Benzafamate tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a bentonamate tablet and a preparation method thereof. The bentonamate tablet is prepared from bentonamate, a filling agent, an adhesive, a disintegrating agent and a lubricating agent, wherein the filling agent and the adhesive are silicified microcrystalline cellulose, the total content of the filling agent and the adhesive is 76-84%, and the content of the disintegrating agent is 3-10%. According to the present invention, the bentonamate tablet is prepared by using a dry direct compression method, the prepared bentonamate tablet has characteristics of high content uniformity, effective treatment effect stability ensuring, rapid dissolution rate, and 15 min dissolution rate reaching 85% or more in a medium with a pH value of 1.2, such that the rapid disintegration and release of the drug in the gastrointestinal tract are easily achieved, and the drug effect is significantly improved; the epileptic seizure is particularly important for the epileptic, and because the epileptic seizure is often sudden and unpredictable, the quick-acting medicine can control the seizure more timely, and the pain and danger of the patient are relieved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, in particular to a phenbarnac ester tablet and a preparation method thereof. Background Art

[0002] As an anti-epileptic drug with a unique mechanism of action, phenbarate can effectively inhibit abnormal discharges of neurons and shows good application prospects in the treatment of epilepsy. It mainly works through two mechanisms: first, as a sodium ion channel blocker, it can inhibit voltage-gated sodium currents, reduce the repeated release of electrical impulses by nerve cells, and thus reduce the excitability of neurons; second, as a positive allosteric modulator of γ-aminobutyric acid (GABA) receptors, it enhances the activity of GABA, further inhibits the transmission of nerve impulses, and exerts an anti-epileptic effect. Since it was approved for marketing by the US FDA in November 2019, phenbarate has shown significant clinical advantages in the treatment of focal epileptic seizures in adults, providing a new treatment option for patients with epilepsy.

[0003] Phenylbutanate is a crystalline powder, and the particle size of the original granules of the raw material medicine is relatively large, and the raw material medicine needs to be crushed and processed in the preparation process to achieve the purpose of rapid dissolution. However, the phenylbutanate raw material is prone to agglomeration after micronization, which not only affects the fluidity of the powder, but also may cause the inhomogeneity in the subsequent processing process, and then affects the content uniformity of the tablet. In addition, the dissolution rate of the existing phenylbutanate tablets is difficult to ensure that the drug is released rapidly and fully in vivo, so that the drug can not play a role in time, and limits the maximization of its clinical efficacy. Therefore, it is necessary to provide a tablet of the phenylbutanate tablets with a stable product quality, good content uniformity and short dissolution time, to improve the safety, effectiveness and stability of the drug, and provide a more high-quality and more reliable therapeutic drug for epilepsy patients. Summary of the invention

[0004] Aiming at the problems that the existing phenbarnate tablets have poor content uniformity and slow and uneven dissolution, which affect the quality and safety of the medicine, the present invention provides a phenbarnate tablet and a preparation method thereof.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] A phenbarate tablet comprising phenbarate, a filler, a binder, a disintegrant and a lubricant;

[0007] Wherein, the filler and the binder are both silicified microcrystalline cellulose, the total content of the filler and the binder is 76% to 84%, and the content of the disintegrant is 3% to 10%.

[0008] The phenbarate raw material is easy to agglomerate after micronization. The filler and the binder of the present invention are both silicified microcrystalline cellulose, which has good fluidity and anti-agglomeration properties, can effectively prevent the agglomeration of the phenbarate raw material after micronization, so that the powder maintains good fluidity, is convenient for subsequent processing steps such as mixing, granulation, and tableting, and improves the quality and consistency of the phenbarate tablets; at the same time, the silicified microcrystalline cellulose is used as a binder to form a strong binding force between particles, ensuring that the tablets maintain a complete physical form during the preparation and subsequent storage process, and are not prone to problems such as splitting and loosening. Compared with other hydrophilic binders, it will not hinder the dissolution of the drug due to excessive adhesion or forming a dense protective film on the surface of the drug, creating favorable conditions for the dissolution of the drug after disintegration; furthermore, through the synergistic effect of the specific content of the disintegrant and the binder, the phenbarate can be quickly and fully released into the gastrointestinal tract, ensuring that the drug can be absorbed in time, effectively improving the dissolution rate, and then ensuring that the drug can quickly exert a therapeutic effect, and achieving maximum clinical efficacy.

