CN111012753A - Method for improving stability of sodium valproate tablets - Google Patents
Method for improving stability of sodium valproate tablets Download PDFInfo
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- CN111012753A CN111012753A CN202010013304.7A CN202010013304A CN111012753A CN 111012753 A CN111012753 A CN 111012753A CN 202010013304 A CN202010013304 A CN 202010013304A CN 111012753 A CN111012753 A CN 111012753A
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- granules
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- sodium valproate
- granulating
- tabletting
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and discloses a method for improving the stability of a sodium valproate tablet, which comprises the following steps: step 1) taking raw materials, preparing soft materials in step 2), granulating in step 3), grading in step 4), and tabletting in step 5). The invention has simple and feasible process and improves the stability of the tablet.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a method for improving the stability of a sodium valproate tablet.
Background
Valproic acid sodium is a nitrogen-free broad-spectrum antiepileptic drug. The product has different degrees of antagonism to convulsion caused by various methods. It is effective on various epilepsy such as small seizures, myoclonic epilepsy, local seizures, grand mal epilepsy and mixed epilepsy. Oral administration is rapid and complete, and is mainly distributed in extracellular fluid, where most of the blood binds to plasma proteins. It is mainly used for various epileptics with ineffective antiepileptic drugs, especially for small seizures.
In the aspect of the current preparation development of sodium valproate, a lot of reports are available on the preparation of liquid preparations (such as injections or oral liquids), while few reports are available on solid preparations, and only a few patent documents report that sodium valproate is used as a raw material to prepare sustained-release preparations: wherein, US5019398 discloses sodium valproate sustained-release tablets, but the sustained-release time of the sodium valproate sustained-release preparation in the article is only 8 hours, and the release speed is too fast; in addition, the sodium valproate sustained-release microspheres disclosed in CN97198537 have a very complex preparation process, the auxiliary materials need to be melted at high temperature during the production process, and the preparation is sprayed under specific conditions, which not only has high requirements on the production conditions, but also causes the sodium valproate to be unstable and generate impurities during the high-temperature dissolution process. How to improve the stability of sodium valproate tablets is a technical problem to be solved.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a method for improving the stability of a sodium valproate tablet.
The invention is realized by the following technical scheme:
a method for improving the stability of a sodium valproate tablet, comprising the steps of:
step 1) taking raw materials, preparing soft materials in step 2), granulating in step 3), grading in step 4), and tabletting in step 5).
Further, the air conditioner is provided with a fan,
the step 1) of taking raw materials comprises the following steps: weighing the raw materials in percentage by weight, wherein: 50-55% of sodium valproate, 25-30% of hydroxypropyl cellulose, 8-10% of pregelatinized starch, 6-8% of microcrystalline cellulose, 0.2-0.3% of magnesium stearate, 0.1-0.2% of silicon dioxide and 0.1-0.2% of sodium lauryl sulfate.
Further, the air conditioner is provided with a fan,
the soft material preparation in the step 2) comprises the following steps: mixing 95% ethanol and purified water to obtain 60% ethanol; then adding sodium valproate, hydroxypropyl cellulose, pregelatinized starch, microcrystalline cellulose and sodium lauryl sulfate into a stirrer, stirring for 10 minutes to obtain a compound mixture, then adding 60% ethanol accounting for one third of the weight of the compound mixture while stirring, and continuously stirring for 10 minutes to obtain a soft material.
Further, the air conditioner is provided with a fan,
the step 3) of granulating comprises the following steps: adding the soft material into a granulator to prepare wet granules; feeding the wet granules into a hot air circulation oven, and drying by blowing; drying at 70 deg.C for 6 hr while turning the dried granules to water content of 3.0 wt%.
Further, the air conditioner is provided with a fan,
the step 4) of granulating comprises the following steps: putting the dried granules into a swing type granulator, granulating through a 18-mesh sieve to prepare granules with uniform sizes, putting the granules into a mixer, adding magnesium stearate and silicon dioxide, setting the rotation speed to 10 rpm, starting the machine, mixing for 5 minutes, and uniformly mixing.
Further, the air conditioner is provided with a fan,
the step 5) tabletting comprises the following steps: tabletting with a tabletting machine to obtain plain tablets, and inspecting to obtain the final product.
The invention also claims tablets prepared according to the above process.
Compared with the prior art, the beneficial effects obtained by the invention mainly comprise:
the preparation process of the sustained-release preparation is simple, the requirements on production environment and equipment conditions are low, the variety of auxiliary materials is few, the production cost is reduced, and the preparation method is very suitable for industrial production; the process of the sustained-release preparation is simple and feasible, and the stability of the tablet is improved; after 8 months of accelerated test, all indexes of the sustained-release tablet prepared by the invention reach the standard, and the stability of the sustained-release tablet meets the requirement.
Detailed Description
In order to make those skilled in the art better understand the technical solutions in the present application, the present invention will be described more clearly and completely below with reference to specific embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
The starting materials used in the following examples are commercially available unless otherwise specified.
