the step d) with a 24-mesh sieve to obtain particles;

f) drying the granules obtained in the step e), granulating, mixing with silicon dioxide, and tabletting.

The weight percentage content of the components is preferably as follows:

the invention also inspects the dosage of ethanol in the process of preparing the soft material, and the result shows that the appearance and the particle size of the particles prepared by adding 150-300 mL of ethanol into every 1kg of material are most suitable. When the ethanol is added in too small amount, because a lot of materials are not wetted and still exist in a dry powder form, the particle size of the obtained particles is small, and the fluidity is not obviously improved. Excessive addition of ethanol can cause excessive ethanol in local materials and excessive induction of viscosity of auxiliary materials, so that the prepared particles have too large particle size and even form viscous micelles difficult to disperse.

The invention simultaneously considers the amount of ethanol required to be added into the materials with different hydroxypropyl methyl cellulose proportions under the condition of the same material, and the result shows that the higher the proportion of the hydroxypropyl methyl cellulose in the materials is, the more the amount of the ethanol required to be added is.

The release degree of the granules prepared by the process is measured after tabletting, and the release result is compared with the release result of the medicines on the market. The results show that the sustained-release tablet has similar in vitro release behavior with the marketed sustained-release medicines, and the process of the invention shows that the sustained-release tablet obtained by the technical scheme of the invention not only solves the problem of particle bonding in the wet granulation process, but also the obtained sample has uniform content, thereby avoiding the great fluctuation of the release rate of the preparation caused by the uneven mixing of the raw material medicines, ensuring the stable process of mass production and being more beneficial to ensuring the safety of the clinical application of the preparation.

Drawings

FIG. 1A illustrates the preparation of the resulting dry granules by a conventional granulation process;

figure 2 the process of the present invention produces a dry granulation.

Detailed Description

The following detailed description of specific embodiments of the present invention is provided to illustrate and explain the present invention and to be understood not to limit the present invention.

The experimental material sources used in the examples illustrate:

medicine preparation: divalproex sodium (medjx pharmaceutical technology ltd, lot number 140705).

Reagents and auxiliary materials: absolute ethanol (kyoto jinshan chemicals limited, lot No. 20140602), hydroxypropylmethylcellulose K4M (dow chemical company, usa, lot No. PD402138), hydroxypropylmethylcellulose K15M (dow chemical company, lot No. PD404259), hydroxypropylmethylcellulose K100M (shanghai kalekang coating technology limited, lot No. SH324227), lactose (netherlands DMV company, lot No. 10758919), microcrystalline cellulose PH102 (asahi chemicals co., lot No. 9212428109), microcrystalline cellulose PH101 (FMC company, usa, lot No. P113826027).

Wet mixing granulator: the model is HLSH2-6, Beijing aviation manufacturing engineering research institute.

EXAMPLE 1 two granulation Processes for the preparation of Divalproex sodium granulate

1. The weight percentage of each component

2. Experimental methods

(1) The process granulation method of the invention is used for preparing divalproex sodium granules

a) Crushing divalproex sodium and sieving with a 100-mesh sieve;

b) mixing hydroxypropyl methyl cellulose, microcrystalline cellulose and lactose to obtain a uniformly dispersed mixed material;

c) adding a proper amount of ethanol into the uniformly mixed material prepared in the step b) under the stirring condition of a wet mixing granulator, wherein the adding amount of the ethanol is 150-300 mL per 1kg of the material, so as to prepare a wet soft material;

d) adding the divalproex sodium prepared in the step a) into the wet soft material prepared in the step c) under the stirring condition of a wet mixing granulator, and continuously mixing the materials by using the wet mixing granulator to prepare the soft material, wherein the stirring speed is 300-400 rpm, and the shearing speed is 3000-4000 rpm;

e) sieving the soft material prepared in the step d) with a 24-mesh sieve to obtain particles;

f) drying the granules prepared in the step e) for 1 hour at the temperature of 40 ℃ to obtain the dried granules.

(2) Method for preparing divalproex sodium granules by conventional process granulation

a) Crushing divalproex sodium and sieving with a 100-mesh sieve;

b) mixing the divalproex sodium prepared in the step a), hydroxypropyl methyl cellulose, microcrystalline cellulose and lactose to obtain a uniformly dispersed mixed material;

c) adding a proper amount of ethanol into the uniformly mixed materials in the step b) under the stirring condition of a wet mixing granulator, wherein the adding amount of the ethanol is 150-300 mL per 1kg of the materials, so as to prepare a wet soft material;

d) sieving the wet soft material prepared in the step c) by a 24-mesh sieve to obtain particles;

f) drying the granules prepared in the step e) for 1 hour at the temperature of 40 ℃ to obtain the dried granules.

