Rifapentine isoniazide tablet and preparation method thereof
By designing a chip-in-package structure, the incompatibility issue between rifapentine and isoniazid was resolved, enhancing drug compliance and safety, and ensuring drug stability and efficacy.
Patent Information
- Application Number
- CN202511529661.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-24
- Publication Date
- 2025-12-19
AI Technical Summary
When rifapentine and isoniazid are used in combination, there are incompatibility issues, leading to increased impurities and potential drug safety risks. In addition, patients need to take two formulations, resulting in poor compliance.
It adopts a chip-and-tablet structure, with the inner core containing rifapentine and specific excipients, and the outer core containing isoniazid and excipients. The three-layer structure design solves incompatibility and ensures drug adherence.
This approach achieves compatibility between rifapentine and isoniazid, reduces impurity generation, and improves patient adherence and drug safety.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of medicine, more particularly to a rifapentine isoniazid tablet and a preparation method thereof. BACKGROUND
[0002] Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB) infection, but most of the people infected with MTB are in a latent tuberculosis infection (LTBI) state. Because there is no typical clinical manifestation, it is easy to miss diagnosis and has the risk of developing into active tuberculosis (ATB). Preventive treatment for LTBI is to prevent the development of active tuberculosis in the process of further deterioration of LTBI. Latent tuberculosis infection refers to the state that the human body reacts to the infection of Mycobacterium tuberculosis, but no obvious pathological damage and clinical manifestations occur. Among them, 5%-10% of LTBI patients may develop the disease in their lifetime, usually within 5 years after the first infection.
[0003] Early treatment is a crucial link in preventing the further deterioration of LTBI. Isoniazid, as an antibiotic, is a key drug for the treatment of pulmonary tuberculosis and the first drug proven to prevent the development of active pulmonary tuberculosis from LTBI. However, due to the consideration of adverse reactions such as liver toxicity of the drug and low compliance of patients requiring long-term treatment leading to drug resistance, USPSTF recommends shortening the treatment course of the drug and using it in combination with other drugs such as rifapentine and rifampicin. Through combination therapy, the dose of a single drug is reduced, thereby reducing side effects, improving treatment effect, and reducing drug resistance. The specific treatment regimen is isoniazid and rifapentine once a week for 3 months (3H-P), which has been proven to be more effective than single-drug therapy and may reduce adverse reactions such as liver toxicity.
[0004] Currently, there are separate rifapentine and isoniazid preparations on the market. When the two preparations are used in combination, the patient needs to take two preparations, and the time is long, and there is a problem of missed or mistaken taking. In order to ensure the effect of prevention and treatment, rifapentine and isoniazid are pressed into one tablet to enhance the compliance of patients. There are already rifapentine / rifampicin and isoniazid compound preparations on the market, among which the degradation product 3-formylrifamycin of rifapentine / rifampicin easily reacts with isoniazid to form 3-formylrifamycin isoniazide, which has the problem of incompatibility. Therefore, there is no good way for the commercially available preparations to solve the incompatibility problem of rifapentine and isoniazid, which increases impurities and increases the safety hazard of the use of compound preparations.
[0005] Therefore, there is an urgent need for a new type of rifapentine isoniazid compound preparation to solve the above problems. SUMMARY
[0006] In order to solve the above problems, the present application provides a rifapentine isoniazid tablet and a preparation method thereof, which solves the inconvenience of taking two preparations when rifapentine and isoniazid are used in combination, increases the drug compliance, and solves the compatibility between rifapentine and isoniazid.
[0007] In one aspect, the present application discloses a rifapentine isoniazid tablet, which is a core-in tablet and comprises an inner tablet core containing rifapentine and an outer tablet layer containing isoniazid. The inner tablet core comprises rifapentine, disodium edetate, vitamin C sodium and sodium lauryl sulfate, the mass of rifapentine accounts for 53%-63% of the total mass of the inner tablet core, and further comprises a filler accounting for 20%-50% of the total mass of the inner tablet core, a stabilizer accounting for 0.5%-5% of the total mass of the inner tablet core, a disintegrant accounting for 0.1%-5% of the total mass of the inner tablet core, a binder accounting for 0.5%-5% of the total mass of the inner tablet core, a surfactant accounting for 0.1%-0.5% of the total mass of the inner tablet core, a lubricant accounting for 0.25%-2% of the total mass of the inner tablet core and a coating layer accounting for 2%-4% of the total mass of the inner tablet core. The coating layer covers the inner tablet core. The outer tablet layer comprises isoniazid, a filler accounting for 1%-10% of the total mass of the outer tablet layer, a disintegrant accounting for 1-8% of the total mass of the outer tablet layer, a binder accounting for 0.5%-5% of the total mass of the outer tablet core, a lubricant accounting for 0.2-2% of the total mass of the outer tablet layer and a binder accounting for 2%-8% of the total mass of the outer tablet core, and the mass of isoniazid accounts for 75%-95% of the total mass of the outer tablet layer.