Example 1
A method for improving the stability of a sodium valproate tablet, comprising the steps of:
step 1) taking raw materials: weighing the raw materials in percentage by weight, wherein: 53.3 percent of sodium valproate, 30 percent of hydroxypropyl cellulose, 10 percent of pregelatinized starch, 6 percent of microcrystalline cellulose, 0.3 percent of magnesium stearate, 0.2 percent of silicon dioxide and 0.2 percent of sodium lauryl sulfate;
step 2) soft material preparation: mixing 95% ethanol and purified water to obtain 60% ethanol; then adding sodium valproate, hydroxypropyl cellulose, pregelatinized starch, microcrystalline cellulose and sodium lauryl sulfate into a stirrer, stirring for 10 minutes to obtain a compound mixture, then adding 60% ethanol accounting for one third of the weight of the compound mixture while stirring, and continuously stirring for 10 minutes to obtain a soft material;
step 3) granulating: adding the soft material into a granulator to prepare wet granules; feeding the wet granules into a hot air circulation oven, and drying by blowing; drying at 70 deg.C for 6 hr, and turning the dried granules once to make the water content of the dried granules reach 3.0 wt%;
step 4), straightening granules: putting the dried granules into a swing type granulator, granulating through a 18-mesh sieve to prepare granules with uniform sizes, putting the granules into a mixer, adding magnesium stearate and silicon dioxide, setting the rotation speed to 10 rpm, starting the mixer, and mixing for 5 minutes to uniformly mix the granules;
step 5), tabletting: tabletting with a tabletting machine to obtain plain tablets, and inspecting to obtain the final product.
Example 2
A method for improving the stability of a sodium valproate tablet, comprising the steps of:
step 1) taking raw materials: weighing the raw materials in percentage by weight, wherein: 54.5% of sodium valproate, 28% of hydroxypropyl cellulose, 9% of pregelatinized starch, 8% of microcrystalline cellulose, 0.2% of magnesium stearate, 0.2% of silicon dioxide and 0.1% of sodium lauryl sulfate;
step 2) soft material preparation: mixing 95% ethanol and purified water to obtain 60% ethanol; then adding sodium valproate, hydroxypropyl cellulose, pregelatinized starch, microcrystalline cellulose and sodium lauryl sulfate into a stirrer, stirring for 10 minutes to obtain a compound mixture, then adding 60% ethanol accounting for one third of the weight of the compound mixture while stirring, and continuously stirring for 10 minutes to obtain a soft material;
step 3) granulating: adding the soft material into a granulator to prepare wet granules; feeding the wet granules into a hot air circulation oven, and drying by blowing; drying at 70 deg.C for 6 hr, and turning the dried granules once to make the water content of the dried granules reach 3.0 wt%;
step 4), straightening granules: putting the dried granules into a swing type granulator, granulating through a 18-mesh sieve to prepare granules with uniform sizes, putting the granules into a mixer, adding magnesium stearate and silicon dioxide, setting the rotation speed to 10 rpm, starting the mixer, and mixing for 5 minutes to uniformly mix the granules;
step 5), tabletting: tabletting with a tabletting machine to obtain plain tablets, and inspecting to obtain the final product.
Example 3
Firstly, stability test:
the sodium valproate tablets in example 1 were used for stability studies, and the stability of the sodium valproate tablets prepared by the above formulation process was examined for 8 months at 35 ℃ and 80% relative humidity. The measurement is carried out at 0, 2, 4 and 8 months, and the details are shown in Table 1.
TABLE 1
| Time of the month | Traits | Content% | Degree of release% | Total impurities<1.5% |
| 0 | White or off-white | 99.9 | Qualified | 0.06 |
| 2 | White or off-white | 99.8 | Qualified | 0.09 |
| 4 | White or off-white | 99.7 | Qualified | 0.12 |
| 8 | White or off-white | 99.3 | Qualified | 0.17 |
The stability test results show that after 8 months of accelerated test, the tablet in example 1 meets all indexes, and the stability meets the requirement.
II, in-vitro release determination:
a first method of XD release degree determination in the 2010 edition appendix of Chinese pharmacopoeia is selected, 900ml of phosphate buffer solution (pH6.8) is used as a release medium, the rotating speed is 60 r/min, samples are taken at preset time points (1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24 h), and the concentration of valproic acid is determined. The release curve was plotted with time (h) as the abscissa and cumulative release (%) as the ordinate. The release results are shown in table 2.
TABLE 2
| Time h | Example 1 degree of Release% | Example 1 degree of Release% |
| 1 | 21.3 | 22.5 |
| 2 | 34.7 | 36.1 |
| 12 | 74.1 | 75.6 |
| 24 | 96.8 | 96.2 |
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (7)
1. A method for improving the stability of a sodium valproate tablet, comprising the steps of:
step 1) taking raw materials, preparing soft materials in step 2), granulating in step 3), grading in step 4), and tabletting in step 5).