(3) Determination of the sieving Rate

Respectively weighing about 50g of dry particles prepared by the conventional process granulation method and the process granulation method of the invention, sieving the dry particles by a 20-mesh sieve, respectively weighing the weight of the particles passing through the 20-mesh sieve, and calculating the sieving rate (%) by dividing the weight of the sieved particles by the total weight of the weighed particles to evaluate the granulation effects of the two methods.

3. Results of the experiment

Test results show that in the process of granulating by using a conventional granulating process, materials form viscous micelles after ethanol is added, and the materials are still difficult to disperse and cannot be used for preparing uniform granules by using a wet mixing granulator for shearing. When the process granulation method is adopted for granulation, no cohesive micelle is formed, uniform granules are easy to prepare, the granules are moderate in size, round and round in appearance and more uniform in content. Specific results can be seen in fig. 1 and 2.

TABLE 1 Dry granulation sieving rates prepared by the two procedures

The sieving rate (%) of the dried granules prepared by the two methods after passing through a 20-mesh sieve, which was calculated by comparing the weight of the granules before and after sieving, is shown in table 1. The result shows that the sieving rate of the dry particles prepared by the granulation method is 99.60 percent, which shows that the granulation effect is good by using the process and the method is suitable for industrial production. The granules prepared by using the conventional process are serious in blocking phenomenon when being dried, only 4.29 percent of the granules can pass through a 20-mesh sieve, the particles which are not sieved are all hard blocks, the granules cannot be used for pressing sustained-release tablets, qualified granules can be obtained for pressing tablets after complex treatment, and the content uniformity of the medicine cannot be ensured. The granules prepared by adopting the process of the invention have no hard block, can pass through a 20-mesh sieve without more treatment, and can be directly used for the next tabletting operation, thereby simplifying the tabletting process and ensuring the uniform content of the medicine.

And (3) sieving the two prepared divalproex sodium dry granules with a 20-mesh sieve for finishing, wherein the granules prepared by adopting the conventional process are dried and agglomerated, and can pass through the 20-mesh sieve after being sufficiently crushed. Respectively mixing with 3.0 wt% of silicon dioxide, tabletting with a tabletting machine (model DP30A, Beijing national medicine Longli technology Co., Ltd.), stamping with a die of 1.9cm × 0.91cm (oval), tablet weight of 1000mg, and pressure of 120-135N. The results show that the particles prepared by the conventional process granulation method need to be crushed again due to bonding, contain more fine powder and have poor flowability and compressibility, and the particles prepared by the process granulation method have good flowability and compressibility and ensure uniform and controllable drug content.

Taking 6 sodium divalproate sustained-release tablets prepared under the two process conditions, respectively placing the 6 sodium divalproate sustained-release tablets in 250mL measuring bottles, adding a proper amount of methanol for ultrasonic dissolution for 30min, cooling to room temperature, diluting to scale, shaking up, precisely measuring 5mL in 10mL measuring bottles, adding a diluent (0.5 g of citric acid monohydrate and 0.4g of disodium hydrogen phosphate are dissolved in 1L of water, adjusting the pH to 2.0 with phosphoric acid), diluting to scale, shaking up to obtain a sample solution, and using the sample solution for measuring the content by using an HPLC method. Methanol pH 5.0 phosphate buffer (0.5 g citric acid monohydrate and 0.4g disodium hydrogen phosphate dissolved in 1L water, pH 5.0 adjusted with phosphoric acid) 11: 9 was used as mobile phase. Using a Phenyl column (Ultimate XB-Phenyl, 3.9 mm. times.150 mm, 4 μm, Yueha science) with a detection wavelength of 210nm, a column temperature of 30 ℃, a flow rate of 0.7mL/min, and a sample injection volume of 20 μ L. The content measurement results are as follows:

TABLE 2 content uniformity of the sustained-release tablets obtained by conventional granulation process

TABLE 3 content uniformity of the sustained release tablets obtained by the granulation process of the present invention

The measured data further show that the active ingredients in the granules prepared by the process granulation method are more uniformly distributed in the granules, the content uniformity of the prepared sustained-release tablets is better, and the content difference among the tablets is small; the active ingredients of the granules prepared by adopting the conventional process granulation method are difficult to be uniformly distributed, the content uniformity of the prepared sustained-release tablets is poor, the content difference among the tablets is overlarge, and the content range of the divalproex sodium sustained-release tablets is reasonably controlled to be 95-105 percent according to the principle established by the quality standard.