[0008] Preferably, the filler in the inner tablet core is one or more of microcrystalline cellulose, lactose and pre-gelatinized starch; the stabilizer is one or more of calcium carbonate, magnesium carbonate and magnesium oxide; the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone and sodium carboxymethyl starch; the binder is hydroxypropyl cellulose and / or povidone K30; the surfactant is one or more of polysorbate 80, poloxamer, sodium lauryl sulfate and Span 20; the lubricant is calcium stearate and / or hard calcium fumarate; and the material of the coating layer is a combination of titanium dioxide, talc, polyethylene glycol, hydroxypropyl methyl cellulose or polyvinyl alcohol.
[0009] Preferably, the filler in the outer tablet layer is one or more of microcrystalline cellulose, pre-gelatinized starch, anhydrous dibasic calcium phosphate and corn starch; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and povidone; and the lubricant is hard calcium fumarate, calcium stearate and / or colloidal silicon dioxide.
[0010] Preferably, 1000 rifapentine isoniazid tablets are prepared from the following components: Inner tablet core: rifapentine 300g, microcrystalline cellulose 121.2g, pregelatinized starch 68g, sodium ascorbate 6.24g, disodium edetate 0.52g, sodium lauryl sulfate 1.04g, hydroxypropyl cellulose EXF 10.2g, sodium carboxymethyl starch 0.8g; additional excipients: calcium stearate 7.8g, sodium carboxymethyl starch 20g; Coating layer: hypromellose E5 24g, polyethylene glycol 4g; Outer tablet layer: isoniazid 300g, povidone 13.2g, calcium stearate 5.3g, pregelatinized starch 23.4g.
[0011] In another aspect, the present application also discloses a preparation method of the rifapentine isoniazid tablet, comprising the following steps: S1, mixing the materials of the inner tablet core and dry granulating, tabletting, and then coating to obtain the inner tablet core containing rifapentine; the mass of rifapentine accounts for 53%-63% of the total mass of the inner tablet core; S2, mixing the materials of the outer tablet layer to obtain the outer tablet layer; S3, tabletting the outer tablet layer and the inner tablet core to obtain the rifapentine isoniazid tablet.
[0012] Preferably, in step S1, the parameters of dry granulation are as follows: oil pressure 45±10 bar; feeding rate 10-40 rpm; whole granulation rate 80-120 rpm; crushing rate 80-120 rpm; and roller gap 0.8-1.3 mm.
[0013] Preferably, the parameters of tabletting are as follows: tabletting main pressure 12-18 KN; the weight difference of the tabletting process is controlled to be ±5.0%, the average hardness range of 10 tablets is 40-70 N, the disintegration time is ≤5 min, and the friability loss weight is ≤1.0%.
[0014] Preferably, the coating parameters are as follows: tablet bed temperature 35±2℃; and atomization pressure 0.2-0.4 mbar.
[0015] Compared with the prior art, the rifapentine isoniazid tablet has the following beneficial effects: The rifapentine isoniazid tablet disclosed by the present application can perfectly solve the problem of incompatibility of rifapentine and isoniazid.
[0016] The rifapentine isoniazid tablet disclosed by the present application enhances the compliance of patients. Meanwhile, the problem of incompatibility of rifapentine and isoniazid and the safety hazard problem of impurity increase are solved, because the rifapentine isoniazid tablet utilizes the three-layer structure, so that after the patient takes the medicine, the isoniazid in the outermost layer is degraded first, then the coating layer, and finally the rifapentine, thereby reducing the generation of impurities. DETAILED DESCRIPTION
[0017] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments of the present application.
[0018] The present application discloses a rifapentine isoniazid tablet, which is a core-in tablet, comprising an inner tablet core containing rifapentine and an outer tablet layer containing isoniazid.
[0019] The inner tablet core comprises rifapentine, disodium edetate, vitamin C sodium and sodium lauryl sulfate, the mass of rifapentine accounts for 53%-63% of the total mass of the inner tablet core, and further comprises a filler accounting for 20%-50% of the total mass of the inner tablet core, a stabilizer accounting for 0.5%-5% of the total mass of the inner tablet core, a disintegrant accounting for 0.1%-5% of the total mass of the inner tablet core, a binder accounting for 0.5%-5% of the total mass of the inner tablet core, a surfactant accounting for 0.1%-0.5% of the total mass of the inner tablet core, a lubricant accounting for 0.25%-2% of the total mass of the inner tablet core and a coating layer accounting for 2%-4% of the total mass of the inner tablet core.