[0009] The phenbarate tablets provided by the present invention have high content uniformity, and can effectively ensure the stability of the therapeutic effect of phenbarate. At the same time, the phenbarate tablets provided by the present invention have a relatively fast dissolution rate. In a pH 1.2 medium, the dissolution amount can reach more than 85% in 15 minutes, so it is beneficial to the rapid disintegration and release of the drug in the gastrointestinal tract, thereby improving the bioavailability of the drug, which is particularly important for epileptic patients, because epileptic seizures are often sudden and unpredictable, and fast-acting drugs can control seizures more timely, reducing the pain and danger of patients.

[0010] Furthermore, the filler is silicified microcrystalline cellulose with a particle size of 190 μm to 300 μm; and the binder is silicified microcrystalline cellulose with a particle size of 100 μm to 180 μm.

[0011] Furthermore, the mass ratio of the adhesive to the filler is 1:2 to 1:5.

[0012] The preferred filler and binder, as well as the ratio of the two, can further increase the dissolution rate of the phenbarnac ester tablets.

[0013] Furthermore, the disintegrant is at least one of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose.

[0014] Furthermore, the disintegrant is cross-linked carboxymethyl cellulose sodium.

[0015] The preferred disintegrant can make the phenbarnate tablets disintegrate rapidly in a short time, thereby accelerating the release rate of the drug, improving the bioavailability of the drug, and enabling patients to obtain the therapeutic effect more quickly.

[0016] Furthermore, the lubricant is magnesium stearate.

[0017] Furthermore, the content of the lubricant is 0.5% to 1.5%.

[0018] Furthermore, the D90 of the phenbarnac ester is less than 500 μm.

[0019] Furthermore, the phenbarnate tablets also include a coating premix.

[0020] Exemplarily, the coating premix is ​​a gastric soluble film coating premix, and the coating weight gain is 3.0%.

[0021] The present invention also provides a method for preparing the above-mentioned phenbarnac ester tablets, comprising the following steps:

[0022] S1, mixing the prescribed amount of phenbarate, filler, binder and disintegrant uniformly, and sieving to obtain a premix;

[0023] S2, adding a lubricant to the premix and mixing evenly to obtain a total mixture;

[0024] S3, tabletting the total mixture, coating, and obtaining phenbarate tablets.

[0025] The preparation method of the phenbarnate tablets provided by the present invention adopts dry granulation, has a simple preparation process, and the prepared phenbarnate tablets have good stability, fast dissolution rate, and high content uniformity, can achieve a good replacement for the original product, and provide more drug options for epilepsy patients.

[0026] Furthermore, in S1, the aperture of the sieve for screening is 40 mesh.

[0027] The present invention uses silicified microcrystalline cellulose of specific particle size as a binder and a filler respectively, and cooperates with a specific content of a disintegrant and a lubricant to significantly improve the fluidity of micronized phenbarnate, improve the content uniformity and dissolution rate of the preparation, ensure that the patient can obtain a stable and accurate dose of the drug each time taking the drug, and can quickly relieve symptoms, and can achieve a good replacement for the original research product, thereby providing more drug options for epilepsy patients, reducing the drug cost of patients, and providing a reliable guarantee for the long-term drug use of epilepsy patients. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0029] In order to better illustrate the present invention, further examples are given below.

[0030] Example 1

[0031] This embodiment provides a phenbarnate tablet, and the prescription dosage is shown in the following table:

[0032]

[0033] The preparation method of the above-mentioned phenbarnac ester tablets is as follows:

[0034] S1, mixing the prescribed amount of phenbarate, filler, binder and disintegrant uniformly, and passing through a 40-mesh sieve to obtain a premix;

[0035] S2, mixing the premix and magnesium stearate to obtain a total mixture;

[0036] S3, tableting the total mixture to obtain plain tablets; coating the plain tablets with a gastric soluble film coating premix, with the coating weight gain being 3.0%, to obtain phenbarnate tablets.

