CN101693113A - Divalproex sodium medicine composition with improved oral absorptivity - Google Patents
Divalproex sodium medicine composition with improved oral absorptivity Download PDFInfo
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- CN101693113A CN101693113A CN200910070894A CN200910070894A CN101693113A CN 101693113 A CN101693113 A CN 101693113A CN 200910070894 A CN200910070894 A CN 200910070894A CN 200910070894 A CN200910070894 A CN 200910070894A CN 101693113 A CN101693113 A CN 101693113A
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- divalproex sodium
- betacyclodextrin
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Abstract
The invention relates to a medicine composition containing divalproex sodium, which can be applied to patients safely, not only can improve the wettability and the flowability of the divalproex sodium, but also can improve the absorptivity of the divalproex sodium in gastrointestinal tracts. Particularly, the invention relates to a medicine composition containing amorphous divalproex sodium and betacyclodextrin. The preparation method of the medicine composition comprises the following steps: grinding, drying and pulverizing the divalproex sodium and the betacyclodextrin to obtain fine powder of 80-100 meshes; mixing with proper assistant materials and making into granules, and then tabletting and coating to obtain the medicine composition. The divalproex sodium medicine composition not only can improve release in vitro to a greater degree, thereby improving bioavailability, but can effectively treat epilepsia and vesania and prevent cephalagra; in addition, the divalproex sodium medicine composition can be taken orally and conveniently, can cover odor, and can be disintegrated and absorbed quickly and carried conveniently.
Description
Technical field
The present invention relates to divalproex sodium medicine composition and preparation method thereof a kind of.Divalproex sodium is scattered in the betacyclodextrin, can improves the release in vitro degree largely, thereby improve bioavailability.
Background technology
Epilepsy is one of ancient disease of the mankind, the epilepsy definition of The World Health Organization (WHO): epilepsy is the chronic disease of a kind of outbreak repeatedly, course of disease delay, paroxysmal cerebral dysfunction.It is characterized by discharge of brain neuron paroxysmal abnormality altofrequency and diffusion towards periphery.Because position, paradoxical discharge neuron place difference, clinical manifestation is different motion, sensation, consciousness and autonomic nervous dysfunction's a symptom.The outbreak type also is divided into partial seizures, comprehensive outbreak, comprehensive tonic clonic seizure, and small part patient's outbreak classification is not sure.According to the WHO statistics, the whole world has about 5,000 ten thousand people of epileptic at present, and wherein 80% people is in developing country.In addition, the new epileptic of 200 myriabits also appears every year.The epilepsy prevalence of developed country, developing country and undeveloped country is respectively 5.0 ‰, 7.2 ‰, 11.2 ‰.The data show that one Xinda medical market research center, east provides, China's epilepsy prevalence are 7 ‰ approaching with the sickness rate of the developing country 7.2 ‰ of WHO report.And one of beginning of the eighties in last century investigation shows, nineteen eighty-three China's epilepsy prevalence only be 4.4 ‰, lower than developed country.Short 20 years, China epileptic number has risen to 9,000,000 more than, and 400,000 New Development patient is nearly arranged every year.In the morbidity crowd, M-F is (1.15～1.7): 1.The sickness rate difference of all ages and classes epilepsy, sickness rate was the highest in 1 years old～10 years old, and sickness rate was low slightly in 10 years old～19 years old, and is all lower later on, but 60 years old increases again later on to some extent.At present, epilepsy is the second largest disease that Neurology Department is only second to cerebrovascular, and due to illness journey is long, and the disability rate height is still one of difficult radical cure disease.
Affective disorder is divided into single-phase (simple depressed) and two-phase (depressed-manic) two classes.Bipolar affective disorder (Bipolar disorder, BPD) also claim the bipolarity affective disorder, claim manic depression again, generally show as existing manic or hypomania, paralepsy is arranged again, and manic and depressed Chang Fanfu circulation or alternately appearance, but also can hybrid mode exist, the outbreak intermission can be alleviated fully.
About in the world 1%～2% people suffers from bipolar affective disorder.In the depressed patient, about 1/5 people has tangible hypomania or manic performance, and many patients have showed in 5 years after being ill by the single-phase two-phase obstacle that becomes in depression.This disease is big to the harm of patient's body and mind, makes the patient lose work, social competence, the risk that disables height, even have 25%～50% patient at a time can attempt committing suiside, patient's committed suicide of 15%～19% brings very big burden for society and family.