[0020] The coating layer covers the inner tablet core.
[0021] The outer tablet layer comprises isoniazid, a filler accounting for 1%-10% of the total mass of the outer tablet layer, a disintegrant accounting for 1-8% of the total mass of the outer tablet layer, a binder accounting for 0.5%-5% of the total mass of the outer tablet core, a lubricant accounting for 0.2-2% of the total mass of the outer tablet layer and a binder accounting for 2%-8% of the total mass of the outer tablet core; the mass of isoniazid accounts for 75%-95% of the total mass of the outer tablet layer.
[0022] The filler in the inner tablet core is one or more of microcrystalline cellulose, lactose and pre-gelatinized starch; the stabilizer is one or more of calcium carbonate, magnesium carbonate and magnesium oxide; the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone and sodium carboxymethyl starch; the binder is hydroxypropyl cellulose and / or povidone K30; the surfactant is one or more of polysorbate 80, poloxamer, sodium lauryl sulfate and Span 20; the lubricant is calcium stearate and / or hard calcium fumarate; and the material of the coating layer is a combination of titanium dioxide, talc powder, polyethylene glycol, hydroxypropyl methyl cellulose or polyvinyl alcohol.
[0023] The filler in the outer tablet layer is one or more of microcrystalline cellulose, pre-gelatinized starch, anhydrous calcium hydrogen phosphate and corn starch; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and povidone; and the lubricant is hard calcium fumarate, calcium stearate and / or colloidal silicon dioxide.
[0024] The application further discloses a preparation method of the rifapentine isoniazid tablet. S1, mixing materials of the inner layer tablet core, dry granulation, tabletting, and coating to obtain the inner layer tablet core containing rifapentine; the mass of rifapentine accounts for 53%-63% of the total mass of the inner layer tablet core; S2, mixing materials of the outer layer tablet layer to obtain the outer layer tablet layer; S3, tabletting the outer layer tablet layer and the inner layer tablet core to obtain the rifapentine isoniazid tablet.
[0025] In step S1, parameters of the dry granulation are as follows: oil pressure 45±10 bar; feeding rate 10-40 rpm; whole granulation rate 80-120 rpm; crushing rate 80-120 rpm; and roller gap 0.8-1.3 mm.
[0026] Parameters of the tabletting are as follows: main pressure 12-18 KN; the weight difference of the tabletting process is controlled to be ±5.0%, the average hardness of 10 tablets is in the range of 40-70 N, the disintegration time is ≤5 min, and the friability is ≤1.0%.
[0027] Parameters of the coating are as follows: tablet bed temperature 35±2 ℃; and atomization pressure 0.2-0.4 mbar.
[0028] The application is further described below through specific examples.
[0029] Example 1 The example discloses a prescription and a preparation method of 1000 rifapentine isoniazid tablets.
[0030] The 1000 rifapentine isoniazid tablets are prepared from the following components: The inner layer tablet core contains rifapentine 300 g, microcrystalline cellulose 121.2 g, pre-gelatinized starch 68 g, sodium ascorbate 6.24 g, disodium edetate 0.52 g, sodium dodecyl sulfate 1.04 g, hydroxypropyl cellulose EXF 10.2 g, and sodium carboxymethyl starch 0.8 g; and additional excipients contain calcium stearate 7.8 g and sodium carboxymethyl starch 20 g. The coating layer contains hydroxypropyl methyl cellulose E5 24 g and polyethylene glycol 4 g. The outer layer tablet layer contains isoniazid 300 g, povidone 13.2 g, and calcium stearate 5.3 g.
[0031] During the preparation, the sodium ascorbate, the disodium edetate, the sodium dodecyl sulfate and the hydroxypropyl cellulose EXF are respectively sieved through a 60-mesh sieve, and then the above materials are sieved through a 40-mesh sieve, mixed for three times and used.
[0032] The above mixed material and the prescribed amount of rifapentine, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch are then mixed for 3 times through a 20-mesh screen, and then dry granulation is performed at an oil pressure of 45±10 bar, a feeding rate of 10-40 rpm, a whole-granulation rate of 80-120 rpm, a crushing rate of 80-120 rpm, and a compression roller gap of 0.9-1.1 mm, and the granules are collected. The additional excipient sodium carboxymethyl starch is added to the granules, and a three-dimensional mixer is used at 8 rpm for 10 min, and then the additional excipient calcium stearate is added, and a three-dimensional mixer is used at 8 rpm for 5 min. Finally, the tablets are compressed, and the main compression pressure is 12-18 KN, and the weight difference during the compression process is controlled to be ±3.0%, and the hardness range is 40-70 N.
