Preparation method of rifapentine tablet
Rifapentine tablets with an inner and outer core structure were prepared by dry granulation and fluidized bed granulation technologies, which solved the problem of increased impurities in rifapentine under high temperature conditions and improved the stability and safety of the drug.
Patent Information
- Application Number
- CN202511529679.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-24
- Publication Date
- 2025-12-05
AI Technical Summary
Rifapentine exhibits poor stability under high temperature and high humidity conditions. During the coating process, impurities (such as nitrosamines) increase, affecting the safety and stability of the drug.
Rifapentine tablets with an inner and outer core structure were prepared using dry granulation and fluidized bed granulation technologies. The inner layer contains rifapentine, disodium edetate, and sodium ascorbate, while the outer layer is coated with polyethylene glycol and hydroxypropyl methylcellulose to avoid the high-temperature coating process and improve stability.
It effectively reduces the formation of nitrosamine impurities, improves the stability and safety of rifapentine tablets, and ensures product quality.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of medicine, more particularly to a preparation method of rifapentine tablets. BACKGROUND
[0002] Rifapentine is a semi-synthetic broad-spectrum bactericide, which is a rifamycin spiro-piperidine derivative. It can further enhance the anti-tuberculosis effect of the drug, and can inhibit the activity of pathogenic bacteria by combining with the DNA-dependent RNA polymerase of the pathogenic bacteria. Rifapentine has strong anti-tuberculosis advantage and obvious enhancement effect. The anti-tuberculosis effect can be enhanced by 3-4 times by using rifapentine. Rifapentine can be used as an auxiliary drug because it has no cross-resistance and can inhibit the emergence of drug-resistant strains of patients and enhance the anti-tuberculosis ability of the drug.
[0003] Rifapentine has poor stability under high temperature, high humidity and light conditions, and impurities obviously increase during storage. In 2020, WHO announced that nitrosamine impurities 1-cyclopentyl-4-nitrosopiperazine were found in Priftin (rifapentine) of Sanofi. The impurity is a potential carcinogen. The nitrosamine impurity is not a raw material process impurity, but a degradation product produced during high temperature. Priftin of Sanofi is a standard preparation published in the United States (a comparative drug for human bioequivalence research), and its process is coated tablets. The heating during the coating process accelerates the growth of nitrosamine impurities.
[0004] Therefore, a new rifapentine preparation is needed to solve the problem of impurities. SUMMARY
[0005] In order to solve the above problems, the present application provides a preparation method of rifapentine tablets, which solves the problem of growth of nitrosamine impurities caused by heating during the coating process of rifapentine.
[0006] The present application discloses a preparation method of rifapentine tablets, which comprises the following steps: S1, mixing the materials of the inner layer tablet core, dry granulation, tabletting, and preparing an inner layer tablet core containing rifapentine; The materials of the inner layer tablet core include rifapentine, disodium edetate, sodium ascorbate, 40-70% of the total mass of the inner layer tablet core as a filler, 0.5-5% of the total mass of the inner layer tablet core as a stabilizer, 0.1-8% of the total mass of the inner layer tablet core as a disintegrant, 0.5-5% of the total mass of the inner layer tablet core as a binder, 0.1-0.5% of the total mass of the inner layer tablet core as a surfactant, and 0.5-5% of the total mass of the inner layer tablet core as a lubricant; The mass of rifapentine accounts for 50-70% of the total mass of the inner layer tablet core. S2, adopting the coating material to make mixed powder, adding fluidized bed granulation, making outer layer tablet layer; S3, the outer layer tablet layer wraps the inner layer tablet core, and is pressed to obtain rifapentine tablets.
[0007] Preferably, in the step S1, the filler comprises one or more of microcrystalline cellulose, lactose and pregelatinized starch; the stabilizer comprises one or more of calcium carbonate, magnesium carbonate and magnesium oxide; the disintegrant comprises one or more of croscarmellose sodium, crosslinked povidone and sodium carboxymethyl starch; the binder comprises hydroxypropyl cellulose and / or povidone K30; the surfactant comprises one or more of polysorbate 80, poloxamer, sodium dodecyl sulfate and Span 20; and the lubricant comprises calcium stearate and / or hard calcium fumarate.
[0008] Preferably, 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.
[0009] Preferably, the parameters of the tablet pressing are as follows: tablet pressing main pressure 10-25 KN; tablet pressing process control weight difference ±5.0%, 10 tablets average hardness range 40-70 N, disintegration time ≤5 min, and friability loss weight ≤1.0%.
[0010] Preferably, in the step S2, the coating material is polyethylene glycol and hydroxypropyl methyl cellulose, the hydroxypropyl methyl cellulose is E3 and / or E5; and the average molecular weight of the polyethylene glycol is ≤6000.
[0011] Preferably, in the fluidized bed granulation process, no liquid material is added, the inlet air temperature is 50-80℃, and the granules are obtained after cooling in the fluidized bed state.