Example 2

Prescription:

the process comprises the following steps: the wet granulation was prepared according to the procedure of example 1, drying the wet granulation at 50 ℃ for 1 hour, sizing the granules with a 24-mesh sieve, mixing the granules with 3.0% by weight of silica uniformly, tabletting, stamping with a die of 1.9cm × 0.91cm (oval), tablet weight of 1000mg, and pressure of 130 to 150N.

Taking the dried granules prepared in the above process, the sieving rate of passing through a 24-mesh sieve was measured by the sieving rate method in example 1, and the result was 99.24%. Taking 6 tablets of the divalproex sodium sustained-release tablets prepared above, determining the content of the divalproex sodium in each tablet by adopting the method in example 1, the results are as follows:

example 3

Prescription:

the process comprises the following steps: the wet granulation was prepared according to the procedure of example 1, drying the wet granulation at 60 ℃ for 1 hour, sizing the granules with a 20-mesh sieve, mixing the granules with 2.0% by weight of silica uniformly, tabletting, stamping with a die of 1.9cm × 0.91cm (oval), tablet weight of 1000mg, and pressure of 120 to 135N.

The dried granules prepared in the above process were taken, and the sieving rate of 20 mesh sieve was measured by the sieving rate method in example 1, and the result was 100%. Taking 6 tablets of the divalproex sodium sustained-release tablets prepared above, determining the content of the divalproex sodium in each tablet by adopting the method in example 1, the results are as follows:

example 4

Prescription:

the process comprises the following steps: the wet granulation was prepared according to the procedure of example 1, drying the wet granulation at 50 ℃ for 1 hour, sizing the granules with a 24-mesh sieve, mixing the granules with 3.0% by weight of silica uniformly, tabletting, stamping with a die of 1.9cm × 0.91cm (oval), tablet weight of 1000mg, and pressure of 135-150N.

The dried granules prepared in the above process were taken, and the sieving rate through a 24-mesh sieve was measured by the sieving rate method in example 1, and the result was 99.81%. Taking 6 tablets of the divalproex sodium sustained-release tablets prepared above, determining the content of the divalproex sodium in each tablet by adopting the method in example 1, the results are as follows:

example 5

Prescription:

the process comprises the following steps: the wet granulation was prepared according to the procedure of example 1, drying the wet granulation at 40 ℃ for 1.5 hours, sizing the granules with a 24-mesh sieve, mixing the granules with 1.0% by weight of silica uniformly, tabletting, stamping with a die of 1.9cm × 0.91cm (oval), tablet weight of 1000mg, and pressure of 130-140N.

Taking the dried granules prepared in the above process, the sieving rate through a 24-mesh sieve was measured by the sieving rate method in example 1, and the result was 99.92%. Taking 6 tablets of the divalproex sodium sustained-release tablets prepared above, determining the content of the divalproex sodium in each tablet by adopting the method in example 1, the results are as follows:

example 6

Prescription:

the process comprises the following steps: the wet granulation was prepared according to the procedure of example 1, drying the wet granulation at 40 ℃ for 1.5 hours, sizing the granules with a 24-mesh sieve, mixing the granules with 3.0% by weight of silica uniformly, tabletting, stamping with a die of 1.9cm × 0.91cm (oval), tablet weight of 650mg, and pressure of 130-150N.

Taking the dried granules prepared in the above process, the sieving rate through a 24-mesh sieve was measured by the sieving rate method in example 1, and the result was 99.76%. And (2) respectively putting 6 tablets of the prepared divalproex sodium sustained-release tablets into 100mL measuring bottles, adding a proper amount of methanol, ultrasonically dissolving for 30min, cooling to room temperature, diluting to a scale, shaking uniformly, precisely measuring 10mL into a 25mL measuring bottle, adding a diluent (0.5 g of citric acid monohydrate and 0.4g of disodium hydrogen phosphate are dissolved in 1L of water, adjusting the pH to 2.0 by using phosphoric acid), diluting to the scale, and shaking uniformly to obtain a sample solution for measuring the content by using an HPLC method. The remaining method in example 1 was used to determine the divalproex sodium content of each tablet, and the following results were obtained:

example 7

Prescription:

the process comprises the following steps: crushing divalproex sodium, sieving with a 80-mesh sieve, preparing wet granules according to the process in the example 1, drying the wet granules at 40 ℃ for 1.5h, grading with a 24-mesh sieve, uniformly mixing with 5.0% by weight of silicon dioxide, tabletting, and stamping with a die of 1.9cm × 0.91cm (oval), wherein the weight of the tablet is 980mg, and the pressure is 130-150N.