[0033] The tablets are coated to obtain an inner core tablet containing rifapentine. During the coating process, the inlet air temperature is set to 60±10℃, the main pot speed is 2 rpm, the tablet bed temperature is preheated to 40~45℃, and then the liquid spraying is started, the main pot speed is 4 rpm, and the peristaltic pump speed is 14 rpm to start the coating. After stabilization, the tablet bed temperature is controlled to be 38-42℃, and the coating weight gain is 1.5%-3.5%.
[0034] Further, the material of the outer tablet layer is added to the three-dimensional mixing barrel, mixed at 8 rpm for 10 min to obtain a mixed powder, and the mixed powder and the inner core tablet are compressed to obtain a rifapentine isoniazid core-coated tablet.
[0035] The rifapentine isoniazid tablet prepared in this embodiment compresses rifapentine and isoniazid into one tablet, and patients who need to take combination drugs only need to take medicine once.
[0036] The following specific experimental examples verify that the rifapentine isoniazid tablet prepared in this embodiment solves the incompatibility problem of rifapentine and isoniazid, does not cause impurity increase, and increases the safety of the drug.
[0037] Stability test (accelerated test) The rifapentine isoniazid tablet prepared in Example 1 and the control drug (Rifapentine 300mg and Isoniazid 300mg Tablets, LUPIN LTD.) are respectively placed at 40℃±2℃ and 75%RH±5%RH, and sampled at 3M and 6M to determine the related substances.
[0038] The test results are shown in Table 1.
[0039] Table 1: In-vitro dissolution test The standard formulations (comparator drug used for bioequivalence study in human) of rifapentine and isoniazid tablets according to FDA Orange Book are PRIFTIN (150 mg; Sanofi Aventis US LLC) and ISONIAZID (300 mg; Genus Lifesciences INC) respectively. The dissolution curves of the rifapentine isoniazid tablets prepared in Example 1 of the present application were compared with 2 tablets of PRIFTIN and 1 tablet of ISONIAZID.
[0040] Dissolution Method One (Determination of dissolution of rifapentine): Dissolution medium: 0.8% sodium lauryl sulfate pH 7.0 phosphate buffer, 900 mL.
[0041] Paddle: 50 rpm.
[0042] Sampling times: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min.
[0043] Sampling / replacement volume: 10 mL.
[0044] The test results are shown in Table 2.
[0045] Table 2: Note* Time points involved in the calculation of F2.
[0046] From the results, it can be seen that the dissolution curves of the rifapentine isoniazid tablets prepared in Example 1 and 2 tablets of PRIFTIN in 0.8% sodium lauryl sulfate pH 7.0 phosphate buffer had a F2 value greater than 50, indicating that the dissolution behavior was similar.
[0047] Dissolution Method Two: Dissolution medium: 0.01 N hydrochloric acid; 900 mL.
[0048] Paddle: 100 rpm.
[0049] Sampling times: 10, 15, 20, 30, 45, 60 min.
[0050] Sampling / replacement volume: 10 mL.
[0051] The test results are shown in Table 3.
[0052] Table 3: Note* Time points involved in the calculation of F2.
[0053] From the results, it can be seen that the F2 value of the dissolution curve of one tablet of rifapentine isoniazid tablet 1 of Example 1 and one tablet of ISONIAZID 1 in 0.01N HCl is greater than 50, indicating that the dissolution behaviors are similar.
[0054] The above results show that the rifapentine isoniazid tablet and the preparation process thereof disclosed in the present embodiment can perfectly solve the problem of incompatibility of rifapentine and isoniazid base, and the in-vitro dissolution is similar to the reference preparation and has developability.
[0055] The rifapentine isoniazid tablet disclosed in the present application can also enhance the compliance of patients.
[0056] The above only describes some embodiments of the present application, and it should be noted that, for those skilled in the art, other modifications and improvements can be made without departing from the inventive concept of the present application, and these all belong to the protection scope of the present application.
