A rifapentine-containing pharmaceutical composition and its preparation method

Abstract

This application relates to a rifapentine-containing pharmaceutical composition and its preparation method. The rifapentine-containing granules are prepared by dry granulation, which reduces the content of impurities present in existing pharmaceutical compositions, especially the content of the genotoxic impurity 1-cyclopentan-4-nitrosopiperazine, thereby improving the safety and efficacy of the drug.

Description

[0001] This invention claims priority to an earlier application filed on September 27, 2020, with the China National Intellectual Property Administration, patent application number 202011036278.6, entitled "A Rifapentine Pharmaceutical Composition and a Method for Preparing the Same". The entire contents of the aforementioned earlier application are incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical preparations, and more specifically, to a pharmaceutical composition containing rifapentine and a method for preparing the same. Background Technology

[0003] Tuberculosis is a common chronic infectious disease in clinical practice. The principle of anti-tuberculosis treatment in clinical practice is mainly based on combination and regular medication, often using rifamycin-type drugs in combination with other anti-tuberculosis drugs. Rifapentine is a newer semi-synthetic rifamycin antibiotic with good clinical efficacy in treating pulmonary tuberculosis, few side effects, and advantages such as strong antibacterial activity and stable blood drug concentrations. Isoniazid has a highly specific antibacterial effect against Mycobacterium tuberculosis; at higher concentrations, it has a strong bactericidal effect on proliferating Mycobacterium tuberculosis and also has a bactericidal effect on intracellular Mycobacterium tuberculosis. Its effect is 500 times stronger than streptomycin. However, Mycobacterium tuberculosis easily develops resistance to isoniazid, and the combined use of other drugs can significantly delay or prevent the emergence of drug-resistant strains.

[0004] Sanofi disclosed a pharmaceutical composition in coated tablet form containing isoniazid granules and rifapentine granules in patent application WO2015011161. The applicant discovered that the disclosed pharmaceutical composition contained numerous impurities, particularly a high level of the genotoxic impurity 1-cyclopentyl-4-nitrosopiperazine. It was found that even eliminating the effects of oxygen (e.g., increasing the amount of antioxidant) could not reduce the content of these impurities. There is an urgent need to provide a high-purity rifapentine pharmaceutical composition and its preparation method. Summary of the Invention

[0005] The purpose of this application is to provide a rifapentine-containing pharmaceutical composition and its preparation method, which reduces the content of impurities present in existing pharmaceutical compositions, especially the content of the genotoxic impurity 1-cyclopentan-4-nitrosopiperazine, thereby improving the safety and efficacy of the medication.

[0006] This application provides a method for preparing a rifapentine-containing pharmaceutical composition, the method comprising: preparing rifapentine-containing particles by dry granulation.

[0007] In some embodiments, the dry granulation method described above involves first mixing rifapentine with granulation excipients, and then performing dry granulation. The granulation excipients include one or more of fillers, binders, co-solvents, disintegrants, and lubricants.

[0008] In some embodiments, the in-particle excipients include fillers, binders, cosolvents, and lubricants.

[0009] In some embodiments, the granular excipients include fillers, binders, disintegrants, and lubricants.

[0010] In some embodiments, the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, lactose, mannitol, sucrose, and sorbitol, preferably microcrystalline cellulose.

[0011] In some embodiments, the microcrystalline cellulose is selected from one or more of microcrystalline cellulose PH102, microcrystalline cellulose PH112, and microcrystalline cellulose KG802, or a mixture thereof.

[0012] In some embodiments, the adhesive is selected from one or more of polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and pregelatinized starch, preferably low-substituted hydroxypropyl cellulose and / or pregelatinized starch.

[0013] In some embodiments, the co-solvent is selected from polyethylene glycol, propylene glycol, glycerin, Tween 20, Tween 80, sodium dodecyl sulfate, or a mixture of one or more, preferably sodium dodecyl sulfate.

[0014] In some embodiments, the disintegrant is selected from one or more of crospovidone, crospovidone, sodium carboxymethyl cellulose, corn starch, and low-substituted hydroxypropyl cellulose, preferably sodium carboxymethyl starch.

[0015] In some embodiments, the lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, talc, and sodium stearate fumarate, preferably calcium stearate.

[0016] In some embodiments, the granular excipients also include antioxidants.

[0017] In some embodiments, the antioxidant is selected from one or more of sodium ascorbate, sodium metabisulfite, disodium EDTA, tocopherol, and butylated hydroxyanisole, preferably sodium ascorbate.

[0018] In some implementations, the rifapentine is a micronized rifapentine.

