A isoniazid tablet and a preparation method thereof

Abstract

The present application relates to the technical field of medicine preparation, more particularly to a kind of isoniazid tablets and preparation method thereof.The weight percentage of the main drug and auxiliary material of the isoniazid tablet is as follows: the main drug is 60% to 80%, the filling agent is 15% to 30%, the binder is 1% to 10%, the disintegrating agent is 1% to 5% and the lubricant is 0.5% to 5%.The present application adopts corn starch as filling agent and binder, pre-gelatinized starch as filling agent, sodium carboxymethyl starch as disintegrating agent to carry out wet granulation process for tablet pressing, adopts oral solid high-density polyethylene bottle for packaging of the preparation, and the related substances of self-made product and reference preparation have no change under the condition of accelerated test for 6 months compared with 0 month.The granules prepared by the present application have uniform particle size, good flowability and compression forming property, low defective rate, excellent tablet core disintegration performance, and the prepared medicine is more stable by adopting oral solid pharmaceutical high-density polyethylene bottle for packaging.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine preparation, more particularly, to a kind of isoniazid tablet and preparation method thereof. BACKGROUND

[0002] Isoniazid is a synthetic antibacterial drug with bactericidal effect, which is only effective on mycobacteria, mainly bacteria in growth and reproduction period, and its mechanism of action has not been elucidated. It is often combined with other antituberculosis drugs for the treatment of all types of tuberculosis, including tuberculous meningitis and other mycobacterial infections. Common side effects include indigestion and peripheral neuritis symptoms such as numbness or finger pain.

[0003] The original research and business of the product is SANDOZ, which was first marketed in the United States in 1952 under the trade name ISONIAZID. Its reference formulation in FDA is two kinds of tablets with content of 100mg and 300mg.

[0004] The molecular formula of isoniazid is C6H7N3O, and the molecular weight is 137.14, and the structural formula is:

[0005]

[0006] Chinese invention patent document publication number CN109953956A discloses a preparation method of isoniazid tablet: 1) the mass fraction of main components is: isoniazid 50 parts, medicinal starch 20 parts, medicinal starch (for beating) 0.5 parts, and magnesium stearate 0.21 parts; 2) the starch for beating is mixed with a small amount of purified water to form a paste, and then sufficient boiling purified water is slowly added to prepare starch slurry; 3) isoniazid is mixed with medicinal starch for 15 minutes, then the above starch slurry is added and mixed for 10 minutes, and then passed through a 16-mesh sieve; 4) the temperature is 60-65℃, and the drying time is 4 hours; after the particles are made with a 16-mesh sieve, magnesium stearate is added and mixed for 15 minutes; 5) 5.5 shallow concave round punch is used, and the hydraulic pressure is about 44KN for tabletting. In the prescription of the patent, only medicinal starch is used as a filler and a disintegrant, and the amount is large. Ordinary starch has poor compressibility, and the tablets are easy to break. High concentration is easy to crack, which is not conducive to the quality control of the medicine, thereby affecting the safety of the patient. SUMMARY

[0007] The present application aims to at least solve one of the technical problems existing in the prior art. Therefore, one aspect of the present application aims to provide an isoniazid tablet, wherein the weight percentage of the main drug and excipients is: the main drug is 60%-80%, the filler is 15%-30%, the binder is 1%-10%, the disintegrant is 1%-5%, and the lubricant is 0.5%-5%.

[0008] Preferably, the main drug is isoniazid, the filler is corn starch and pre-gelatinized starch, the binder is corn starch, the disintegrant is sodium starch glycolate, and the lubricant is magnesium stearate; the corn starch is 10% to 20%, and the pre-gelatinized starch is 5% to 10%.