[0037] Example 2

[0038] This embodiment provides a phenbarnate tablet, and the prescription dosage is shown in the following table:

[0039]

[0040] The preparation method of the above-mentioned phenbarnac ester tablets is as follows:

[0041] S1, mixing the prescribed amount of phenbarate, filler, binder and disintegrant uniformly, and passing through a 40-mesh sieve to obtain a premix;

[0042] S2, mixing the premix and magnesium stearate to obtain a total mixture;

[0043] S3, tableting the total mixture to obtain plain tablets; coating the plain tablets with a gastric soluble film coating premix, with the coating weight gain being 3.0%, to obtain phenbarnate tablets.

[0044] Example 3

[0045] This embodiment provides a phenbarnate tablet, and the prescription dosage is shown in the following table:

[0046]

[0047]

[0048] The preparation method of the above-mentioned phenbarnac ester tablets is as follows:

[0049] S1, mixing the prescribed amount of phenbarate, filler, binder and disintegrant uniformly, and passing through a 40-mesh sieve to obtain a premix;

[0050] S2, mixing the premix and magnesium stearate to obtain a total mixture;

[0051] S3, tableting the total mixture to obtain plain tablets; coating the plain tablets with a gastric soluble film coating premix, with the coating weight gain being 3.0%, to obtain phenbarnate tablets.

[0052] Example 4

[0053] This embodiment provides a phenbarnate tablet, and the prescription dosage is shown in the following table:

[0054]

[0055]

[0056] The preparation method of the above-mentioned phenbarnac ester tablets is as follows:

[0057] S1, mixing the prescribed amount of phenbarate, filler, binder and disintegrant uniformly, and passing through a 40-mesh sieve to obtain a premix;

[0058] S2, mixing the premix and magnesium stearate to obtain a total mixture;

[0059] S3, tableting the total mixture to obtain plain tablets; coating the plain tablets with a gastric soluble film coating premix, with the coating weight gain being 3.0%, to obtain phenbarnate tablets.

[0060] Example 5

[0061] This embodiment provides a phenbarnate tablet, and the prescription dosage is shown in the following table:

[0062]

[0063] The preparation method of the above-mentioned phenbarnac ester tablets is as follows:

[0064] S1, mixing the prescribed amount of phenbarate, filler, binder and disintegrant uniformly, and passing through a 40-mesh sieve to obtain a premix;

[0065] S2, mixing the premix and magnesium stearate to obtain a total mixture;

[0066] S3, tableting the total mixture to obtain plain tablets; coating the plain tablets with a gastric soluble film coating premix, with the coating weight gain being 3.0%, to obtain phenbarnate tablets.

[0067] Comparative Example 1

[0068] This comparative example provides a phenbarnate tablet, which is different from Example 4 only in that the filler and the binder are replaced with equal amounts of microcrystalline cellulose. The specific prescription is as follows:

[0069] Components effect mg / tablet Phenylbutyrate (D90 = 465 μm) Active ingredients 50 Microcrystalline cellulose 102 Fillers 266 Microcrystalline Cellulose 101 Adhesives 60 Croscarmellose Sodium Disintegrants 20 Magnesium Stearate Lubricants 4

[0070] The phenbarate tablets were prepared in exactly the same manner as in Example 4, which will not be described again.

[0071] Comparative Example 2

[0072] This comparative example provides a phenbarnate tablet, which is different from Example 4 only in that the filler is replaced by an equal amount of microcrystalline cellulose, and the binder is replaced by an equal amount of povidone. The specific prescription is as follows:

[0073]

[0074]

[0075] The phenbarate tablets were prepared in exactly the same manner as in Example 4, which will not be described again.

[0076] Comparative Example 3

[0077] This comparative example provides a phenbarnate tablet, which is different from Example 2 only in that the filler is replaced with an equal amount of lactose. The specific prescription is as follows:

[0078]

[0079] The phenbarate tablets were prepared in exactly the same manner as in Example 2, which will not be described again herein.

[0080] Comparative Example 4

[0081] This comparative example provides a phenbarnate tablet, which is different from Example 2 only in that the amount of filler and disintegrant is changed. The specific prescription is as follows:

[0082]

[0083]

[0084] The phenbarate tablets were prepared in exactly the same manner as in Example 2, which will not be described again herein.

[0085] Content uniformity testing

[0086] According to the provisions of the content uniformity test method of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the content uniformity of the phenbarnac ester tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 3 of the present invention was tested, and the results are shown in Table 1.