[0019] In some embodiments, the particle size D(90) of the micronized rifapentine is ≤10 μm.

[0020] In some embodiments, this application provides a method for preparing a rifapentine-containing pharmaceutical composition, the method comprising:

[0021] (1) Prepare granules containing rifapentine by dry granulation;

[0022] (2) Mix the rifapentine granules obtained in step (1) with the granule excipients.

[0023] In some embodiments, the excipients include one or more of fillers, disintegrants, lubricants, and antioxidants.

[0024] Optionally, the preparation method further includes:

[0025] (3) Preparation of isoniazid-containing intermediates;

[0026] (4) Prepare the mixture from step (2) into a rifampin layer, add the isoniazid intermediate from step (3) to compress it into a bilayer sheet;

[0027] (5) Coating.

[0028] In some implementations, step (1) includes:

[0029] Mix micronized rifampin with granulation additives other than lubricant until homogeneous, add lubricant and mix, then add the mixture to a dry granulator for granulation.

[0030] In some implementations, step (2) includes

[0031] Mix the rifapentine granules obtained in step (1) with the granules other than the lubricant until they are evenly mixed, and then add the lubricant and mix.

[0032] In some implementations, step (3) includes:

[0033] After mixing isoniazid with fillers, binders, and disintegrants evenly, lubricant is added and mixed evenly.

[0034] In some embodiments, the rifampicin layer comprises the following components:

[0035] Rifapentine 50%–60%

[0036] Filler 20%–45%

[0037] Adhesive 1% to 8%

[0038] Lubricant 0.5%–3%.

[0039] In some embodiments, the rifampin layer further includes a co-solvent, the co-solvent content being 0.1% to 2%.

[0040] In some embodiments, the rifapentine layer further includes a disintegrant in an amount of 0.1% to 8%.

[0041] In some embodiments, the rifampin layer further includes an antioxidant, the antioxidant content being 1%-4%.

[0042] In some embodiments, the isoniazid layer comprises the following components:

[0043] Isoniazid 50%–60%

[0044] Filler 20%–40%

[0045] Adhesive 1% to 15%

[0046] Disintegrant 2%–10%

[0047] Lubricant 0.02%–0.1%

[0048] In some embodiments, the filler is microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the binder is pregelatinized starch and / or low-substituted hydroxypropyl cellulose, the lubricant is calcium stearate, the antioxidant is sodium ascorbate, and the solubilizer is sodium dodecyl sulfate.

[0049] On the other hand, this application provides a rifapentine pharmaceutical composition containing 1-cyclopentyl-4-nitrosopiperazine at a mass of not more than 14 ppm based on the mass of rifapentine.

[0050] In some embodiments, the rifapentine pharmaceutical composition of this application contains no more than 5.0 ppm of 1-cyclopentyl-4-nitrosopiperazine based on the mass of rifapentine.

[0051] In some embodiments, the rifapentine pharmaceutical composition of this application contains no more than 4.0 ppm of 1-cyclopentyl-4-nitrosopiperazine based on the mass of rifapentine.

[0052] In some embodiments, the rifapentine pharmaceutical composition of this application contains no more than 3.5 ppm of 1-cyclopentyl-4-nitrosopiperazine based on the mass of rifapentine.

[0053] In some embodiments, the rifapentine pharmaceutical composition of this application contains no more than 3.0 ppm of 1-cyclopentyl-4-nitrosopiperazine based on the mass of rifapentine.

[0054] In some embodiments, the rifapentine pharmaceutical composition of this application contains no more than 2.5 ppm of 1-cyclopentyl-4-nitrosopiperazine based on the mass of rifapentine.

[0055] In some embodiments, the rifapentine-containing pharmaceutical composition of this application is prepared using the above-described preparation method.

[0056] This application, through the preparation of a rifapentine-containing pharmaceutical composition using dry granulation, unexpectedly discovered that the content of impurities in the pharmaceutical composition, especially the genotoxic impurity 1-cyclopentyl-4-nitrosopiperazine, was significantly reduced. The impurity content in the obtained pharmaceutical composition was far lower than that in the pharmaceutical compositions disclosed in the prior art, thereby improving the safety and efficacy of the medication. Detailed Implementation

[0057] The present application will be further described below with reference to specific embodiments. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0058] The embodiments described in this application are merely exemplary and do not constitute any limitation on the scope of this application. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions in this application without departing from the spirit and scope of this application, but all such modifications and substitutions fall within the protection scope of this application.

