CN106389368B - Sodium valproate sustained-release preparation and preparation process and application thereof - Google Patents
Sodium valproate sustained-release preparation and preparation process and application thereof Download PDFInfo
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Abstract
A sodium valproate sustained release preparation, a preparation process and application thereof, wherein the sodium valproate sustained release preparation can release drug stably within 24 hours. The sodium valproate sustained-release preparation creatively and independently uses the sustained-release framework material, particularly uses high-viscosity hypromellose as a retarder of the sodium valproate sustained-release preparation, overcomes the technical bias that hypromellose K100M is not preferred or independently used in the prescription of the sodium valproate sustained-release preparation due to extremely high viscosity, overcomes the technical defect of preparation by adopting a new process, and finally manufactures the sodium valproate sustained-release tablet capable of stably releasing drugs within 24 hours.
Description
Technical Field
The invention relates to a sodium valproate sustained-release preparation, a preparation process and application thereof, and particularly provides a sodium valproate sustained-release tablet. Belongs to the field of pharmaceutical preparation.
Background
Sodium valproate belongs to a first-line antiepileptic drug, has wide antiepileptic spectrum, and can be used for treating epileptic seizures, myoclonic seizures, systemic seizures, partial motor seizures, absence seizures, infantile spasm and the like. The field of treatment with sodium valproate is now further expanded, and FDA-approved indications include bipolar affective disorders and migraine headaches, in addition to anti-epileptic activity.
In clinical application, the effective blood concentration of valproic acid drugs is usually in the range of 40-100 μ g/ml, but because of its short biological half-life, the drug therapy usually needs to be administered several times a day (for example, three times a day) to maintain sufficient blood concentration. However, too frequent administration of the drug may reduce the compliance of the patient to take the drug, thereby affecting the therapeutic effect. Therefore, the method has very important practical significance for the development of oral sustained-release preparations of the sodium valproate.
However, different salts of valproic acid have very large differences in hygroscopicity and stability, for example, magnesium valproate and divalproex sodium have very small hygroscopicity, and it is reported that one sample of magnesium valproate contains 3.14% of water and the water content is only 3.72% after standing for 4 years; sodium valproate has extremely strong hygroscopicity, and the sodium valproate is completely dissolved after being placed in an environment with the relative humidity of 53% overnight, so that the water absorption of the sample reaches 43%. It is due to the strong hygroscopicity and instability of sodium valproate that it is a solid formulation that is very difficult to develop. Therefore, in the development of a preparation using sodium valproate as a raw material, there are many cases where sodium valproate is preferentially used for preparing a liquid preparation, including an injection or an oral liquid, such as depion injection developed by yapei pharmaceutical in the united states and debarkin oral liquid developed by sunofil pharmaceutical in france, but the preparation of a solid preparation, particularly a long-acting sustained-release preparation, still faces many insurmountable difficulties in terms of prescription and process.
According to the search, only two patent documents report oral sustained release preparations taking sodium valproate as a raw material drug: among them, patent US5019398 discloses a sodium valproate sustained release tablet, but the sustained release time of the sustained release tablet is only 8 hours, and the sustained release time of the drug is still not long enough; in addition, patent CN97198537 discloses a sodium valproate sustained release microsphere, which adopts a very complicated preparation process, wherein the auxiliary material needs to be melted at high temperature during the production process, and then spray granulation is performed under specific conditions, the process not only has high requirements on the production conditions, but also causes the sodium valproate to be unstable in the liquid auxiliary material melted at high temperature and generate excessive impurities.