Because the particularity of disease, bipolar affective disorder is very big with simple depressed Therapeutic Principle's difference, can not use antidepressants to treat separately usually, because of it may bring out manic or formation Rapid Cycle type disease, thereby increases the treatment difficulty.Up to the present, mood stabilizers (MS) is being played the part of irreplaceable role in the treatment of bipolar affective disorder.
Mood stabilizers has another name called mental state and adjusts agent.As its name suggests, this is a class has the medicine of therapeutic effect to emotional instability, impulsion, intense, evil mood etc.Main application has two classes: be used for the treatment and the prevention of affective disorders 1..Be most widely used, this class medicine all has certain therapeutic effect for maniac access or paralepsy.Especially for the patient who shows effect repeatedly, be the main medication of prevention outbreak at present.2. be used to adjust bad mental state.Such as abnormality of personality person's irritability, inflammable emotion; The teenager emotional lability, even lead to violence person in the family; The unstable emotion of alcohol dependence and junkie; Residual after the psychosis; In moving control obstacle and dysthymic disorder; Mental retardation person's anxious state of mind and control ability of weakening or the like.This class crowd's universal face is wider, and is proper if mood stabilizers is used, and can not only strengthen psychological diathesis, is convenient to family and social management, and the generation that can diminish crime, and ensures social stability.The application of mood stabilizers in this class crowd is still general inadequately at present, do not come into one's own, and be to should be noted that exploitation from now on.The medication of one line comprises lithium salts, valproate and carbamazepine; The two wires medication comprises lamotrigine, topiramate and atypical antipsychotic etc.
Simultaneously, main mood stabilizers itself also is an antiepileptic, so both markets can not distinguish fully.Since (phenobarbitone) became first epilepsy therapy medicine, nowadays nearly 17 kinds of medicines can be used for treating epilepsy from phenobarbital in 1912, and wherein the part medicine belongs to label and uses outward.About 80% epileptic uses a line medicine phenobarbital, phenytoin Sodium, lithium carbonate, carbamazepine and sodium valproate list to use or the coupling treatment.
Divalproex sodium has better safety than lithium salts, need not monitor blood drug level, and side effect and patient tolerability are better, has become the main medication in the mood stabilizers over nearly 10 years, and external doctor's acceptance level is all higher.2003, the sodium valproate slow releasing tablet " Sodium Valproate " of Sai Nuofei-An Wante entered the Chinese market market of promptly taking the lead in race then; In present domestic sodium valproate medication market, the share of consumption sum 90% is occupied by " Sodium Valproate ".But what external clinical main at present recommendation was used is divalproex sodium, compares with sodium valproate, and divalproex sodium is because gastrointestinal side effect is lighter, drug interaction is less, replaces the market position of traditional sodium valproate gradually.Following divalproex sodium belongs to " cookle " level medicine certainly, but domestic still do not have declare.Because FDA approved divalproex sodium is used for epilepsy, manic and migraine.So this product is used safely clinical, do not exist the label of other drug to use outward.
Simultaneously, the divalproex sodium migraine is a kind of common disease, and about 75% outbreak can prevent, and avoids risk factor to prevent migraine in daily life as far as possible.The selection of its medicine depends on frequency, intensity, simultaneous phenomenon, the adverse effect of outbreak.The continuous appearance of newtype drug for migrainous treatment provides new platform, has also been satisfied more and more patients and doctor's demand.
The conventional preparation method of prior art prepares the divalproex sodium preparation, because of the physicochemical property of divalproex sodium material, easily causes in the preparation tablet mobility of particle bad, sticking, and tablet appearance is defective, and release is lower.Can not large-scale industrialized production.
In order to improve production quality, overcome the problem of can not industrialization producing, we have carried out the design and the research of a large amount of technical schemes, choose optimum prescription and technology, have solved above-mentioned technological deficiency.
The divalproex sodium Pharmaceutical composition of the present invention's preparation, employing is scattered in divalproex sodium in the betacyclodextrin, obviously overcomes in the production technology to adopt conventional preparation method the low and shortcoming that is difficult for making of release, this method has improved its release in vitro degree greatly, and then improves its bioavailability.
Therefore, the inventor has solved this conventional formulation relevant issues, and successfully develops a kind of divalproex sodium medicine composition with oral absorption of improvement.Have higher stability and high bioavailability.
Summary of the invention
The purpose of this invention is to provide a kind of divalproex sodium medicine composition with oral absorption of improvement, it is in the performance characteristic that has high expectations aspect raising bioavailability and the high stability.
