Sodium valproate sustained release tablet with stable crystal form and preparation method of sodium valproate sustained release tablet

Abstract

The invention provides a sodium valproate sustained release tablet with a stable crystal form and a preparation method of the sodium valproate sustained release tablet, and relates to the technical field of pharmacy. The preparation method comprises the following steps: dissolving sodium valproate, valproic acid and ethyl cellulose in a solvent to prepare a medicine solution; putting hydroxypropyl methylcellulose and silicon dioxide into a fluidized bed, controlling the air inlet volume, the air inlet temperature and the atomization pressure, spraying the medicine solution into a fluidization chamber, maintaining the material temperature to be stable, granulating, finishing granules, adding saccharin sodium salt and colloidal silicon dioxide, and totally mixing; tabletting to obtain a tablet core; and controlling the temperature of the tablet bed, and coating the tablet core to prepare the sodium valproate sustained-release tablet. The preparation process is simple, the sodium valproate and the valproic acid can be fully contacted to form a complete solvate, the obtained preparation is consistent in crystal form between batches, the crystal form is stable in the storage process, and the medicine can be continuously and stably released within 24 hours.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and particularly relates to a sodium valproate sustained-release tablet with a stable crystal form and a preparation method thereof. Background Art

[0002] As a first-line anti-epileptic drug, sodium valproate is widely used in clinical practice due to its broad anti-disease spectrum and effective treatment of various types of epileptic seizures. Since its first launch on the market, sodium valproate has been used in more than 100 countries around the world and has become a key drug for the treatment of epilepsy. However, despite the significant efficacy of sodium valproate in the treatment of epilepsy, there are still some technical challenges in the production process of its preparation.

[0003] Sodium valproate is a white crystalline powder or granules with strong hygroscopicity, and the critical relative humidity of the liquid state is about 43% RH. Due to its strong hygroscopicity, solid preparations are difficult to produce during the production process, and strict temperature and humidity conditions need to be controlled. The temperature and humidity environment of conventional GMP workshops cannot meet the production requirements of preparations, and the production workshop needs to be dehumidified, which consumes a lot of energy. Valproic acid is a colorless to light yellow, slightly viscous, transparent liquid with a special smell. Sodium valproate and valproic acid are not convenient to use alone as oral solid preparations.

[0004] After valproic acid and sodium valproate come into contact, a solvate (also known as a eutectic) is formed. The commercially available preparation DEPAKINE is a solvate of valproic acid and sodium valproate. Studies have found that commercially available preparations or preparations prepared by prior art have inconsistent crystal forms in different batches. The root cause of this phenomenon is that the degree of solvation of sodium valproate and valproic acid is inconsistent during the production process, which not only affects the quality and efficacy of the drug, but also brings challenges to the standardized production of preparations.

[0005] CN113304117A discloses a method for preparing a sodium valproate sustained-release tablet, wherein the obtained granules have good fluidity and compressibility, and the prepared product has good stability. The technology first uses an adsorbent to adsorb valproic acid, then mixes it with sodium valproate and other materials, and then uses a fluidized bed to granulate the mixture. During the preparation process, valproic acid and sodium valproate cannot fully contact to form a complete solvate, the preparation crystal form is unstable, and the hygroscopicity of sodium valproate cannot be effectively reduced.

[0006] CN106389368A discloses a sodium valproate sustained-release agent and its preparation process and use, and produces a sodium valproate sustained-release tablet that can release the drug stably within 24 hours. The technology first mixes sodium valproate with other excipients, and then sprays an ethanol solution of valproic acid into the granules. In the product prepared by the technology, some sodium valproate still has difficulty in fully contacting with valproic acid to form a complete solvate, and cannot form a preparation with stable crystal form.

[0007] At present, the main problem of sodium valproate sustained-release tablets prepared by the prior art is that sodium valproate is not easy to fully contact with valproic acid during the preparation process, so it is not easy to form a complete solvate, which will lead to inconsistent crystal forms between different batches; and part of sodium valproate that has not formed a solvate with valproic acid may continue to form a solvate as time goes by during the storage of the product, which will lead to different crystal forms despite different product storage times. These problems will affect the efficacy and quality controllability of the drug. Summary of the invention

[0008] The object of the present invention is to provide a sodium valproate sustained-release tablet with a stable crystal form and a preparation method thereof, so as to solve the problems raised in the above-mentioned background technology; sodium valproate and valproic acid can fully contact to form a complete solvate, and the crystal form of the preparation is consistent between different batches and does not change with storage time.