The dried granules prepared in the above process were taken, and the sieving rate through a 24-mesh sieve was determined by the sieving rate method in example 1, and the result was 99.43%. Taking 6 tablets of the divalproex sodium sustained-release tablets prepared above, determining the content of the divalproex sodium in each tablet by adopting the method in example 1, the results are as follows:

example 8

Prescription:

the process comprises the following steps: crushing divalproex sodium, sieving with a 80-mesh sieve, preparing wet granules according to the process in example 1, drying the wet granules at 55 ℃ for 1h, grading with a 24-mesh sieve, uniformly mixing with magnesium stearate with the weight ratio of 3.0%, tabletting, and stamping with a die of 1.9cm × 0.91cm (oval), wherein the tablet weight is 650mg, and the pressure is 130-150N.

The dried granules prepared in the above process were taken, and the sieving rate through a 24-mesh sieve was measured by the sieving rate method in example 1, and the result was 100%. Taking 6 tablets of the divalproex sodium sustained-release tablets prepared above, determining the content of the divalproex sodium in each tablet by adopting the method in the example 6, the results are as follows:

example 9

Self-made samples: the divalproex sodium sustained-release tablet prepared in example 2 (specification of 500mg, lot number 150512) was taken.

The drug is listed on the market: divalproex sodium sustained-release tablets (Yapek, USA, 500mg, lot number 1019635).

And (3) measuring the release degree: taking a self-made sample and a marketed drug, using a paddle method, under the conditions of 37 ℃ and 100rpm, respectively using 500mL of 0.1mol/L hydrochloric acid solution and 900mL of pH 5.5 phosphate buffer solution as dissolution media of an acid stage and a phosphate stage. In the acid stage, after 45min from the sample introduction, the sample solution was used as the acid stage sample solution, and then the dissolution medium was changed to pH 5.5 phosphate buffer solution, 6mL of the sample solution was used as the sample at 1, 2, 3, 4, 5, 6, 8, 9, 10, 12, and 24h, and the same volume of phosphate buffer solution was supplemented. And (3) measuring and calculating the release degree of the self-made sample and the marketed drug by using a high performance liquid chromatograph. The results are shown in Table 4.

TABLE 4 Release data for 500mg home-made samples and marketed drugs (n ═ 6)

The experimental results are as follows: the measurement results of the release rates of the self-made preparation with the specification of 500mg and the marketed medicine show that the f2 similarity factor of the release rates of the self-made preparation and the marketed medicine is 74.78, which indicates that the in vitro release behaviors of the self-made preparation and the marketed medicine have better similarity. The granulation process of the invention can ensure that the medicine and the auxiliary materials are mixed evenly and can achieve the similar release characteristics with the medicine on the market.

Example 10

Self-made samples: the divalproex sodium sustained-release tablets prepared in example 6 (specification of 250mg, lot number 150128) were taken.

And (3) measuring the release degree: a self-made sample is taken, and 500mL of 0.1mol/L hydrochloric acid solution and 900mL of pH 5.5 phosphate buffer solution are respectively used as dissolution media of an acid stage and a phosphate stage by using a paddle method under the conditions of 37 ℃ and 100 rpm. In the acid stage, after 45min from the sample introduction, the sample solution was used as the acid stage sample solution, and then the dissolution medium was changed to pH 5.5 phosphate buffer solution, 6mL of the sample solution was used as the sample at 1, 2, 3, 4, 5, 6, 8, 9, 10, 12, and 24h, and the same volume of phosphate buffer solution was supplemented. And (3) measuring and calculating the release degree of the self-made sample and the marketed drug by using a high performance liquid chromatograph. The results are shown in Table 5.

TABLE 5 Release data for a 250mg home-made sample and a 500mg drug on the market (n ═ 6)

The experimental results are as follows: the release rate measurement results of the self-made preparation with the specification of 250mg and the marketed medicine with the specification of 500mg show that the f2 similarity factor of the release rates of the self-made preparation and the marketed medicine is 82.68, which shows that the in vitro release behaviors of the self-made preparation and the marketed medicine are better similar. The granulation by adopting the process of the invention can ensure that the medicine and the auxiliary materials are uniformly mixed and can achieve the similar release characteristics with the marketed medicine (the specification is 500 mg).