[0012] Preferably, 1000 rifapentine tablets are prepared from the following components: Inner layer tablet core: rifapentine 300 g, microcrystalline cellulose 110 g, pregelatinized starch 52 g, sodium ascorbate 6.24 g, edetate disodium 0.52 g, sodium dodecyl sulfate 1.04 g, hydroxypropyl cellulose EXF 10.2 g, calcium stearate 7.5 g, and sodium carboxymethyl starch 20 g; Outer layer tablet layer: hydroxypropyl methyl cellulose E5 13.2 g, and polyethylene glycol 6000 5.3 g.
[0013] Compared with the prior art, the present application has the following beneficial effects: The present application solves the situation that the increase of impurities caused by high temperature in the coating process of rifapentine tablets, further improves the stability of rifapentine, ensures the quality of the product, and improves the stability and safety of the product. DETAILED DESCRIPTION
[0014] 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 part of the embodiments of the present application, rather than all the embodiments of the present application.
[0015] The present application discloses a preparation method of rifapentine tablets, which comprises the following steps: S1, dry granulation after mixing the material of the inner tablet core, tabletting, to prepare the inner tablet core containing rifapentine; The material of the inner tablet core includes rifapentine, disodium edetate, sodium ascorbate, 40-70% of the total mass of the inner tablet core of a filler, 0.5-5% of the total mass of the inner tablet core of a stabilizer, 0.1-8% of the total mass of the inner tablet core of a disintegrant, 0.5-5% of the total mass of the inner tablet core of a binder, 0.1-0.5% of the total mass of the inner tablet core of a surfactant, and 0.5-5% of the total mass of the inner tablet core of a lubricant; Among them, the mass of rifapentine accounts for 50-70% of the total mass of the inner tablet core; S2, mixing powder with coating material, fluidized bed granulation, to prepare the outer tablet layer; S3, the outer tablet layer wraps the inner tablet core, and is compressed to obtain rifapentine tablets.
[0016] In step S1, the filler includes one or more of microcrystalline cellulose, lactose, and pre-gelatinized starch; the stabilizer includes one or more of calcium carbonate, magnesium carbonate, and magnesium oxide; the disintegrant includes one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, and sodium carboxymethyl starch; the binder includes hydroxypropyl cellulose and / or povidone K30; the surfactant includes one or more of polysorbate 80, poloxamer, sodium dodecyl sulfate, and Span 20; and the lubricant includes calcium stearate and / or hard calcium fumarate.
[0017] 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 compression roller gap 0.8-1.3 mm.
[0018] The parameters for tabletting are: main pressure of 10-25 KN; the weight difference is ±5.0% during the tabletting process, the average hardness of 10 tablets is 40-70 N, the disintegration time is ≤5 min, and the friability is ≤1.0%.
[0019] In step S2, the coating material is polyethylene glycol and hydroxypropyl methyl cellulose, and the hydroxypropyl methyl cellulose is E3 and / or E5; the average molecular weight of the polyethylene glycol is ≤6000.
[0020] In the fluidized bed granulation process, no liquid material is added, the inlet air temperature is 50-80°C, and the granules are obtained after cooling in the fluidized bed state.
[0021] The application is further described below through specific examples.
[0022] Example 1 This example discloses a specific method for preparing 1000 rifapentine tablets.
[0023] 1000 rifapentine tablets are prepared from the following components: Inner tablet core: rifapentine 300 g, microcrystalline cellulose 110 g, pre-gelatinized starch 52 g, sodium ascorbate 6.24 g, edetate disodium 0.52 g, sodium dodecyl sulfate 1.04 g, hydroxypropyl cellulose EXF 10.2 g, calcium stearate 7.5 g, sodium carboxymethyl starch 20 g; Outer tablet layer: hydroxypropyl methyl cellulose E5 13.2 g, polyethylene glycol 6000 5.3 g.
[0024] Specific preparation steps: 1) After the sodium ascorbate, edetate disodium, sodium dodecyl sulfate, and hydroxypropyl cellulose EXF are sieved through a 60-mesh sieve, the above-mentioned materials are weighed according to the prescription amount, sieved through a 40-mesh sieve, mixed for 3 times, and then used.
[0025] 2) The rifapentine, microcrystalline cellulose, pre-gelatinized starch, sodium carboxymethyl starch, and the mixed materials in step 1) are sieved through a 20-mesh sieve, mixed for 3 times, and can be mixed for 10 min using a three-dimensional mixer at 8 rpm.
[0026] 3) The mixed materials in step 2) are subjected to dry granulation, the oil pressure is 45±10 bar; the granulation speed is 100 rpm; the crushing speed is 100 pm; the roller gap is 1.0-1.1 mm, and the granules are collected.
[0027] 4) Sodium carboxymethyl starch is added, the three-dimensional mixer is at 8 rpm, and mixed for 10 min; additional calcium stearate is added, the three-dimensional mixer is at 8 rpm, and mixed for 5 min.