Claims
1. A rifapentine isoniazid tablet, characterized in that, The rifapentine isoniazid tablet is a core-in-sheath tablet, comprising an inner layer tablet core containing rifapentine and an outer layer tablet layer containing isoniazid; The inner layer tablet core comprises rifapentine, disodium edetate, sodium ascorbate and sodium dodecyl sulfate, the mass of rifapentine accounts for 53%-63% of the total mass of the inner layer tablet core, and further comprises a filler accounting for 20%-50% of the total mass of the inner layer tablet core, a stabilizer accounting for 0.5%-5% of the total mass of the inner layer tablet core, a disintegrant accounting for 0.1%-5% of the total mass of the inner layer tablet core, a binder accounting for 0.5%-5% of the total mass of the inner layer tablet core, a surfactant accounting for 0.1%-0.5% of the total mass of the inner layer tablet core, a lubricant accounting for 0.25%-2% of the total mass of the inner layer tablet core and a coating layer accounting for 2%-4% of the total mass of the inner layer tablet core; The coating layer coats the inner layer tablet core; The outer layer tablet layer comprises isoniazid, a filler accounting for 1%-10% of the total mass of the outer layer tablet layer, a disintegrant accounting for 1%-8% of the total mass of the outer layer tablet layer, a binder accounting for 0.5%-5% of the total mass of the outer layer tablet core, a lubricant accounting for 0.2%-2% of the total mass of the outer layer tablet layer and a binder accounting for 2%-8% of the total mass of the outer layer tablet core; the mass of isoniazid accounts for 75%-95% of the total mass of the outer layer tablet layer.
2. A rifapentine isoniazid tablet according to claim 1, wherein The filler in the inner layer tablet core is one or more of microcrystalline cellulose, lactose and pre-gelatinized starch; the stabilizer is one or more of calcium carbonate, magnesium carbonate and magnesium oxide; the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone and sodium carboxymethyl starch; the binder is hydroxypropyl cellulose and / or povidone K30; the surfactant is one or more of polysorbate 80, poloxamer, sodium dodecyl sulfate and Span 20; the lubricant is calcium stearate and / or hard calcium fumarate; and the material of the coating layer is a combination of titanium dioxide, talc, polyethylene glycol, hydroxypropyl methyl cellulose or polyvinyl alcohol.
3. A rifapentine isoniazid tablet according to claim 2, wherein The filler in the outer layer tablet layer is one or more of microcrystalline cellulose, pre-gelatinized starch, anhydrous calcium hydrogen phosphate and corn starch; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and povidone; and the lubricant is hard calcium fumarate, calcium stearate and / or colloidal silicon dioxide.
4. A rifapentine isoniazid tablet according to claim 3, wherein 1000 pieces of rifapentine isoniazid tablets are prepared from the following components: The inner layer tablet core: rifapentine 300 g, microcrystalline cellulose 121.2 g, pre-gelatinized starch 68 g, sodium ascorbate 6.24 g, disodium edetate 0.52 g, sodium dodecyl sulfate 1.04 g, hydroxypropyl cellulose EXF 10.2 g, sodium carboxymethyl starch 0.8 g; additional excipients: calcium stearate 7.8 g, sodium carboxymethyl starch 20 g; The coating layer: hydroxypropyl methyl cellulose E5 24 g, polyethylene glycol 4 g; The outer layer tablet layer: isoniazid 300 g, povidone 13.2 g, calcium stearate 5.3 g, pre-gelatinized starch 23.4 g.
5. A process for the preparation of rifapentine isoniazid tablets, characterized in that, The preparation method comprises the following steps: S1, mixing the materials of the inner layer tablet core, dry granulating, tabletting and then coating to obtain the inner layer tablet core containing rifapentine; the mass of rifapentine accounts for 53%-63% of the total mass of the inner layer tablet core; S2, mixing the materials of the outer layer tablet layer to obtain a mixed powder and then tabletting to obtain the outer layer tablet layer. S3, compressing the outer layer sheet and the inner layer sheet core to obtain rifapentine isoniazid tablets.
6. The production method according to claim 5, wherein In step S1, the parameters of the dry granulation are as follows: oil pressure 45±10 bar; feeding rate 10-40 rpm; whole granulation rate 80-120 rpm; crushing rate 80-120 rpm; and pressure roller gap 0.8-1.3 mm.
7. The production method according to claim 6, wherein The parameters of the tabletting are as follows: main pressure 12-18 KN; the weight difference of the tabletting process is controlled to be ±5.0%, the average hardness of 10 tablets is in the range of 40-70 N, the disintegration time is ≤5 min, and the friability is ≤1.0%.
8. The preparation method according to claim 7, characterized in that, The parameters of the coating are as follows: tablet bed temperature 35±2 ℃; and atomization pressure 0.2-0.4 mbar.