[0059] Example 1: Rifapentine raw material

[0060] The method disclosed in patent application CN111018886A was adopted, in which the crystallization and recrystallization purification process in step five was repeated multiple times to obtain rifapentine raw material. The content of 1-cyclopentyl-4-nitrosopiperazine was detected to be 1.33 ppm.

[0061] Example 2

[0062] prescription

[0063] Rifa spray layer

[0064] Intragranular Weight (mg / tablet) Rifanote 300.0 Microcrystalline cellulose PH112 150 Sodium carboxymethyl starch 20 Pregelatinized starch 30 Calcium stearate 3 Particle exterior Microcrystalline cellulose PH112 60 Sodium ascorbate 10 Sodium carboxymethyl starch 26 Calcium stearate 4 total 603

[0065] Isoniazid layer

[0066] Isoniazid 300.0 Microcrystalline cellulose PH102 150.0 Microcrystalline cellulose KG802 40.0 Sodium carboxymethyl starch 20.0 Calcium stearate 0.25 total 510.25

[0067] Preparation process (dry granulation)

[0068] (1) The prescribed amount of rifapentine was pre-micronized and mixed with microcrystalline cellulose PH112, sodium carboxymethyl starch and pregelatinized starch for 10 min. Then, calcium stearate that had passed through a 60-mesh sieve was added and mixed for 3 min. The particle size D(90) of the micronized rifapentine was measured to be ≤10 μm using a Malvern 3000 wet particle size analyzer.

[0069] (2) Add the mixed powder to a dry granulator for dry granulation, wherein the oil pressure is 3MPa, the feed speed is 19-20rpm, the pressure roller speed is 0.9-1.1rpm, and then granulate it in an 18-mesh dry granulator.

[0070] (3) After granulation, mix the granules with the granules and other auxiliary materials except calcium stearate for 10 minutes, then add calcium stearate that has been sieved through 60 mesh and mix for 3 minutes to obtain the rifapentine intermediate for later use.

[0071] (4) First, isoniazid is pulverized to a particle size of 200-300μm;

[0072] (5) Weigh out the prescribed amount of pulverized isoniazid, mix it with microcrystalline cellulose PH102, microcrystalline cellulose KG802 and sodium carboxymethyl starch for 20 minutes, then add calcium stearate and mix for 5 minutes to obtain isoniazid intermediate for later use.

[0073] (6) Then, after pressing the rifapentine intermediate to obtain the rifapentine layer, add the isoniazid intermediate and press to obtain a double-layer tablet.

[0074] (7) Coating: First use brown Opadry coating, then switch to red Opadry coating when the weight gain is about 2%, and control the total weight gain at 4±1%; control the air inlet temperature at 55-65℃, control the sheet bed temperature at about 40℃, and dry for 30 minutes after coating.

[0075] Example 3

[0076] prescription

[0077] Rifa spray layer

[0078] Intragranular Weight (mg / tablet) Rifanote 300.0 Microcrystalline cellulose PH102 145.5 Low-substituted hydroxypropyl cellulose LC21 10 Pregelatinized starch 20 Sodium dodecyl sulfate 2.5 Calcium stearate 3 Particle exterior Microcrystalline cellulose KG802 40 Sodium ascorbate 10 Sodium carboxymethyl starch 5 Calcium stearate 4 total 540

[0079] Isoniazid layer

[0080] Isoniazid 300.0 Microcrystalline cellulose PH102 159.75 Microcrystalline cellulose KG802 40.0 Sodium carboxymethyl starch 30.0 Low-substituted hydroxypropyl cellulose LC21 15.0 Calcium stearate 0.25 total 545

[0081] Preparation process (dry granulation)

[0082] The rifapentine-containing composition was prepared according to the prescription in the table above using the preparation method of Example 2.

[0083] Example 4

[0084] prescription

[0085] Rifa spray layer

[0086] Intragranular Weight (mg / tablet) Rifanote 300.0 Microcrystalline cellulose PH102 155.5 Low-substituted hydroxypropyl cellulose LC21 10 Pregelatinized starch 20 Sodium dodecyl sulfate 2.5 Calcium stearate 3 Particle exterior Microcrystalline cellulose KG802 40 Sodium carboxymethyl starch 5 Calcium stearate 4 total 540

[0087] Isoniazid layer same as in Example 3

[0088] Preparation process (dry granulation)

[0089] The rifapentine-containing composition was prepared according to the prescription in the table above using the preparation method of Example 2.

[0090] Experimental Example 1

[0091] The determination methods for 1-cyclopentyl-4-nitrosoperpiperazine and related substances were all performed by high performance liquid chromatography, in accordance with the General Chapter of Part IV of the Chinese Pharmacopoeia 2020 edition. The following is a detailed description.