From the situation of the prior art, the sustained release preparation prepared by taking sodium valproate as a raw material has the following defects:
1. the production process is not perfect. Due to the strong hygroscopicity of sodium valproate and the high viscosity of the sustained-release framework material, the main drug and the auxiliary materials are not uniformly mixed, a large amount of hard blocks are agglomerated during mixing, a lot of hard blocks cannot be granulated, the content of the main drug in the remaining prepared granules is not uniform, and the yield and the quality of a final product are seriously influenced;
2. the production process is rigorous, and the production condition is strict. Due to the strong hygroscopicity of sodium valproate, the requirements on production conditions for preparing solid preparations are very strict, the environmental temperature and humidity need to be strictly controlled, for example, the humidity needs to be controlled at least about 20%, and in the case of the harsh production conditions, the energy consumption in a production link and the process difficulty are obviously increased, while the high energy consumption causes the cost to be increased, and the method is very unfavorable for industrial mass production;
3. the preparation has complicated prescription, various adjuvants and large dosage. In order to achieve a better drug release effect, the prior art needs to use a combination of multiple release-retarding materials to adjust the drug release performance of the drug, which leads to a complex prescription or a large dosage of the preparation, thereby increasing the chances of introducing impurities, increasing the preparation cost and the difficulty of controlling the quality;
4. the medicine release time is not long enough, and the medicine still needs to be taken for many times a day, and the medicine release is only 8 hours in the prior art which is reported by published documents;
5. the drug release process is not ideal, and the drug release uniformity is poor. The sustained-release tablets prepared by the prior art have unsatisfactory drug release uniformity and large blood concentration fluctuation, and are not beneficial to clinical treatment.
Disclosure of Invention
The invention aims to provide a sodium valproate sustained-release preparation and a preparation process thereof, and particularly provides a sodium valproate sustained-release tablet capable of releasing drug stably within 24 hours, a preparation process and application thereof.
The sodium valproate sustained release agent provided by the invention comprises sodium valproate, valproic acid, a sustained release framework material, a filler and a glidant, and is characterized by being prepared by the following steps: mixing sodium valproate and part of glidant to obtain a mixture, mixing the mixture with the sustained-release framework material and the filler, granulating by using valproic acid as an adhesive, and mixing the obtained granules with the rest of glidant.
The sustained-release matrix material may be, for example, Hydroxypropylmethylcellulose (HPMC), preferably selected from one or any combination of HPMC K4M, HPMC K10M, HPMC K15M and HPMC K100M, and more preferably, the sustained-release matrix material is HPMC K100M.
Preferably, the sodium valproate sustained release preparation is a sustained release preparation of sodium valproate, wherein the filler is selected from one or any combination of lactose, sucrose, mannitol, sorbitol, starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and pregelatinized starch, preferably microcrystalline cellulose.
Preferably, the sodium valproate sustained release agent is prepared by mixing sodium valproate, sodium hydroxide, magnesium hydroxide, sodium hydroxide, magnesium hydroxide; silica gel micropowder is preferred.
Preferably, the sodium valproate sustained release agent is prepared by taking HPMC K100M as the sustained release matrix material, taking microcrystalline cellulose as the filler, and taking silica gel as the glidant.
Particularly preferably, the sodium valproate sustained release agent provided by the invention is prepared by taking sodium valproate and valproic acid as active ingredients, taking the valproic acid as an adhesive, adding pharmaceutically common auxiliary materials and high-viscosity hydroxypropyl methylcellulose.
The dosage of the sodium valproate is 35-60% of the total tablet weight, preferably 44.52-50.99%, and the dosage of the valproic acid is 15-25% of the total tablet weight, preferably 19.39-22.21%.
The viscosity range of the high-viscosity grade hydroxypropyl methylcellulose is 80000-120000 mPa & s, the type is K100M, and the dosage of the high-viscosity grade hydroxypropyl methylcellulose is 10% -25% of the total weight of the tablet, and the preferred dosage is 11.48% -19.39%.
The auxiliary materials commonly used in pharmacy consist of a filling agent and a glidant. Wherein the filler accounts for 3% -20% of the total weight of the tablet, preferably 4.56% -16.04%; glidants or lubricants are 2% to 14%, preferably 4.12% to 10.82% of the total tablet weight.
Wherein the filler is selected from one or any combination of lactose, sucrose, mannitol, sorbitol, starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and pregelatinized starch, preferably microcrystalline cellulose.
Wherein, the glidant or the lubricant is selected from one or any combination of talcum powder, superfine silica gel powder, corn starch and magnesium stearate; silica gel micropowder is preferred.