[0009] Another aspect of the present application aims to provide a preparation method of isoniazid tablets, and the specific steps of the preparation method are as follows:

[0010] S1. crushing and sieving the raw material main drug;

[0011] S2. mixing the main drug, the filler and the disintegrant crushed and sieved in S1 in a wet mixing granulator, granulating by spraying the binder, and wet granulating to obtain wet granules;

[0012] S3. drying the wet granules obtained in S2 in a multifunctional boiling granulator, and granulating by a granulator to obtain dry granules;

[0013] S4. mixing the dry granules obtained in S3 and the lubricant in a double-pinch square-cone mixer to obtain total mixed granules, and testing the semi-finished product;

[0014] S5. placing the semi-finished product tested in S4 in a high-speed tablet press to obtain isoniazid tablets;

[0015] S6. sealing and packaging the tablets in S5 in a bottle filling machine to obtain isoniazid tablet finished products.

[0016] Preferably, the crushing in S1 is through a 60-mesh sieve.

[0017] Preferably, the mixing speed in S2 is 150 rpm, the granulating cutter speed is 1500 rpm, and the mixing time is 300 s.

[0018] Preferably, the granulating speed in S2 is 100 rpm, the cutter speed is 1500 rpm, the granulating time is 60 s, the wet granulating is through a 6*6 mm stainless steel screen with a speed of 500 rpm.

[0019] Preferably, the frequency of the fan in the multifunctional boiling granulator in S3 is controlled to be 35 HZ to 40 HZ, the air inlet temperature is 50℃±5℃, the material temperature is 38℃±2℃, and the moisture content is ≤3.0%, and the granulator is passed through a 1.5 mm stainless steel screen with a speed of 500 rpm.

[0020] Preferably, the mixing speed in S4 is 10 rpm, and the mixing time is 300 s.

[0021] Preferably, the S5 standard for tabletting is 0.135g per tablet, using Φ6.5mm shallow concave punch, the main pressure of the tablet machine is 10KN-50KN, and the hardness control is 30N-80N.

[0022] Preferably, the S6 packaging material is an oral solid pharmaceutical high-density polyethylene bottle, and the tablet is placed in the packaging machine for packaging.

[0023] The present application has the following beneficial effects:

[0024] The present application adopts corn starch as a filler and a binder, pre-gelatinized starch as a filler, sodium carboxymethyl starch as a disintegrant, and a wet granulation process for tabletting, and an oral solid high-density polyethylene bottle for packaging. The related substances of the self-prepared product and the reference preparation under accelerated test conditions for 6 months have no change compared with 0 months. The granules prepared by the present application have uniform particle size, good flowability and compression forming property, low defective rate, excellent tablet core disintegration performance, and the prepared medicine is more stable when packaged in an oral solid pharmaceutical high-density polyethylene bottle.

[0025] The process steps of the present application are short, the operation is more simple and convenient, the product yield is improved, and the production cost is reduced, which is suitable for industrial large-scale production.

[0026] Additional aspects and advantages of the present application will become apparent in the light of the following description and accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0027] The above and / or additional aspects and advantages of the present application will become apparent and be readily understood from the following description, taken in conjunction with the accompanying drawings, in which:

[0028] Figure 1 is the dissolution curve graph of Example One of the present application and the reference preparation in hydrochloric acid and pH4.5 buffer solution;

[0029] Figure 2 is the dissolution curve graph of Example One of the present application and the reference preparation in pH6.8 buffer solution and water;

[0030] Figure 3 is the dissolution curve graph of Example Two of the present application and the reference preparation in hydrochloric acid and pH4.5 buffer solution;

[0031] Figure 4 is the dissolution curve graph of Example Two of the present application and the reference preparation in pH6.8 buffer solution and water;

[0032] Figure 5 is the dissolution curve graph of Example Three of the present application and the reference preparation in hydrochloric acid and pH4.5 buffer solution;

[0033] Figure 6is the dissolution curve of Example 3 of the present application and the reference preparation in pH 6.8 buffer and water. DETAILED DESCRIPTION

[0034] In order to more clearly understand the above-mentioned purposes, features and advantages of the present application, the present application will be further described in detail below with reference to the accompanying drawings and specific examples. It should be noted that the examples of the present application and the features in the examples can be combined with each other without conflict.

[0035] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present application, however, the present application can also be implemented in other different ways from the description, therefore, the protection scope of the present application is not limited by the specific examples disclosed below.