[0092] The determination method for 1-cyclopentyl-4-nitrosoperpiperazine is as follows:

[0093] 1) Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material, 0.2% formic acid solution was used as mobile phase A, and acetonitrile was used as mobile phase B. Linear gradient elution was adopted (the volumes of mobile phase A and mobile phase B at different times are shown in the table below); the flow rate was 0.5 ml / min; the column temperature was 45 ℃; the injection volume was 2 μl; the detector was a mass spectrometer detector, the ion source was an ESI source, and multiple reaction detection (MRM) mode was selected.

[0094]

[0095] 2) Assay: Take an appropriate amount of finely ground powder (containing approximately 50 mg of rifapentine) and place it in a 50 ml volumetric flask. Add 12.5 ml of acetonitrile and sonicate for 10 min to dissolve the rifapentine. Dilute with water to the mark, shake well, filter, and use the filtrate as the test solution. Accurately weigh an appropriate amount of the reference standard, dissolve it in solvent, and quantitatively dilute to prepare a solution containing approximately 0.014 μg per ml. Accurately measure the test solution and the reference solution, and inject them separately into the liquid chromatograph, recording the chromatograms. Take the average value of two tests.

[0096] The methods for determining related substances are as follows:

[0097] 1) Chromatographic conditions and system suitability test: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.025 mol / L potassium dihydrogen phosphate solution (pH adjusted to 6.2 with potassium hydroxide solution) was used as mobile phase A, and acetonitrile was used as mobile phase B. Linear gradient elution was employed (the volumes of mobile phase A and mobile phase B at different times are shown in the table below), with a flow rate of 1.0 mL / min; column temperature was 30 °C; detection wavelength was 254 nm; and injection volume was 10 μL. The elution order of peaks in the solution chromatogram was isoniazid, isoniazid-rifamycin hydrazone, and rifapentine. The resolution between isoniazid-rifamycin hydrazone and rifapentine should be greater than 4.0, and the resolution between rifapentine and adjacent impurity peaks should meet the requirements.

[0098]

[0099] 2) Assay: Accurately weigh an appropriate amount of the fine sample powder (containing approximately 50 mg of rifapentine), dissolve it in solvent, and quantitatively dilute it to prepare a solution containing approximately 1 mg of rifapentine per ml. Shake well, filter, and use the filtrate as the test solution. Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the mark with solvent, and shake well to prepare the control solution. Accurately inject the test solution and control solution separately into the liquid chromatograph and record the chromatograms.

[0100] Table 1. Content of 1-cyclopentyl-4-nitrosoperpiperazine

[0101]

[0102] Note: The 1-cyclopentyl-4-nitrosopiperazine content (ppm) is the percentage of the mass of 1-cyclopentyl-4-nitrosopiperazine to the mass of rifapentine raw material in parts per million.

[0103] As can be seen from the table above, the growth of nitrosamine impurities during the rifapentine dry granulation process is significantly better than that during the wet granulation and isopropanol granulation processes. Therefore, the use of dry granulation in the production of rifapentine-containing drug combinations can effectively control genotoxic impurities, resulting in lower levels of related substances and improved drug stability.

[0104] Comparative Example 1

[0105] prescription

[0106] Rifa spray layer

[0107] Intragranular Weight (mg / tablet) Rifanote 300.0 Microcrystalline cellulose PH102 166.0 Sodium carboxymethyl starch 1.0 Pregelatinized starch 10.0 Sodium ascorbate 10.0 Hydroxypropyl cellulose 20 water Appropriate amount Particle exterior Sodium dodecyl sulfate 5.0 Sodium carboxymethyl starch 9.0 Calcium stearate 5.0 Sodium ascorbate 5.0 total 531

[0108] Isoniazid layer

[0109] Isoniazid 300.0 Microcrystalline cellulose PH102 150.0 Microcrystalline cellulose KG802 40.0 Sodium carboxymethyl starch 20.0 Calcium stearate 0.25 total 510.25

[0110] Preparation process (wet granulation)

[0111] (1) The prescribed amount of rifapentine was pre-micronized and mixed with the prescribed amount of microcrystalline cellulose PH102, sodium carboxymethyl starch, pregelatinized starch and sodium ascorbate. The particle size D(90) of the pulverized rifapentine was ≤10μm as measured by a Malvern 3000 wet particle size analyzer.

[0112] (2) Dissolve hydroxypropyl cellulose in water under stirring conditions until fully dissolved and ready for use;

[0113] (3) In a wet granulation machine, the material from step 1 above is dry-mixed for 15 minutes at a stirring speed of 100 rpm and a cutter speed of 1000 rpm to ensure that it is fully mixed.