Further, the sodium valproate sustained release agent is prepared from one of the following raw materials in parts by weight:
preferably, the sodium valproate sustained release agent is prepared from one of the following raw materials in parts by weight:
the sodium valproate sustained release preparation can be tablets, granules or capsules, and is preferably sodium valproate sustained release tablets.
The invention also provides a preparation process of the sodium valproate sustained release agent, which comprises the following steps:
a. crushing a sodium valproate raw material medicine;
b. mixing sodium valproate and part of glidant;
c. filling the mixture obtained in the step b, the slow-release framework material and the filler into a fluidized bed;
d. setting parameters of a fluidization granulator, and spraying a binder solution for granulation;
e. and d, adding the granules prepared in the step d into the rest glidant and mixing uniformly.
Preferably, it comprises the following steps:
a. crushing a sodium valproate raw material medicine;
b. mixing sodium valproate and part of micropowder silica gel, and sieving;
c. filling the mixture of sodium valproate and superfine silica powder, HPMC and microcrystalline cellulose into a fluidized bed;
d. setting parameters of a fluidization granulator, and spraying a binder solution for granulation, wherein the binder solution is an ethanol solution of valproic acid;
e. adding the rest micropowder silica gel into the obtained granule, and mixing;
f. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
More preferably, the preparation process of the sodium valproate sustained release tablet comprises the following steps:
a. crushing the sodium valproate raw material and sieving the crushed sodium valproate raw material by a 40-100-mesh sieve;
b. mixing the sieved sodium valproate with micropowder silica gel accounting for 25-75% of the total amount, and sieving with a 40-100 mesh sieve;
c. feeding the sieved mixture of sodium valproate and aerosol, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 15-45 Hz and the air inlet temperature to be 40-70 ℃; setting the spraying pressure to be 1-5 MPa and the spraying speed to be 5-15 mL/min, spraying an adhesive solution in a top spraying or bottom spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the dosage of the 95% ethanol is 0.5-3 times of that of the valproic acid;
e. after the granulation is finished, finishing the granules by using a 16-28-mesh sieve;
f. adding the rest micropowder silica gel into the obtained granule, and mixing;
g. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
Or more preferably, the preferable preparation process of the sodium valproate sustained release tablet comprises the following steps:
a. crushing the sodium valproate raw material and sieving the crushed sodium valproate raw material by a 60-80-mesh sieve;
b. mixing the sieved sodium valproate with micro silica gel powder accounting for 50% -60% of the total amount, and sieving with a 60-80 mesh sieve;
c. feeding the sieved mixture of sodium valproate and micropowder silica gel, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 25-35 Hz and the air inlet temperature to be 60-65 ℃; setting the spraying pressure to be 2-3MPa and the spraying speed to be 8-12mL/min, spraying an adhesive solution in a top spraying or bottom spraying mode for granulating, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the using amount of the 95% ethanol is 1-2 times of that of the valproic acid;
e. after the granulation is finished, the prepared granules are sized by a sieve with 20-24 meshes;
f. adding the rest micropowder silica gel into the obtained granule, and mixing;
g. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
Or, the sodium valproate sustained release tablet of the present invention may be further coated with a film coating to prepare a coated preparation, as required.
The invention also provides application of the sodium valproate sustained-release tablet in preparing medicines for treating epilepsy, bipolar disorder and/or migraine.
After the comparative study on the types and proportions of different auxiliary materials, the high-viscosity grade hydroxypropyl methylcellulose is creatively and independently used as the retarder of the sodium valproate sustained-release tablet, so that the defect that the viscosity of the hydroxypropyl methylcellulose, especially the high-viscosity grade hydroxypropyl methylcellulose such as hydroxypropyl methylcellulose K100M is extremely high, is not preferred or is not technically bias to be independently used in the prescription of the sodium valproate sustained-release preparation is overcome, the defect of the preparation technology is overcome by adopting a new process, and the sodium valproate sustained-release tablet capable of stably releasing the drug within 24 hours is finally manufactured.