[0028] 5) The mixed material is compressed into tablets, the main compression pressure is 12-18 KN; the weight difference is controlled to be ±3.0% and the hardness range is 40-70 N during the compression process.
[0029] 6) The material of the outer layer tablet is mixed for 3 times through a 40-mesh sieve, then is added into a fluidized bed granulator, the inlet air temperature is 65°C±5°C and the fan frequency is 1200 Hz.
[0030] 7) The mixed powder of step 6) and the inner layer tablet core of step 5) are compressed to obtain a core-coated tablet, i.e. rifapentine tablet.
[0031] Stability test-accelerated test The rifapentine tablet prepared in Example 1 and the reference preparation (commercial priftin; 150 mg; Sanofi Aventis US LLC.) are respectively placed in a condition of 40°C±2°C and 75%RH±5%RH, and sampled at 0d, 3M and 6M to determine the related substances in the preparation.
[0032] The results of the stability test are shown in Table 1.
[0033] Table 1: The results of the stability test show that, compared with the commercial Priftin, the rifapentine tablet prepared in Example 1 effectively reduces the degradation impurities, especially the increase of impurity 1-cyclopentyl-4-nitrosopiperazine.
[0034] In-vitro dissolution experiment The rifapentine tablet prepared in Example 1 and the reference preparation Priftin are compared in terms of dissolution curve.
[0035] Dissolution method: Dissolution medium: 0.8% sodium dodecyl sulfate pH 7.0 phosphate buffer, 900 mL; Paddle method: 50 rpm; Sampling time: 5, 10, 15, 20, 30, 45, 60 min; Sampling / replenishment volume: 10 mL.
[0036] The dissolution results are shown in Table 2.
[0037] Table 2: The dissolution results show that, compared with the reference preparation Priftin, the rifapentine tablet prepared in Example 1 has F2>50 and similar dissolution behavior, and the rifapentine tablet prepared in Example 1 is developable.
[0038] The above merely describes some embodiments of the present application, and it should be pointed out that, for those skilled in the art, other variations 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 process for the preparation of rifapentine tablets, characterized in that, The preparation method comprises the following steps: S1, dry granulation after mixing the material of the inner layer tablet core, tabletting, to prepare the inner layer tablet core containing rifapentine; The material of the inner layer tablet core comprises rifapentine, disodium edetate, sodium ascorbate, and 40-70% of the total mass of the inner layer tablet core of a filler, 0.5-5% of the total mass of the inner layer tablet core of a stabilizer, 0.1-8% of the total mass of the inner layer tablet core of a disintegrant, 0.5-5% of the total mass of the inner layer tablet core of a binder, 0.1-0.5% of the total mass of the inner layer tablet core of a surfactant, and 0.5-5% of the total mass of the inner layer tablet core of a lubricant; Wherein, the mass of rifapentine accounts for 50-70% of the total mass of the inner layer tablet core; S2, using coating material to make mixed powder, adding fluidized bed granulation, to prepare the outer layer tablet layer; S3, the outer layer tablet layer wraps the inner layer tablet core, and is pressed to obtain rifapentine tablets.
2. The production method according to claim 1, characterized by, In step S1, the filler comprises one or more of microcrystalline cellulose, lactose, and pregelatinized starch; the stabilizer comprises one or more of calcium carbonate, magnesium carbonate, and magnesium oxide; the disintegrant comprises one or more of croscarmellose sodium, crospovidone, and sodium starch glycolate; the binder comprises hydroxypropyl cellulose and / or povidone K30; the surfactant comprises one or more of polysorbate 80, poloxamer, sodium dodecyl sulfate, and Span 20; and the lubricant comprises calcium stearate and / or hard calcium fumarate.
3. The preparation method according to claim 2, characterized in that, 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.
4. The production method according to claim 3, characterized by, The parameters of the tabletting are as follows: tabletting main pressure 10-25 KN; the tabletting process controls the weight difference 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%.
5. The preparation method according to claim 1, characterized in that, In step S2, the coating material is polyethylene glycol and hydroxypropyl methyl cellulose, and the hydroxypropyl methyl cellulose is E3 and / or E5; and the average molecular weight of the polyethylene glycol is ≤6000.
6. The production method according to claim 5, wherein No liquid material is added in the fluidized bed granulation process, and the inlet air temperature is 50-80℃, and the granules are obtained after cooling in the fluidized bed state.
7. The production method according to claim 6, characterized by, 1000 rifapentine tablets are prepared from the following components: Inner layer tablet core: rifapentine 300 g, microcrystalline cellulose 110 g, pregelatinized starch 52 g, sodium ascorbate 6.24 g, disodium edetate 0.52 g, sodium dodecyl sulfate 1.04 g, hydroxypropyl cellulose EXF 10.2 g, calcium stearate 7.5 g, and sodium starch glycolate 20 g; Outer layer tablet layer: hydroxypropyl methyl cellulose E5 13.2 g, and polyethylene glycol 6000 5.3 g.