[0009] To solve the above problems, the present invention provides the following technical solutions:

[0010] In a first aspect, the present application provides a method for preparing a sodium valproate sustained-release tablet in a stable crystalline form, comprising the following steps:

[0011] dissolving sodium valproate, valproic acid and ethyl cellulose in a solvent to prepare a drug solution;

[0012] Place hydroxypropyl methylcellulose and silicon dioxide in a fluidized bed, control the air volume, air temperature and atomization pressure, spray the drug solution into the fluidized bed, maintain the material temperature stable, granulate, granulate, add saccharin sodium and colloidal silicon dioxide for total mixing;

[0013] tabletting to obtain tablet cores;

[0014] The tablet bed temperature is controlled and the tablet cores are coated to obtain sodium valproate sustained-release tablets.

[0015] In one embodiment of the present application, the solvent is selected from ethanol, isopropanol, purified water, or a mixture of any two thereof.

[0016] In one embodiment of the present application, ethanol is selected from anhydrous ethanol or 95% ethanol.

[0017] In one embodiment of the present application, ethanol is selected from anhydrous ethanol.

[0018] In one embodiment of the present application, in every 1000 sodium valproate sustained-release tablets, the dosage ratio of sodium valproate, valproic acid, ethyl cellulose, hydroxypropyl methylcellulose, colloidal silicon dioxide, sodium saccharin, silicon dioxide, and anhydrous ethanol is 333:145:12:176:4:10:50:450.

[0019] In one embodiment of the present application, in the drug solution, the total concentration of sodium valproate and valproic acid is 20% to 80% w / w.

[0020] In one embodiment of the present application, in the drug solution, the total concentration of sodium valproate and valproic acid is 40% to 50% w / w.

[0021] In one embodiment of the present application, the air volume is 70-120 m 3 / h, the inlet air temperature is 50-90℃, the atomization pressure is 0.5-2.0bar, the flow rate of the drug solution sprayed into the fluidizing chamber is 5-10g / min, and the material temperature is 40-80℃.

[0022] In one embodiment of the present application, the tablet bed temperature is 35-55° C., and the coating weight gain is 2.0-5.0%.

[0023] In a second aspect, the present application provides a sodium valproate sustained-release tablet in a stable crystalline form prepared by the above method.

[0024] In one embodiment of the present application, in the sodium valproate sustained-release tablet, sodium valproate and valproic acid form a solvate.

[0025] In a third aspect, the present application provides a stable crystalline sodium valproate sustained-release tablet for use in the preparation of a drug for preventing, treating or alleviating epilepsy, bipolar disorder and / or migraine.

[0026] Compared with the prior art, the present application provides a sodium valproate sustained-release tablet with a stable crystal form and a preparation method thereof, wherein sodium valproate and valproic acid can fully contact to form a complete solvate, thereby making the crystal form of preparations of different batches stable and being able to continuously and stably release drugs within 24 hours. The preparation process of the present application is simple and has low energy consumption. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the PXRD diffraction pattern of the crystal form of preparation Batch 1 of Example 1 after accelerated storage for 0 days;

[0028] Figure 2 This is the PXRD diffraction pattern of the crystal form of preparation Batch 2 of Example 1 after accelerated storage for 0 days;

[0029] Figure 3 This is the PXRD diffraction pattern of the crystal form of preparation batch 3 of Example 1 after accelerated storage for 0 days;

[0030] Figure 4 This is the PXRD diffraction pattern of the crystalline form of preparation Batch 1 of Example 1 after accelerated storage for 6 months;

[0031] Figure 5This is the PXRD diffraction pattern of the crystalline form of preparation Batch 2 of Example 1 after accelerated storage for 6 months;

[0032] Figure 6 This is the PXRD diffraction pattern of the crystalline form of preparation Batch 3 of Example 1 after accelerated storage for 6 months;

[0033] Figure 7 This is the PXRD diffraction pattern of the crystal form of preparation 1 of batch 1 of comparative example 1 after accelerated storage for 0 days;

[0034] Figure 8 This is the PXRD diffraction pattern of the crystal form of preparation 2 of batch 1 of comparative example after accelerated storage for 0 days;

[0035] Fig. 9 This is the PXRD diffraction pattern of the crystal form of preparation 3 of batch 1 of comparative example after accelerated storage for 0 days;

[0036] Fig.10 This is the PXRD diffraction pattern of the crystal form of preparation 1 of batch 2 of comparative example after accelerated storage for 0 days;

[0037] Fig.11 This is the PXRD diffraction pattern of the crystal form of preparation 2 of batch 2 of comparative example 2 after accelerated storage for 0 days;

[0038] Fig.12 This is the PXRD diffraction pattern of the crystal form of preparation 1 of batch 1 of comparative example 1 after accelerated storage for 6 months;

[0039] Fig.13 This is the PXRD diffraction pattern of the crystalline form of preparation No. 2 in Batch 2 of Comparative Example after accelerated storage for 6 months. DETAILED DESCRIPTION

[0040] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all of the embodiments.

[0041] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range.