The invention has the following beneficial effects:
1. the process is creative: the new process solves the problem of mixing the strong hygroscopic material such as sodium valproate and the high-viscosity release inhibitor, can greatly reduce the loss of auxiliary materials, solves the problem of unqualified content uniformity of the medicine in the granules and improves the yield; the new process completes the mixing, pelletizing and drying processes simultaneously, thus improving the heat efficiency, reducing the energy consumption, simplifying the process steps and shortening the production time.
2. The invention creatively and separately uses the hydroxypropyl methylcellulose K100M, overcomes the technical prejudice that the high-viscosity hydroxypropyl methylcellulose K100M in the prior art can not be separately applied to the sodium valproate preparation slowly released within 24 hours, can continuously release the medicine within 24 hours, and only needs to be taken once a day when a patient takes the sustained-release preparation, thereby increasing the medicine taking compliance of the patient.
3. Compared with other existing valproic acid sustained-release preparations, the sustained-release preparation has more stable blood concentration, greatly reduces side effects, increases the medication safety, and overcomes the defects of unstable release speed and incomplete release of the sustained-release preparation in the prior art as can be seen from the release curve of the sustained-release preparation.
The various types and relevant characteristics of hydroxypropyl methylcellulose (HPMC) referred to in the specification are described as follows: the viscosity range of the HPMC K4M is 3000-5600 mPa s; the viscosity range of the HPMC K10M is 8000-12000 mPa & s; the viscosity range of the HPMC K15M is 11250-21000 mPa & s; the viscosity of HPMC K100M is 80000-120000 mPas.
The present invention is described in further detail with reference to the following detailed description, but the present invention is not limited thereto, and those skilled in the art can make various changes and modifications according to the present invention without departing from the spirit of the present invention, which falls within the scope of the appended claims.
Detailed Description
Example 1
Prescription:
the preparation process comprises the following steps:
a. crushing the sodium valproate raw material and sieving the crushed sodium valproate raw material with a 40-mesh sieve;
b. mixing the sieved sodium valproate with micropowder silica gel accounting for 25% of the total amount, and sieving with a 40-mesh sieve;
c. feeding the sieved mixture of sodium valproate and micropowder silica gel, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 15Hz and the air inlet temperature to be 40 ℃; setting the spraying pressure to be 1MPa and the spraying speed to be 5mL/min, spraying an adhesive solution in a top spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the using amount of the 95% ethanol is 0.5 times of that of the valproic acid;
e. after the granulation is finished, the prepared granules are sized by a 16-mesh sieve;
f. adding the rest micropowder silica gel into the obtained granule, and mixing;
g. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
Example 2
The preparation process comprises the following steps:
a. crushing the sodium valproate raw material and then sieving the crushed sodium valproate raw material with a 60-mesh sieve;
b. mixing the sieved sodium valproate with micro silica gel powder accounting for 50% of the total amount, and sieving the mixture through a 60-mesh sieve;
c. feeding the sieved mixture of sodium valproate and micropowder silica gel, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 25Hz and the air inlet temperature to be 60 ℃; setting the spraying pressure to be 2MPa and the spraying speed to be 8mL/min, spraying an adhesive solution in a top spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the using amount of the 95% ethanol is 1 time of that of the valproic acid;
e. after the granulation is finished, the prepared granules are sized by a 20-mesh sieve;
f. adding the rest micropowder silica gel into the obtained granule, and mixing;
g. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
Example 3
The preparation process comprises the following steps:
a. crushing the sodium valproate raw material and sieving the crushed sodium valproate raw material with a 80-mesh sieve;
b. mixing the sieved sodium valproate with micropowder silica gel accounting for 60% of the total amount, and sieving with a 80-mesh sieve;