Another object of the present invention provides a kind of method of utilizing described preparation of compositions divalproex sodium medicine composition.
According to an aspect of the present invention, divalproex sodium medicine composition is provided, and its divalproex sodium is scattered in the betacyclodextrin, and is formulated by following weight ratio: divalproex sodium 15%-80%, betacyclodextrin 20%-60%, cross-linking sodium carboxymethyl cellulose 3%-20%, microcrystalline Cellulose 10-70%, lactose 10%-30%, pregelatinized Starch 2%-20%, Pulvis Talci 1%-50%, magnesium stearate 0.1-5%, coating powder 1%-30%.
According to another aspect of the present invention, provide a kind of method for preparing the sodium valproate pharmaceutical composition, comprise step:
1) divalproex sodium, betacyclodextrin are put in the mortar, added low amounts of water and grind to form pastel, dry below 50 ℃, be ground into 80-100 order fine powder, standby;
2) with microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, and is standby;
3) with the adjuvant 2 of recipe quantity) add 1) in, mix homogeneously, standby;
4) get 3) the middle 5% starch slurry solution that adopts, mixing is made 30-40 order granule, dry below 50 ℃, granulate, tabletting;
5) with 4) sample that makes puts in the coating pan, coating, promptly.
Following data declaration beneficial effect of the present invention by experiment.
Carried out constant temperature accelerated stability test and the room temperature stability test that keeps sample with the product of prior art embodiment 1 of the present invention and embodiment 2-4, the result is as follows:
Constant temperature accelerated stability test result
The room temperature stability test result that keeps sample
Above result of the test explanation, embodiment 2-4 is in acceleration and long-term put procedure, and the sample related substance is not significantly increased, and release is qualified, and quality is comparatively stable; The embodiment 1 that adopts prior art for preparing is in acceleration and long-term put procedure, though the sample related substance is not significantly increased, release reduces comparatively obvious, and product is defective.
Advantage of the present invention is technical maturity, and is simple to operate, is fit to industrial large-scale production.
Advantage of the present invention also is to adopt divalproex sodium is scattered in the betacyclodextrin, obviously overcome and adopt conventional preparation method in the production technology, low and the mobile difference of release such as is difficult for making at shortcoming, and this method has improved its release in vitro degree greatly, and then improves its bioavailability.
Cyclodextrin is a starch derivatives, mainly as oral and injection medicine preparation, and the most frequently used is α-, β-, gamma-cyclodextrin has 6,7,8 glucose units respectively.Cyclodextrin is the ring molecule of the cavity by rigid structure and center thereof " tubbiness " or " coniform " that constitute, its size is according to the difference of the type of cyclodextrin and difference, the cavity inner surface is a hydrophobicity, and the outside of ring is a hydrophilic, this is by due to the arrangement in the polyhydroxylated molecule, this arrangement makes cyclodextrin hold enclosed molecule in the cavity again, forms clathrate.Cyclodextrin can be used to prepare the clathrate of multiple drug molecule, mainly plays and improves the effect that improves release and bioavailability, and this is attributable to the increase of dissolubility, and the raising of chemistry and physical stability.The clathrate of cyclodextrin also is used for covering the disagreeable taste of active substance and liquid substance is converted into solid material.
It is oral nontoxic that beta-schardinger dextrin-is considered to, so safety when using in solid preparation.
Below prescription design and optimization Test are used to illustrate the present invention:
The physicochemical property of divalproex sodium: this product is a white crystalline powder, and special odor is arranged.Follow the general preparation principle of tablet, we have designed pre-prescription:
Method for making: supplementary material is crossed 100 eye mesh screens respectively, then will be except that the adjuvant mix homogeneously magnesium stearate, the Pulvis Talci, make soft material in right amount with 5% polyvidone, 50% alcoholic solution, with 20 eye mesh screen system granules, dry back reuse 20 eye mesh screen granulate for 55 ± 5 ℃, add lubricant Pulvis Talci mixing, tabletting is promptly investigated under the result.
Conclusion: this good fluidity of writing out a prescription, but compressibility is relatively poor, sticking is more serious, and the granule after granulating is harder, disintegration behind the tabletting is against regulation greater than 30 minutes, so we solve the sticking phenomenon with employing accessory package and technology by high spot reviews wetting agent usage and dosage, and investigate the situation of disintegration on this basis.
Granule after finding in 5% polyvidone, the 50% alcoholic solution pelletization to granulate is harder, disintegration behind the tabletting was greater than 30 minutes, so we select for use the ethanol solution of 5% polyvidone to granulate respectively and the aqueous solution of 5% polyvidone is granulated, investigate pellet hardness, flowability and disintegration, prescription is formed as follows.