[0042] Unless otherwise specified, the terms used in this application have the commonly known meanings generally understood by those skilled in the art. Unless otherwise specified, the numerical values ​​of the parameters mentioned in this application can be measured using various measurement methods commonly used in the art.

[0043] Example 1

[0044] The formula of a stable crystalline sodium valproate sustained-release tablet is shown in Table 1 below:

[0045] Table 1

[0046]

[0047] The preparation process is as follows:

[0048] Sodium valproate, valproic acid, and ethylcellulose (EC) 20 were dissolved in anhydrous ethanol;

[0049] Place hydroxypropyl methylcellulose and silicon dioxide in a physical and chemical bed and set the air volume to 70-120m 3 / h, air inlet temperature 50-90℃, control the adhesive flow rate 5-10g / min, atomization pressure 0.5-2.0bar, control the material temperature 40-80℃, spray the drug solution into the fluidized bed;

[0050] The granulated particles are sieved with a φ2.0 mm screen;

[0051] Add colloidal silicon dioxide and sodium saccharin and mix for 5 minutes;

[0052] The tablets are pressed with a 17×9mm oval double-engraved punch, and the tablet core hardness is controlled to be 6-16kg;

[0053] Control air volume 70~150m 3 / h, inlet air temperature 50-70°C, atomization pressure 0.15-0.35MPa, fan pressure 0.15-0.35MPa, coating liquid flow rate 1.2-3g / min, tablet bed temperature controlled at 35-55°C, and tablet cores coated until coating weight gain is 2.0-5.0%.

[0054] Among them, ethyl cellulose (EC) 20, the number after EC represents the viscosity specification of ethyl cellulose, the unit is mPa·s.

[0055] The crystal forms of multiple batches of the preparation of Example 1 were studied, see Figure 1-Figure 6 The crystal form of the preparation is stable, and sodium valproate and valproic acid form stable solvates during the process. The three batches of preparations are placed under accelerated conditions of 40±2°C, 75%±5%RH for 6 months, and the crystal form is stable. The X-ray diffraction analysis diagram has characteristic absorption peaks at 2θ=6.1°±0.2° and 7.2°±0.2°.

[0056] Comparative Example 1

[0057] The formula of a sodium valproate sustained-release tablet is shown in Table 2 below:

[0058] Table 2

[0059]

[0060] The preparation process is as follows:

[0061] Dissolve valproic acid and ethylcellulose (EC) 20 in anhydrous ethanol;

[0062] Sodium valproate, hypromellose and silicon dioxide were placed in a high shear wet granulator, stirring was set at 75 rpm, shearing was set at 2000 rpm, and atomization pressure was set at 0.08-0.25 MPa, and the drug solution was sprayed into the high shear wet granulator for granulation;

[0063] The granulated particles are sieved with a φ2.0 mm screen;

[0064] Add colloidal silicon dioxide and sodium saccharin and mix for 5 minutes;

[0065] The tablets are pressed with a 17×9mm oval double-engraved punch, and the tablet core hardness is controlled to be 6-16kg;

[0066] Control air volume 70~150m 3 / h, inlet air temperature 50-70°C, atomization pressure 0.15-0.35MPa, fan pressure 0.15-0.35MPa, coating liquid flow rate 1.2-3g / min, tablet bed temperature controlled at 35-55°C, and tablet cores coated until coating weight gain is 2.0-5.0%.

[0067] from Figures 7 to 9 It can be seen that the crystal forms of the preparations in different batches of Comparative Example 1 are unstable and the degree of solvation is inconsistent.

[0068] The dissolution curves of the preparations of Example 1 and Comparative Example 1 are shown in Table 3.

[0069] Table 3 Dissolution data of the preparations of Example 1 and Comparative Example 1 (pH 6.8 phosphate buffer)

[0070]

[0071] As can be seen from Table 3, the dissolution curve of the preparation of Example 1 is consistent with the dissolution curve of the preparation of Comparative Example 1.

[0072] Cocrystals / solvates have advantages in solubility, dissolution rate, bioavailability and stability. Sodium valproate has strong hygroscopicity, while the hygroscopicity of sodium valproate and valproic acid after solvation is significantly reduced, as shown in Table 4.

[0073] Example 1: Sodium valproate is dissolved in anhydrous ethanol, which avoids moisture absorption of sodium valproate during the production process. The risk of moisture absorption of materials in the entire production process is relatively small, and there is no need to strictly control the production environment, which can effectively reduce production energy consumption.