c. feeding the sieved mixture of sodium valproate and micropowder silica gel, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 35Hz and the air inlet temperature to be 65 ℃; setting the spraying pressure to be 3MPa and the spraying speed to be 12mL/min, spraying an adhesive solution in a top spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the using amount of the 95% ethanol is 2 times of that of the valproic acid;
e. after the granulation is finished, the prepared granules are granulated by a 24-mesh sieve;
f. adding the rest micropowder silica gel into the obtained granule, and mixing;
g. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
Example 4
The preparation process comprises the following steps:
a. crushing the sodium valproate raw material and then sieving the crushed sodium valproate raw material with a 100-mesh sieve;
b. mixing the sieved sodium valproate with micropowder silica gel accounting for 70% of the total amount, and sieving with a 100-mesh sieve;
c. feeding the sieved mixture of sodium valproate and micropowder silica gel, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 40Hz and the air inlet temperature to be 70 ℃; setting the spraying pressure to be 4MPa and the spraying speed to be 12mL/min, spraying an adhesive solution in a top spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the using amount of the 95% ethanol is 2.5 times that of the valproic acid;
e. after the granulation is finished, the prepared granules are sized by a 28-mesh sieve;
f. adding the rest micropowder silica gel into the obtained granule, and mixing;
g. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
Example 5
The preparation process comprises the following steps:
a. crushing the sodium valproate raw material and sieving the crushed sodium valproate raw material with a 40-mesh sieve;
b. mixing the sieved sodium valproate with micropowder silica gel accounting for 75% of the total amount, and sieving with a 40-mesh sieve;
c. feeding the sieved mixture of sodium valproate and micropowder silica gel, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 45Hz and the air inlet temperature to be 80 ℃; setting the spraying pressure to be 5MPa and the spraying speed to be 15mL/min, spraying an adhesive solution in a bottom spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the using amount of the 95% ethanol is 3 times that of the valproic acid;
e. after the granulation is finished, the prepared granules are sized by a 16-mesh sieve;
f. adding the rest micropowder silica gel into the obtained granule, and mixing;
g. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
Example 6
The preparation process comprises the following steps:
a. crushing the sodium valproate raw material and then sieving the crushed sodium valproate raw material with a 60-mesh sieve;
b. mixing the sieved sodium valproate with micropowder silica gel accounting for 60% of the total amount, and sieving with a 60-mesh sieve;
c. feeding the sieved mixture of sodium valproate and micropowder silica gel, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 35Hz and the air inlet temperature to be 65 ℃; setting the spraying pressure to be 2.5MPa and the spraying speed to be 10mL/min, spraying an adhesive solution in a top spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the using amount of the 95% ethanol is 2 times of that of the valproic acid;
e. after the granulation is finished, the prepared granules are sized by a 20-mesh sieve;
f. adding the rest micropowder silica gel into the obtained granule, and mixing;
g. tabletting the above mixture with a suitable tabletting machine to obtain the sustained release tablet.
Comparative example 1
Prescription:
the preparation process comprises the following steps:
sieving sodium valproate, hydroxypropyl methylcellulose and microcrystalline cellulose with 40 mesh sieve, and mixing; adding valproic acid and appropriate amount of 95% ethanol into the above mixture respectively to obtain soft material; sieving with 40 mesh sieve to obtain wet granule, drying at 60 deg.C for 2 hr, and grading with 16 mesh sieve; adding the obtained granules into the superfine silica gel powder, uniformly mixing, and tabletting to obtain the sustained-release tablet.
Comparative example 2
Prescription:
the preparation process comprises the following steps:
sieving sodium valproate, hydroxypropyl methylcellulose and microcrystalline cellulose with 60 mesh sieve, and mixing; mixing valproic acid with appropriate amount of 95% ethanol, adding into the above mixture, and making into soft material; sieving with 60 mesh sieve to obtain wet granule, drying at 60 deg.C for 2 hr, and grading with 20 mesh sieve; adding the obtained granules into the superfine silica gel powder, uniformly mixing, and tabletting to obtain the sustained-release tablet.