[0087] Table 1 Content uniformity

[0088]

[0089]

[0090] From the content uniformity results, it can be seen that the content difference between the phenbarnate tablets prepared in the embodiment of the present invention is less than 5%, and the product content uniformity is good, while the content difference between the phenbarnate tablets prepared in the comparative example is large, reaching about 10%, and the content uniformity is poor.

[0091] Sample content and related substances detection

[0092] The content and related substances of this product were detected by HPLC on the phenbarnac ester tablets prepared in Examples 1 to 5 of the present invention and Comparative Examples 1 to 4. The test results are shown in Table 2.

[0093] Table 2 Content and related substances

[0094]

[0095] Dissolution curve testing

[0096] According to the second method under the dissolution and release determination method of Part IV of the 202 edition of the Chinese Pharmacopoeia, a standard medium pH 1.0 hydrochloric acid medium was selected, and a paddle method was used at 75r / min to investigate the dissolution curves of the phenbarate tablets prepared in Examples 1 to 5 of the present invention and Comparative Examples 1 to 4. The dissolution samples were tested by HPLC, and the results are shown in Table 3.

[0097] Table 3 Dissolution curve

[0098] Sample / Time 5min 10min 15min 20min 30min 45min Example 1 60 90 98 98 98 98 Example 2 64 93 99 99 99 99 Example 3 66 96 98 99 99 99 Example 4 70 96 99 99 99 99 Example 5 51 78 87 94 99 99 Original research products 53 82 90 92 95 97 Comparative Example 1 35 58 73 80 85 88 Comparative Example 2 38 68 77 82 85 91 Comparative Example 3 43 73 81 86 91 94 Comparative Example 4 42 71 79 87 90 95

[0099] As a result, the dissolution amount of the phenbarnac ester tablets prepared in Examples 1 to 4 of the present invention in 15 min is higher than 85%. After changing the ratio of the binder and the filler in Example 5, the dissolution rate slows down, which is equivalent to the original dissolution rate. It can be seen that the present invention controls the ratio of the filler and the binder to 1:2 to 1:5, which helps to improve the dissolution rate. In Comparative Examples 1 to 3, changing the filler and the binder to other commonly used binders and fillers in the art, and reducing the amount of the disintegrant in Comparative Example 4, all lead to a decrease in the dissolution rate.

[0100] In summary, the phenbarnate tablets provided by the present invention have fewer types of auxiliary materials and simple process, which solves the problem of poor content uniformity in the preparation process of existing phenbarnate preparation products. In addition, the product also has rapid dissolution performance, which is conducive to quickly relieving the symptoms of epilepsy patients, and provides a safe and stable drug for epilepsy patients, which has a high application prospect in the field of epilepsy treatment.

[0101] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A phenbarnate tablet, characterized in that: including phenbarnate, fillers, binders, disintegrants and lubricants; Wherein, the filler and the binder are both silicified microcrystalline cellulose, the total content of the filler and the binder is 76% to 84%, and the content of the disintegrant is 3% to 10%.

2. The phenbarnate tablet according to claim 1, wherein The filler is silicified microcrystalline cellulose with a particle size of 190 μm to 300 μm; the binder is silicified microcrystalline cellulose with a particle size of 100 μm to 180 μm.

3. The phenbarnate tablet according to claim 2, characterized in that The mass ratio of the adhesive to the filler is 1:2 to 1:

5.

4. The phenbarnate tablet according to claim 1, wherein The disintegrant is at least one of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose.

5. The phenbarnate tablet according to claim 4, characterized in that: The disintegrant is cross-linked carboxymethyl cellulose sodium.

6. The phenbarnate tablet according to claim 1, characterized in that The lubricant is magnesium stearate.

7. The phenbarnate tablet according to claim 6, characterized in that: The content of the lubricant is 0.5% to 1.5%.

8. The phenbarnate tablet according to any one of claims 1 to 7, characterized in that: The D90 of the phenbarate is less than 500 μm.

9. The phenbarnate tablet according to any one of claims 1 to 7, characterized in that: The phenbarnate tablets also include a coating premix.

10. The method for preparing the phenbarnate tablets according to any one of claims 1 to 9, characterized in that: The steps include: S1, mixing the prescribed amount of phenbarate, filler, binder and disintegrant uniformly, and sieving to obtain a premix; S2, adding a lubricant to the premix and mixing evenly to obtain a total mixture; S3, tabletting the total mixture, coating, and obtaining phenbarate tablets.

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