[0074] Table 4 Comparison of hygroscopicity of sodium valproate, Example 1, and Comparative Example 1 at 25°C and 65%RH

[0075]

[0076] Comparative Example 2

[0077] Referring to the patent CN 106389368 A, only valproic acid was dissolved in 95% ethanol and the preparation was prepared by fluidized bed granulation process. The formula is shown in Table 5 below:

[0078] Table 5

[0079]

[0080]

[0081] The preparation process is as follows:

[0082] Dissolve valproic acid and ethylcellulose in 95% ethanol;

[0083] Place sodium valproate, hypromellose and silicon dioxide in a physical and chemical bed and set the air volume to 70-120m 3 / h, the air inlet temperature is set at 50-90°C, the adhesive flow rate is controlled at 5-10g / min, the atomization pressure is 0.5-2.0bar, the material temperature is controlled at 40-80°C, and the drug solution is sprayed into the fluidized bed;

[0084] The granulated particles are sieved with a φ2.0 mm screen;

[0085] The tablet is pressed with a 17*9mm oval double-engraved punch to control the tablet core hardness to 6-16kg;

[0086] Control air volume 70~150m 3 / h, inlet air temperature 50-70°C, atomization pressure 0.15-0.35MPa, fan pressure 0.15-0.35MPa, coating liquid flow rate 1.2-3g / min, tablet bed temperature controlled at 35-55°C, and tablet cores coated until coating weight gain is 2.0-5.0%.

[0087] like Fig.10 , Fig.11 , Fig.13As shown, the crystal form of multiple batches of preparations in Comparative Example 2 is unstable, and the degree of solvation of sodium valproate and valproic acid is inconsistent under different production environments and when the process parameters fluctuate, but during the stability study (40°C ± 2°C, 75% ± 5% RH), the product crystal form is still continuously changing. After 6 months of storage, sodium valproate and valproic acid have fully contacted to form a complete solvate. The crystal form of the preparation obtained in this comparative example is unstable during storage, and the quality of the preparation is relatively uncontrollable.

[0088] The present application is described in detail above in conjunction with specific implementation methods and exemplary embodiments, but these descriptions cannot be understood as limiting the present application. Those skilled in the art understand that, without departing from the spirit and scope of the present application, the technical solution of the present application and its implementation methods may be subjected to a variety of equivalent substitutions, modifications or improvements, all of which fall within the scope of the present application.

Claims

1. A method for preparing a stable crystalline sodium valproate sustained-release tablet, characterized in that: The following steps are involved: dissolving sodium valproate, valproic acid and ethyl cellulose in a solvent to prepare a drug solution; Place hydroxypropyl methylcellulose and silicon dioxide in a fluidized bed, control the air volume, air temperature and atomization pressure, spray the drug solution into the fluidized bed, maintain the material temperature stable, granulate, granulate, add saccharin sodium and colloidal silicon dioxide for total mixing; tabletting to obtain tablet cores; The tablet bed temperature is controlled and the tablet cores are coated to obtain sodium valproate sustained-release tablets.

2. The method for preparing the stable crystalline sodium valproate sustained-release tablets according to claim 1, characterized in that: The solvent is selected from ethanol, isopropanol, purified water or a mixture of any two thereof.

3. The method for preparing the stable crystalline sodium valproate sustained-release tablets according to claim 2, characterized in that: The ethanol is selected from anhydrous ethanol or 95% ethanol.

4. The method for preparing the stable crystalline sodium valproate sustained-release tablets according to claim 3, characterized in that: The ethanol is selected from anhydrous ethanol.

5. The method for preparing the stable crystalline sodium valproate sustained-release tablets according to claim 1, characterized in that: In every 1,000 sodium valproate sustained-release tablets, the dosage ratio of sodium valproate, valproic acid, ethyl cellulose, hypromellose, colloidal silicon dioxide, sodium saccharin, silicon dioxide, and anhydrous ethanol is 333:145:12:176:4:10:50:

450.

6. The method for preparing the stable crystalline sodium valproate sustained-release tablets according to claim 1, characterized in that: In the drug solution, the total concentration of sodium valproate and valproic acid is 20% to 80% w / w.

7. The method for preparing the stable crystalline sodium valproate sustained-release tablets according to claim 6, characterized in that: In the drug solution, the total concentration of sodium valproate and valproic acid is 40% to 50% w / w.

8. The method for preparing the stable crystalline sodium valproate sustained-release tablets according to claim 1, characterized in that: The air volume is 70-120m 3 / h, the air inlet temperature is 50-90°C, the atomization pressure is 0.5-2.0 bar, the flow rate of the drug solution sprayed into the fluidizing chamber is 5-10 g / min, the material temperature is 40-80°C, the tablet bed temperature is 35-55°C, and the coating weight gain is 2.0-5.0%.

9. The stable crystalline sodium valproate sustained-release tablets prepared by the method according to any one of claims 1 to 8, characterized in that: In the sodium valproate sustained-release tablet, sodium valproate and valproic acid form a solvate.

10. Use of the stable crystalline sodium valproate sustained-release tablets according to claim 9 in the preparation of drugs for preventing, treating or alleviating epilepsy, bipolar disorder and / or migraine.

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