Example 7 and comparative example 3
Sustained-release tablets were prepared according to the example and comparative example formulations in table 1 below, using the process in example 6:
TABLE 1
Test example 1
Evaluation of the preparation process:
(1) particle forming rate: calculating the total mass of the prepared particles divided by the total mass of the fed materials multiplied by 100 percent;
(2) fluidity: discharging the granules from the bottom gap of the container, and obtaining the angle of repose when the inclined plane and the bottom curved surface of the material form an included angle after the material stops flowing. The particle repose angle is used for evaluating the particle fluidity, the smaller the repose angle is, the smaller the friction force is, the better the fluidity is, the fluidity is considered to be good when theta is less than or equal to 30 degrees, and the fluidity requirement in the production process can be met when theta is less than or equal to 40 degrees;
(3) the content uniformity is measured by a content uniformity inspection method in the appendix X E of the 2010 version of Chinese pharmacopoeia; the content uniformity refers to the degree that the content of each tablet (one) of the solid preparation with small dose or single dose meets the marked amount, and the content uniformity of the prepared granule is qualified only if the medicine content uniformity is qualified, and the content uniformity of the prepared final product can be qualified.
TABLE 2
From the results in table 2, it can be seen that the granule molding rate obtained by the process of the present invention is above 90%, wherein the granule molding rate of the examples 2, 3 and 6 is more 98%, therefore, the material utilization rate of the new process is extremely high, the granule fluidity completely meets the tabletting requirement, and the content uniformity is all qualified; however, the forming rate of the granules of comparative example 1 and comparative example 2 adopting the common granulation process is only about 70% at most, the flowability is barely in line with the tabletting requirement, and the content uniformity is not qualified.
Test example 2
In vitro release experiments:
the first method of the XD release determination method in the 2010 edition of the Chinese pharmacopoeia was adopted, 900ml of phosphate buffer solution (pH6.8) was used as a release medium, the rotation speed was 60 rpm, samples were taken at predetermined time points (1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24h), the concentration of valproic acid was measured, and the cumulative release (%) was calculated. The cumulative release results are shown in Table 3 below.
TABLE 3
As can be seen from the release results in Table 3, examples 7-1, 7-2 and 7-3 released more than 90% within 12 hours, almost completely, and although the effect of exerting the drug effect by sustained release within 12 hours was satisfied, the effect of exerting the drug effect by sustained release within 24 hours was not satisfied; whereas comparative example 3 was slow and released no more than 85% within 24 hours, leaving a large amount of drug unreleased. The release results of examples 1 to 6, 7 to 4, 7 to 5 and 7 to 6 show that the hydroxypropyl methylcellulose K100M with a certain proportion in the formula can be matched with a filler (such as microcrystalline cellulose) to achieve the effects of slow release and complete release within 24 hours.
Claims (7)
1. A sodium valproate sustained release agent comprises sodium valproate, valproic acid, a sustained release framework material, a filler and a glidant, and is characterized by being prepared by the following steps: uniformly mixing 25-75% of the total amount of sodium valproate and glidant micropowder silica gel to obtain a mixture, loading the mixture, a slow-release framework material HPMC K100M and filler microcrystalline cellulose into a fluidized bed granulator, and uniformly mixing, wherein the air inlet speed of the fluidized bed is set to be 15-45 Hz, and the air inlet temperature is set to be 40-70 ℃; setting the spraying pressure to be 1-5 MPa and the spraying speed to be 5-15 mL/min, spraying an adhesive solution in a top spraying or bottom spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the dosage of the 95% ethanol is 0.5-3 times of that of the valproic acid; granulating, and mixing the obtained granules with the rest glidant micropowder silica gel;
the sodium valproate sustained release preparation comprises 44.52-50.99% of sodium valproate, 19.39-22.21% of valproic acid, 11.48-19.39% of HPMC K100M, 4.56-16.04% of microcrystalline cellulose and 4.12-10.82% of superfine silica gel powder by weight percentage.
2. The sodium valproate sustained release formulation according to claim 1, which is a tablet, granule or capsule.
3. The sodium valproate sustained release formulation according to claim 2, wherein the sodium valproate sustained release formulation is sodium valproate sustained release tablets.