[0036] Example 1

[0037] Prescription information:

[0038]

[0039] Preparation method:

[0040] S1. Crush isoniazid through a 60-mesh sieve.

[0041] S2. Place the crushed isoniazid, corn starch, pregelatinized starch and sodium carboxymethyl starch into a LHSZ-300 whole-granule wet mixing granulator, control the rotating speed at 150 rpm, the granulating cutter rotating speed at 1500 rpm, the mixing time at 300 s, the granulating at the rotating speed of 100 rpm, the cutter rotating speed at 1500 rpm, the granulating time at 60 s, the wet whole-granulating at the stainless steel screen mesh of 6*6 mm, the rotating speed at 500 rpm to obtain wet granules;

[0042] S3. Place the wet granules into an FBW80 multifunctional boiling granulator, control the fan frequency at 35 HZ~40 HZ, the air inlet temperature at 50℃±5℃, the material temperature at 38℃±2℃, the moisture content at ≤3.0%, pass through a 1.5 mm stainless steel screen mesh in the whole-granulator at the rotating speed of 500 rpm to obtain dry granules;

[0043] S4. Place the obtained dry granules and magnesium stearate into a HZD2000 double-pinch square-cone mixer, control the rotating speed at 10 rpm, the mixing time at 300 s to obtain total mixed granules, and inspect the semi-finished product;

[0044] S5. Place the inspected semi-finished product into a GZPS-73 high-speed tablet press to press tablets with a Φ6.5 mm shallow concave punch die, the main pressure of the tablet press is 10 KN~50 KN, the hardness is controlled at 30 N~80 N to obtain isoniazid tablets;

[0045] S6. The tablets are placed in a BZ-120 III bottling machine to seal and package the tablets in high-density polyethylene bottles for oral administration, to obtain the finished product of isoniazid tablets.

[0046] Example 2

[0047] Prescription information:

[0048]

[0049] Preparation method:

[0050] S1. Isoniazid is ground to pass through a 60-mesh sieve.

[0051] S2. The ground isoniazid, corn starch, pregelatinized starch, and sodium carboxymethyl starch are placed in an LHSZ-300 whole-granule wet mixing granulator, the rotating speed is controlled at 150 rpm, the rotating speed of the granulating cutter is 1500 rpm, the mixing time is 300 s, the granulating is performed at a rotating speed of 100 rpm and a cutter rotating speed of 1500 rpm for 60 s, and the wet whole granulation is performed at a rotating speed of 500 rpm to obtain wet granules;

[0052] S3. The wet granules are placed in an FBW80 multifunctional boiling granulator, the frequency of the fan is controlled at 35-40 HZ, the air inlet temperature is 50°C ± 5°C, the material temperature reaches 38°C ± 2°C, and the moisture content is ≤3.0%; the whole granulator is passed through a 1.5 mm stainless steel screen at a rotating speed of 500 rpm to obtain dry granules;

[0053] S4. The obtained dry granules and magnesium stearate are placed in an HZD2000 double-pinch square-cone mixer, the rotating speed is controlled at 10 rpm, and the mixing time is 300 s to obtain total mixed granules for inspection of the semi-finished product;

[0054] S5. The inspected semi-finished product is placed in a GZPS-73 high-speed tablet press to press tablets using a Φ6.5 mm shallow concave punch, the main pressure of the tablet press is 10-50 KN, the hardness is controlled at 30-80 N, and isoniazid tablets are obtained.

[0055] S6. The tablets are placed in a BZ-120 III bottling machine to seal and package the tablets in high-density polyethylene bottles for oral administration, to obtain the finished product of isoniazid tablets.

[0056] Example 3

[0057] Prescription information:

[0058]

[0059] Preparation method:

[0060] S1. Isoniazid is ground to pass through a 60-mesh sieve.