2. The method as claimed in claim 1, wherein the step 1) of taking raw materials comprises the following steps: weighing the raw materials in percentage by weight, wherein: 50-55% of sodium valproate, 25-30% of hydroxypropyl cellulose, 8-10% of pregelatinized starch, 6-8% of microcrystalline cellulose, 0.2-0.3% of magnesium stearate, 0.1-0.2% of silicon dioxide and 0.1-0.2% of sodium lauryl sulfate.
3. The method of claim 2, wherein the step 2) of making a soft material comprises the steps of: mixing 95% ethanol and purified water to obtain 60% ethanol; then adding sodium valproate, hydroxypropyl cellulose, pregelatinized starch, microcrystalline cellulose and sodium lauryl sulfate into a stirrer, stirring for 10 minutes to obtain a compound mixture, then adding 60% ethanol accounting for one third of the weight of the compound mixture while stirring, and continuously stirring for 10 minutes to obtain a soft material.
4. The method according to claim 3, wherein said step 3) of granulating comprises the steps of: adding the soft material into a granulator to prepare wet granules; feeding the wet granules into a hot air circulation oven, and drying by blowing; drying at 70 deg.C for 6 hr while turning the dried granules to water content of 3.0 wt%.
5. The method according to claim 4, characterized in that said step 4) of straightening granules comprises the following steps: putting the dried granules into a swing type granulator, granulating through a 18-mesh sieve to prepare granules with uniform sizes, putting the granules into a mixer, adding magnesium stearate and silicon dioxide, setting the rotation speed to 10 rpm, starting the machine, mixing for 5 minutes, and uniformly mixing.
6. The method of claim 5, wherein said step 5) of tableting comprises the steps of: tabletting with a tabletting machine to obtain plain tablets, and inspecting to obtain the final product.
7. A tablet prepared according to the process of claims 1-6.
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| CN202010013304.7A CN111012753A (en) | 2020-01-07 | 2020-01-07 | Method for improving stability of sodium valproate tablets |
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| CN202010013304.7A CN111012753A (en) | 2020-01-07 | 2020-01-07 | Method for improving stability of sodium valproate tablets |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111568872A (en) * | 2020-06-11 | 2020-08-25 | 仁和堂药业有限公司 | Sodium valproate preparation and application thereof |
| CN112274499A (en) * | 2020-11-16 | 2021-01-29 | 仁和堂药业有限公司 | Method for improving stability of sodium valproate tablets |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5019398A (en) * | 1989-02-27 | 1991-05-28 | Sanofi | Pharmaceutical composition providing the sustained-release of valproic acid |
| CN1232391A (en) * | 1996-10-07 | 1999-10-20 | 萨诺费公司 | Pharmaceutical microspheres of valproic acid for oral administration |
| US20010020039A1 (en) * | 1998-12-18 | 2001-09-06 | Yihong Qiu | Controlled release formulation of divalproex sodium |
| CN1671363A (en) * | 2002-06-07 | 2005-09-21 | 兰贝克赛实验室有限公司 | Extended release formulation of divalproex sodium |
| US20050276849A1 (en) * | 2004-06-15 | 2005-12-15 | Nilobon Podhipleux | Sustained release dosage forms |
| CN106389368A (en) * | 2015-07-29 | 2017-02-15 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained release preparation as well as preparation process and applications thereof |
-
2020
- 2020-01-07 CN CN202010013304.7A patent/CN111012753A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5019398A (en) * | 1989-02-27 | 1991-05-28 | Sanofi | Pharmaceutical composition providing the sustained-release of valproic acid |
| CN1232391A (en) * | 1996-10-07 | 1999-10-20 | 萨诺费公司 | Pharmaceutical microspheres of valproic acid for oral administration |
| US20010020039A1 (en) * | 1998-12-18 | 2001-09-06 | Yihong Qiu | Controlled release formulation of divalproex sodium |
| CN1671363A (en) * | 2002-06-07 | 2005-09-21 | 兰贝克赛实验室有限公司 | Extended release formulation of divalproex sodium |
| US20050276849A1 (en) * | 2004-06-15 | 2005-12-15 | Nilobon Podhipleux | Sustained release dosage forms |
| CN106389368A (en) * | 2015-07-29 | 2017-02-15 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained release preparation as well as preparation process and applications thereof |
Non-Patent Citations (1)
| Title |
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| 陈肖东等: "Plackett-Burman设计联用星点设计－效应面法优化双丙戊酸钠缓释片处方", 《安徽医药》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111568872A (en) * | 2020-06-11 | 2020-08-25 | 仁和堂药业有限公司 | Sodium valproate preparation and application thereof |
| CN112274499A (en) * | 2020-11-16 | 2021-01-29 | 仁和堂药业有限公司 | Method for improving stability of sodium valproate tablets |
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Application publication date: 20200417 |