Method for making: supplementary material is crossed 100 eye mesh screens respectively, then will be except that Pulvis Talci, the adjuvant mix homogeneously that magnesium stearate is outer, make soft material in right amount with 5% polyvidone ethanol solution and 5% polyvidone aqueous solution respectively, with 20 eye mesh screen system granules, dry back reuse 20 eye mesh screen granulate, add magnesium stearate lubricant, Pulvis Talci mixing for 55 ± 5 ℃, tabletting is promptly investigated and be the results are shown in down.
From result of the test, it is relatively good to granulate with the ethanol solution of 5% polyvidone, granulates under this wetting agent moistening situation, mobility of particle is good, hardness is moderate, and time disintegration is short, so we select to use the ethanol solution of 5% polyvidone to granulate.
Cyclodextrin is a starch derivatives, mainly as oral and injection medicine preparation, and the most frequently used is α-, β-, gamma-cyclodextrin has 6,7,8 glucose units respectively.Cyclodextrin is the ring molecule of the cavity by rigid structure and center thereof " tubbiness " or " coniform " that constitute, its size is according to the difference of the type of cyclodextrin and difference, the cavity inner surface is a hydrophobicity, and the outside of ring is a hydrophilic, this is by due to the arrangement in the polyhydroxylated molecule, this arrangement makes cyclodextrin hold enclosed molecule in the cavity again, forms clathrate.Cyclodextrin can be used to prepare the clathrate of multiple drug molecule, mainly plays and improves the effect that improves release and bioavailability, and this is attributable to the increase of dissolubility, and the raising of chemistry and physical stability.The clathrate of cyclodextrin also is used for covering the disagreeable taste of active substance and liquid substance is converted into solid material.
Technology:
1) divalproex sodium, betacyclodextrin are put in the mortar, added low amounts of water and grind to form pastel, dry below 50 ℃, be ground into 80-100 order fine powder, standby;
2) with microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, and is standby;
3) with the adjuvant 2 of recipe quantity) add 1) in, mix homogeneously, standby;
4) get 3) in adopt binding agent an amount of, mixing is made 30-40 order granule, dry below 50 ℃, granulate adds magnesium stearate lubricant and Pulvis Talci, tabletting behind the mix homogeneously;
Result of the test shows, adopts the prescription of clathrate process preparation, has all overcome the sticking problem, obtains good surface appearance and hardness, and release is also all qualified, and we further screen art for coating on prescription 3 bases.
Divalproex sodium has zest to stomach, so we select enteric coatedly to increase patient's adaptability to reduce patient's GI irritation, we select credulity gram coating powder to carry out coating.
1, coating fluid prescription:
Enteric coating powder 10g
80% ethanol adds to 100ml
2, operating procedure: according to the product operation rules of enteric coating powder producer, 30 ℃ of coating inlet temperature, coating solution sprays fast 2g/min, and the product behind the coating descended dry 1 hour at 30 ℃, promptly.
3, the coating weightening finish determines
Determining of weightening finish is the major control index with the acid-resistant strength mainly, should not have disintegrate or crack in 1 hour in the 0.08mol/L hydrochloric acid solution.According to the requirement of the product operation rules of enteric coating powder producer, we increase weight 10%, 11%, 12% and 13% respectively, detect the release in its acid-resistant strength and the buffer successively.
The burst size of coating prescription 2-4 in buffer
Result of the test shows, the sample of coating prescription 1 had 1 disintegrate in 6 in 1 hour in acid, and cracking appears in 3 clothing films; The sample of coating prescription 2 had 2 clothing films cracking to occur in 6 in 1 hour in acid, and the sample of coating prescription 3 and coating prescription 4 did not have the crack in 1 hour in acid, and acid-resistant strength is up to specification; Sheet release profiles in phosphate buffer (pH7.5) of coating prescription 3 and coating prescription 4 is level and smooth, release is all up to specification, but the rate of release of coating prescription 3 is better than coating prescription 4, so we select coating prescription 3 to be best coating prescription, i.e. coating weightening finish is 12%.