[0061] S2. The crushed and sieved isoniazid, corn starch and sodium carboxymethyl starch were placed in the LHSZ-300 whole-granule wet mixing granulator, the rotating speed was controlled at 150 rpm, the rotating speed of the granulating knife was 1500 rpm, the mixing time was 300 s, the granulating was at a rotating speed of 100 rpm, the rotating speed of the knife was 1500 rpm, the granulating time was 60 s, the wet granulation was obtained by using a 6*6 mm stainless steel screen at a rotating speed of 500 rpm;

[0062] S3. The wet granulation was placed in the FBW80 multifunctional boiling granulator, the frequency of the fan was controlled at 35 HZ~40 HZ, the inlet air temperature was 50℃±5℃, the material temperature reached 38℃±2℃, the moisture content was ≤3.0%; the whole-granulation was obtained by passing through a 1.5 mm stainless steel screen at a rotating speed of 500 rpm, to obtain dry granulation;

[0063] S4. The obtained dry granulation and magnesium stearate were placed in the HZD2000 double-pinch square-cone mixer, the rotating speed was controlled at 10 rpm, the mixing time was 300 s, to obtain the total mixed granulation, and the semi-finished product was tested;

[0064] S5. The tested semi-finished product was placed in the GZPS-73 high-speed tablet press, and tablets were pressed by using a Φ6.5 mm shallow concave punch, the main pressure of the tablet press was 10 KN~50 KN, the hardness was controlled at 30 N~80 N, to obtain isoniazid tablets;

[0065] S6. The tablets were placed in the BZ-120 III bottling machine, and the high-density polyethylene bottles for oral solid drugs were sealed and packaged, to obtain isoniazid tablet finished products.

[0066] Fragility determination:

[0067] The product was detected according to the 0923 tablet fragility detection method in the 2020 edition of Chinese Pharmacopoeia, and the fragility results are shown in Table 1.

[0068] Table 1. Comparison table of fragility results of Example 1, Example 2 and Example 3

[0069]

[0070] Example 2 (batch number: G201202Y) prepared with water as a wetting agent had a tablet core fragility that did not meet the pharmacopoeia requirements (the 2020 edition of Chinese Pharmacopoeia stipulates that the weight loss shall not exceed 1%), and Example 1 (batch number: G201201Y) and Example 3 (batch number: G201203Y) both met the pharmacopoeia requirements.

[0071] Dissolution determination:

[0072] The dissolution of the sample was determined according to the method for determining the dissolution of isoniazid tablets in the 2020 edition of Chinese Pharmacopoeia, the medium was hydrochloric acid, pH 4.5 buffer, pH 6.8 buffer and water, respectively, and the dissolution of the reference preparation sample of the product (Batch No.: 34033104A) was compared. The dissolution results are shown in Tables 2 to 7, and the dissolution curves are shown in Figures 1 to 6 .

[0073] Table 2. Comparison of dissolution results of Example 1 and reference preparation in hydrochloric acid and pH 4.5 medium

[0074]

[0075] Table 3. Comparison of dissolution results of Example 1 and reference preparation in pH 6.8 medium and water medium

[0076]

[0077] Table 4. Comparison of dissolution results of Example 2 and reference preparation in hydrochloric acid and pH 4.5 medium

[0078]

[0079] Table 5. Comparison of dissolution results of Example 2 and reference preparation in pH 6.8 medium and water medium

[0080]

[0081]

[0082] Table 6. Comparison of dissolution results of Example 3 and reference preparation in hydrochloric acid and pH 4.5 medium

[0083]

[0084] Table 7. Comparison of dissolution results of Example 3 and reference preparation in pH 6.8 medium and water medium

[0085]

[0086] The dissolution of Example 1 and Example 2 is completely consistent with the reference preparation, and the dissolution of Example 3 is significantly slower than the reference preparation.

[0087] Example 1 is simple, feasible and easy to realize industrial large-scale production.

[0088] The stability of the product of the present application was studied:

[0089] ​According to the Guiding Principles for Stability Test of Raw Materials and Pharmaceutical Preparations in Chinese Pharmacopoeia 2020 Edition Volume IV (9001), the samples of Example 1, Example 2 and Example 3 were placed under accelerated test conditions (40℃±2℃, RH 75%±5%) for 6 months. The change trend of the related substances of the samples was investigated, and the data were compared with those at 0 day. The results of the related substances of the samples of each batch are shown in Table 8.