4. The sodium valproate sustained release formulation according to claim 1, wherein the preparation method of the sodium valproate sustained release formulation comprises the following steps:
a. crushing the sodium valproate raw material and sieving the crushed sodium valproate raw material by a 40-100-mesh sieve;
b. mixing the sieved sodium valproate with micropowder silica gel accounting for 25-75% of the total amount, and sieving with a 40-100 mesh sieve;
c. feeding the sieved mixture of sodium valproate and aerosol, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 15-45 Hz and the air inlet temperature to be 40-70 ℃; setting the spraying pressure to be 1-5 MPa and the spraying speed to be 5-15 mL/min, spraying an adhesive solution in a top spraying or bottom spraying mode for granulation, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the dosage of the 95% ethanol is 0.5-3 times of that of the valproic acid; after the granulation is finished, finishing the granules by using a 16-28-mesh sieve;
e. d, adding the rest micropowder silica gel into the particles prepared in the step d and uniformly mixing;
f. and e, tabletting the mixture prepared in the step e by using a proper tabletting machine to obtain the sustained release tablets.
5. The sodium valproate sustained release formulation according to claim 4, wherein:
a. crushing the sodium valproate raw material and sieving the crushed sodium valproate raw material by a 60-80-mesh sieve;
b. mixing the sieved sodium valproate with micro silica gel powder accounting for 50% -60% of the total amount, and sieving with a 60-80 mesh sieve;
c. feeding the sieved mixture of sodium valproate and micropowder silica gel, HPMC and microcrystalline cellulose into a fluid bed granulator;
d. setting the air inlet speed of the fluidized bed to be 25-35 Hz and the air inlet temperature to be 60-65 ℃; setting the spraying pressure to be 2-3MPa and the spraying speed to be 8-12mL/min, spraying an adhesive solution in a top spraying or bottom spraying mode for granulating, wherein the adhesive solution is prepared by dissolving valproic acid in 95% ethanol, and the using amount of the 95% ethanol is 1-2 times of that of the valproic acid; after the granulation is finished, the prepared granules are sized by a sieve with 20-24 meshes;
e. d, adding the rest micropowder silica gel into the particles prepared in the step d and uniformly mixing;
f. and e, tabletting the mixture prepared in the step e by using a proper tabletting machine to obtain the sustained release tablets.
6. The sodium valproate sustained release formulation according to claim 5, further comprising a step of further film-coating the tablet obtained in step f to prepare a coated formulation.
7. Use of a sodium valproate sustained release formulation according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of epilepsy, bipolar disorder and/or migraine.
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| CN113304117B (en) * | 2021-04-30 | 2023-05-12 | 山东京卫制药有限公司 | Preparation method of sodium valproate sustained release tablet |
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| EP0571973B1 (en) * | 1992-05-29 | 2000-02-02 | Nikken Chemicals Co., Ltd. | Slow-release sodium valproate tablets |
| WO2000037055A1 (en) * | 1998-12-18 | 2000-06-29 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| GB0001449D0 (en) * | 2000-01-21 | 2000-03-08 | Cortendo Ab | Compositions |
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| WO2002051402A1 (en) * | 2000-12-22 | 2002-07-04 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| WO2003096874A2 (en) * | 2002-05-15 | 2003-11-27 | Sun Pharmaceutical Industries Limited | Coated sustained release tablets of a hygroscopic compound for once-a-day therapy |
| US20050276848A1 (en) * | 2004-06-15 | 2005-12-15 | Nilobon Podhipleux | Sustained release neutralized divalproex sodium |
| CN102048722A (en) * | 2009-11-02 | 2011-05-11 | 扬子江药业集团北京海燕药业有限公司 | Divalproex sodium sustained-release tablet and preparation process thereof |
| CN102138911B (en) * | 2011-03-28 | 2012-12-12 | 孙卫东 | Divalproex sodium sustained release tablets and preparation method thereof |
| CN105012264B (en) * | 2014-04-16 | 2019-11-29 | 四川科瑞德制药股份有限公司 | Sustained-release Sodium Valproate and its preparation process and purposes |
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