Final definite best prescription and technology
(1) prescription
Form 1
Divalproex sodium 250g
Betacyclodextrin 125g
Form 2
Cross-linking sodium carboxymethyl cellulose 20g
Microcrystalline Cellulose 100g
Lactose 120g
Pregelatinized Starch 40g
Pulvis Talci 10g
Magnesium stearate 10g
5% polyvidone ethanol solution is an amount of
Coating is formed
Coating powder (enteric solubility) 81g
80% alcoholic solution 810ml
(2) preparation method
1) divalproex sodium, betacyclodextrin are put in the mortar, added low amounts of water and grind to form pastel, dry below 50 ℃, be ground into 80-100 order fine powder, standby;
2) with microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, and is standby;
3) with the adjuvant 2 of recipe quantity) add 1) in, mix homogeneously, standby;
4) get 3) the middle 5% polyvidone ethanol solution that adopts, mixing is made 30-40 order granule, and dry below 50 ℃, granulate adds lubricant, mix homogeneously, tabletting;
5) with 4) sample that makes puts in the coating pan, coating, promptly.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1 (prior art)
(1) prescription
Label is formed
Divalproex sodium 250g
Cross-linking sodium carboxymethyl cellulose 30g
Microcrystalline Cellulose 150g
Lactose 90g
Pregelatinized Starch 120g
Pulvis Talci 10g
Magnesium stearate 10g
5% polyvidone dehydrated alcohol is an amount of
Coating is formed
Coating powder (enteric solubility) 72.8g
80% alcoholic solution 728ml
Make 1000
(2) preparation method
1) divalproex sodium is pulverized, sieved, standby; With microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, magnesium stearate, Pulvis Talci sieves respectively, and is standby;
2) take by weighing supplementary material by recipe quantity respectively, standby;
3) get the mix homogeneously supplementary material and adopt 50% alcoholic solution to granulate respectively, 50 ℃ of dryings, 20 eye mesh screen granulate with 20 eye mesh screens;
4) adjust the loading amount tabletting according to content;
5) with 4) sample that makes puts in the coating pan, coating, promptly.
Embodiment 2
(1) prescription
Form 1
Divalproex sodium 250g
Betacyclodextrin 125g
Form 2
Cross-linking sodium carboxymethyl cellulose 20g
Microcrystalline Cellulose 100g
Lactose 120g
Pregelatinized Starch 40g
Pulvis Talci 10g
Magnesium stearate 10g
5% polyvidone ethanol solution is an amount of
Coating is formed
Coating powder (enteric solubility) 81g
80% alcoholic solution 810ml
(2) preparation method
6) divalproex sodium, betacyclodextrin are put in the mortar, added low amounts of water and grind to form pastel, dry below 50 ℃, be ground into 80-100 order fine powder, standby;
7) with microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, and is standby;
8) with the adjuvant 2 of recipe quantity) add 1) in, mix homogeneously, standby;
9) get 3) the middle 5% polyvidone ethanol solution that adopts, mixing is made 30-40 order granule, and dry below 50 ℃, granulate adds lubricant, mix homogeneously, tabletting;
10) with 4) sample that makes puts in the coating pan, coating, promptly.
Embodiment 3
(1) prescription
Form 1
Divalproex sodium 250g
Betacyclodextrin 250g
Form 2
Cross-linking sodium carboxymethyl cellulose 30g
Microcrystalline Cellulose 60g
Lactose 80g
Pregelatinized Starch 30g
Pulvis Talci 10g
Magnesium stearate 10g
5% polyvidone ethanol solution is an amount of
Coating is formed
Coating powder (enteric solubility) 79.2g
80% alcoholic solution 792ml
(2) preparation method
1) divalproex sodium, betacyclodextrin are put in the mortar, added low amounts of water and grind to form pastel, dry below 50 ℃, be ground into 80-100 order fine powder, standby;
2) with microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, and is standby;
3) with the adjuvant 2 of recipe quantity) add 1) in, mix homogeneously, standby;
4) get 3) the middle 5% polyvidone ethanol solution that adopts, mixing is made 30-40 order granule, and dry below 50 ℃, granulate adds lubricant, mix homogeneously, tabletting;
5) with 4) sample that makes puts in the coating pan, coating, promptly.
Embodiment 4
(1) prescription
Form 1
Divalproex sodium 250g
Betacyclodextrin 375g
Form 2
Cross-linking sodium carboxymethyl cellulose 20g
Microcrystalline Cellulose 50g
Lactose 60g
Pregelatinized Starch 40g
Pulvis Talci 10g
Magnesium stearate 10g
5% starch slurry solution is an amount of
Coating is formed
Coating powder (enteric solubility) 89.6g
80% alcoholic solution 896ml
(2) preparation method
1) divalproex sodium, betacyclodextrin are put in the mortar, added low amounts of water and grind to form pastel, dry below 50 ℃, be ground into 80-100 order fine powder, standby;
2) with microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, and is standby;
3) with the adjuvant 2 of recipe quantity) add 1) in, mix homogeneously, standby;
4) get 3) the middle 5% starch slurry solution that adopts, mixing is made 30-40 order granule, and dry below 50 ℃, granulate adds lubricant, mix homogeneously, tabletting;
5) with 4) sample that makes puts in the coating pan, coating, promptly.