[0090] The wet granulation process using corn starch as a filler and a binder, pre-gelatinized starch as a filler, and sodium carboxymethyl starch as a disintegrant was used for tabletting. The preparation was packaged in oral solid high-density polyethylene bottles. The self-prepared product and the reference preparation were placed under accelerated test conditions for 6 months. The related substances were not changed compared with those at 0 month.

[0091] Table 8. Results of related substances under different sample storage conditions

[0092]

[0093]

[0094] The related substances of Example 1 and Example 2 placed under accelerated test conditions for 6 months were not changed compared with those at 0 month. The other single impurities and total impurities of Example 3 significantly increased.

[0095] The test results showed that the dissolution behavior of Example 1 and the reference preparation in hydrochloric acid, pH 4.5 buffer, pH 6.8 buffer and water medium was similar to that of the reference preparation. The related substances of Example 1 and the reference preparation placed under accelerated test conditions for 6 months were not changed compared with those at 0 month. This indicated that the wet granulation process using corn starch as a filler and a binder, pre-gelatinized starch as a filler, and sodium carboxymethyl starch as a disintegrant was used for tabletting. The preparation was packaged in oral solid high-density polyethylene bottles. The quality of the self-prepared product was similar to that of the reference preparation.

[0096] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A tablet of isoniazid, characterized in that: The weight percentage of the main drug and excipients of the isoniazid tablet is as follows: the main drug isoniazid is 60-80%, the filler corn starch is 10-20%, the filler pregelatinized starch is 5-10%, the binder corn starch is 1-10%, the disintegrant sodium carboxymethyl starch is 1-5%, and the lubricant magnesium stearate is 0.5-5%. The specific steps of the preparation method are as follows: S1. crushing the raw material main drug and sieving; S2. placing the main drug, filler and disintegrant crushed and sieved in S1 into a wet mixing granulator, mixing uniformly, then spraying the binder to granulate and wet granulating to obtain wet granules; S3. drying the wet granules obtained in S2 in a multifunctional boiling granulator, and granulating in a granulator to obtain dry granules; S4. placing the dry granules obtained in S3 and the lubricant into a pair of square cone mixers, mixing uniformly to obtain total mixed granules, and testing the semi-finished product; S5. placing the semi-finished product tested in S4 into a high-speed tablet press to press the tablet, and obtaining isoniazid tablets; S6. placing the tablets in S5 into a bottle filling machine to seal and package, and obtaining isoniazid tablet finished product; The crushing in S1 is sieved through a 60-mesh sieve.

2. A process for the preparation of isoniazid tablets as claimed in claim 1, wherein: The mixing speed of the main drug, filler and disintegrant in S2 is 150 rpm, the granulating knife rotating speed is 1500 rpm, and the mixing time is 300 s.

3. A process for the preparation of isoniazid tablets as claimed in claim 1, wherein: The spraying speed of the binder in S2 is 100 rpm, the cutting knife rotating speed is 1500 rpm, and the granulating time is 60 s; the wet granulating is 6*6 mm stainless steel screen, and the rotating speed is 500 rpm.

4. A process for the preparation of isoniazid tablets as claimed in claim 1, wherein: The frequency of the fan in the multifunctional boiling granulator in S3 is controlled at 35-40 HZ, the air inlet temperature is 50℃±5℃, the material temperature is 38℃±2℃, and the moisture content is ≤3.0%; the granulator is sieved through a 1.5 mm stainless steel screen, and the rotating speed is 500 rpm.

5. The process for the preparation of isoniazid tablets as claimed in claim 1 wherein: The mixing speed in S4 is 10 rpm, and the mixing time is 300 s.

6. The process for the preparation of isoniazid tablets as claimed in claim 1 wherein: The standard of tabletting in S5 is 0.135 g per tablet, and the tablet is pressed by Φ6.5 mm shallow concave punch, the main pressure of the tablet press is 10-50 KN, and the hardness is controlled at 30-80 N.

7. The process for the preparation of isoniazid tablets as claimed in claim 1 wherein: The packaging material in S6 is oral solid drug high-density polyethylene bottle, and the tablet is packaged in the packaging machine.

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