EXAMPLE 11 measurement of related substances

Self-made samples: the divalproex sodium sustained-release tablet prepared in example 2 (specification of 500mg, lot number 150512) was taken.

Detection conditions are as follows: the chromatographic column was a Phenyl column (Ultimate XB-Phenyl, 3.9 mm. times.150 mm, 4 μm, Yuehahi technology), the mobile phase was acetonitrile/sodium dihydrogen phosphate buffer (1: 1), the detection wavelength was 215nm, the column temperature was 30 ℃ and the flow rate was 0.7 mL/min.

Sample concentration: about 2mg/mL of valproic acid; sample introduction amount: 20 μ L.

The determination result shows that the content of the impurity A in the divalproex sodium sustained-release tablet is 0.1 percent, and the total content of the impurities is 0.48 percent. The method meets the regulation of quality standards, the related substances of the divalproex sodium sustained-release tablets prepared by adopting the granulation process of the invention are not obviously increased, and the total amount of the related substances is lower, which indicates that the granulation process of the invention is stable and can be used for industrial production.

Claims (11)

1. The divalproex sodium sustained-release tablet is characterized by comprising divalproex sodium, a hydrophilic gel matrix sustained-release material, a diluent and a wetting agent, and the preparation method of the sustained-release tablet comprises the following steps:

(1) uniformly mixing the hydrophilic gel framework material and the diluent, and adding a wetting agent to prepare a soft material;

(2) adding divalproex sodium into the soft material prepared in the step (1), uniformly stirring and mixing to prepare a medicine-containing soft material, sieving the prepared medicine-containing soft material with a 20-24-mesh sieve for granulation, drying, and grading with a 20-24-mesh sieve;

(3) adding 1-5 wt% of glidant into the granules obtained in the step (2), uniformly mixing, and tabletting to obtain the granules; the weight percentage content of the divalproex sodium is 41.4-55%, the weight percentage content of the hydrophilic gel framework material is 20-36%, the weight percentage content of the diluent is 10-35%, the hydrophilic gel framework is hydroxypropyl methyl cellulose, and the diluent is lactose and microcrystalline cellulose.

2. The divalproex sodium sustained-release tablet of claim 1, wherein the diluent comprises lactose and microcrystalline cellulose at a weight ratio of 0.3-2.

3. The divalproex sodium sustained-release tablet of claim 1, wherein said wetting agent is one or both of ethanol and water.

4. The divalproex sodium sustained-release tablet of claim 3, characterized in that said wetting agent is ethanol.

5. The divalproex sodium sustained-release tablet of claim 1, characterized in that the glidant is silicon dioxide or magnesium stearate.

6. The divalproex sodium sustained-release tablet of claim 5, characterized in that the glidant is silicon dioxide.

7. The divalproex sodium sustained-release tablet of claim 6, wherein the mixing and stirring are carried out by a wet mixing granulator.

8. The divalproex sodium sustained-release tablet of claim 1, wherein the mixing speed is 300-400 rpm, and the shearing speed is 3000-4000 rpm.

9. The divalproex sodium sustained-release tablet of claim 1, wherein the divalproex sodium is first pulverized and then passed through a 80-100 mesh sieve.

10. The divalproex sodium sustained-release tablet according to any one of claims 1 to 9, characterized by comprising the following components in percentage by weight:

the preparation method of the sustained-release tablet comprises the following steps:

a) crushing divalproex sodium and sieving with a 100-mesh sieve;

b) mixing hydroxypropyl methyl cellulose, microcrystalline cellulose and lactose to obtain a uniformly dispersed mixed material;

c) under the condition of stirring, adding a proper amount of ethanol into the uniformly mixed material prepared in the step b), wherein the adding amount of the ethanol is 150-300 mL per 1kg of the material, so as to prepare a wet soft material;

d) adding 50-55 wt% of divalproex sodium prepared in the step a) into the soft wet material prepared in the step c) under stirring conditions, and continuously mixing the materials by using a wet mixing granulator to prepare the soft material, wherein the stirring speed is 300-400 rpm, and the shearing speed is 3000-4000 rpm;

e) sieving the soft material prepared in the step d) with a 24-mesh sieve to obtain wet granules;

f) drying the granules obtained in the step e), granulating, mixing with silicon dioxide, and tabletting.

11. The divalproex sodium sustained-release tablet according to claim 10, characterized by comprising the following components in percentage by weight:

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