Claims (3)
1. the Pharmaceutical composition that contains divalproex sodium and betacyclodextrin, it is characterized in that: divalproex sodium is scattered in the betacyclodextrin, formulated by following weight ratio: divalproex sodium 15%-80%, betacyclodextrin 20%-60%, cross-linking sodium carboxymethyl cellulose 1%-20%, microcrystalline Cellulose 5-70%, lactose 1%-30%, pregelatinized Starch 1%-20%, Pulvis Talci 0.1%-50%, magnesium stearate 0.1-5%, coating powder 1%-30%.
2. according to the described Pharmaceutical composition that contains divalproex sodium and betacyclodextrin of claim 1, the relative weight ratio that it is characterized in that being used for component divalproex sodium and betacyclodextrin is 1: 0.5～1.5.
3. the preparation method that contains the Pharmaceutical composition of divalproex sodium and betacyclodextrin according to claim 1 is characterized in that comprising following preparation steps:
1) divalproex sodium, betacyclodextrin are put in the mortar, added low amounts of water and grind to form pastel, dry below 50 ℃, be ground into 80-100 order fine powder, standby;
2) with microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, Pulvis Talci, magnesium stearate is sieved respectively, and is standby;
3) with the adjuvant 2 of recipe quantity) add 1) in, mix homogeneously, standby;
4) get 3) the middle 5% polyvidone ethanol solution that adopts, mixing is made 30-40 order granule, and dry below 50 ℃, granulate adds lubricant, mix homogeneously, tabletting;
5) with 4) sample that makes puts in the coating pan, coating, promptly.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038685A (en) * | 2010-11-29 | 2011-05-04 | 天津市汉康医药生物技术有限公司 | Blonanserin medicine composition with capacity of improving oral absorbability |
| CN102188392A (en) * | 2011-04-17 | 2011-09-21 | 浙江华海药业股份有限公司 | Stabilized divalproex sodium coated granules, preparation method and solid preparation thereof |
| CN102895201A (en) * | 2011-07-26 | 2013-01-30 | 北大方正集团有限公司 | Valproate semisodium tablet and its preparation method |
| CN103623019A (en) * | 2013-12-12 | 2014-03-12 | 成都乾坤动物药业有限公司 | Wettable herba andrographitis solid dispersion powder and preparation method thereof |
| CN108578678A (en) * | 2018-03-13 | 2018-09-28 | 孟斯琴 | A kind of antiepileptic compositions and preparation method thereof |
-
2009
- 2009-10-21 CN CN2009100708940A patent/CN101693113B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038685A (en) * | 2010-11-29 | 2011-05-04 | 天津市汉康医药生物技术有限公司 | Blonanserin medicine composition with capacity of improving oral absorbability |
| CN102188392A (en) * | 2011-04-17 | 2011-09-21 | 浙江华海药业股份有限公司 | Stabilized divalproex sodium coated granules, preparation method and solid preparation thereof |
| CN102188392B (en) * | 2011-04-17 | 2017-05-10 | 浙江华海药业股份有限公司 | Stabilized divalproex sodium coated granules, preparation method and solid preparation thereof |
| CN102895201A (en) * | 2011-07-26 | 2013-01-30 | 北大方正集团有限公司 | Valproate semisodium tablet and its preparation method |
| CN102895201B (en) * | 2011-07-26 | 2014-09-10 | 北大方正集团有限公司 | Valproate semisodium tablet and its preparation method |
| CN103623019A (en) * | 2013-12-12 | 2014-03-12 | 成都乾坤动物药业有限公司 | Wettable herba andrographitis solid dispersion powder and preparation method thereof |
| CN103623019B (en) * | 2013-12-12 | 2015-11-11 | 成都乾坤动物药业有限公司 | A kind of wettability Herba Andrographis solid dispersal powder and preparation method thereof |
| CN108578678A (en) * | 2018-03-13 | 2018-09-28 | 孟斯琴 | A kind of antiepileptic compositions and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN101693113B (en) | 2011-09-28 |
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