[0114] (4) Slowly add the binder prepared in step 2 to the mixture in step 3. The addition time is 10 min. The stirring speed is 100 rpm and the cutting speed is 1000 rpm. After the binder is added, continue granulation for 2 min at a stirring speed of 100 rpm and a cutting speed of 1000 rpm. After granulation, dry the material in a fluidized bed at 80°C.

[0115] (5) Pass the dried granules from step 4 through an 18-mesh sieve;

[0116] (6) Mix the granules from step 5 with sodium dodecyl sulfate, sodium carboxymethyl starch and sodium ascorbate for 10 minutes;

[0117] (7) Lubricate the particles in step 6 with calcium stearate after passing through a 60-mesh sieve for 5 minutes to obtain the Rifapentine intermediate, for later use.

[0118] (8) First, isoniazid is pulverized to a particle size of 250-300μm;

[0119] (9) Weigh out the prescribed amount of pulverized isoniazid, mix it with microcrystalline cellulose PH102, microcrystalline cellulose KG802 and sodium carboxymethyl starch for 20 minutes, then add calcium stearate and mix for 5 minutes.

[0120] (10) Then, after pressing the rifampin layer, press the isoniazid layer;

[0121] (11) Finally, use brown Opadry coating first, and switch to red Opadry coating when the weight gain is about 2%. The total weight gain is controlled at 4±1%. The air inlet temperature is controlled at 55-65℃, the sheet bed temperature is controlled at about 40℃, and the coating is dried for 30 minutes.

[0122] Comparative Example 2

[0123] prescription

[0124] Rifa spray layer

[0125] Intragranular Weight (mg / tablet) Rifanote 300.0 Microcrystalline cellulose PH102 166.0 Hydroxypropyl cellulose (powder added) 10.0 Sodium carboxymethyl starch 1.0 Pregelatinized starch 10.0 Sodium ascorbate 10.0 Hydroxypropyl cellulose 20 Isopropanol Appropriate amount Particle exterior Sodium dodecyl sulfate 5.0 Sodium carboxymethyl starch 9.0 Calcium stearate 5.0 Sodium ascorbate 5.0 total 541

[0126] Isoniazid layer same as Comparative Example 1

[0127] Preparation process (isopropanol granulation)

[0128] The rifapentine-containing composition was prepared according to the formulation in the table above using the preparation method of Comparative Example 1, wherein isopropanol was used instead of water to prepare the hydroxypropyl cellulose solution.

Claims

1. A process for the preparation of a pharmaceutical composition containing rifapentine, characterized in that, The preparation method comprises: preparing granules containing rifampicin by dry granulation; the dry granulation is to mix rifampicin with intragranular excipients, and then to perform dry granulation, the intragranular excipients comprise one or more of fillers, binders, solubilizers, disintegrants and lubricants; the fillers are selected from a mixture of one or more of microcrystalline cellulose, pregelatinized starch, lactose, mannitol, sucrose and sorbitol; the binders are selected from a mixture of one or more of povidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and pregelatinized starch; the solubilizers are selected from a mixture of one or more of polyethylene glycol, propylene glycol, glycerol, Tween 20, Tween 80 and sodium dodecyl sulfate; the disintegrants are selected from a mixture of one or more of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch and low-substituted hydroxypropyl cellulose; and the lubricants are selected from a mixture of one or more of magnesium stearate, calcium stearate, zinc stearate, talc and sodium stearyl fumarate.

2. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 1, wherein The intragranular excipients comprise fillers, binders, solubilizers and lubricants.

3. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 1, wherein the rifapentine is dissolved in a solvent, and the solution is mixed with a pharmaceutically acceptable carrier. The intragranular excipients comprise fillers, binders, disintegrants and lubricants.

4. The process for preparing a pharmaceutical composition containing rifapentine according to any one of claims 1 to 3, wherein The fillers are microcrystalline cellulose.

5. The process for preparing a pharmaceutical composition containing rifapentine according to any one of claims 1 to 3, wherein The binders are low-substituted hydroxypropyl cellulose and / or pregelatinized starch.

6. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 1 or 2, wherein The solubilizers are dodecyl sulfate.

7. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 1 or 3, wherein The disintegrants are sodium carboxymethyl starch.

8. The method of preparing a pharmaceutical composition containing rifapentine according to any one of claims 1 to 3, wherein The lubricants are calcium stearate.

9. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 1, wherein The intragranular excipients further comprise antioxidants.

10. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 9, wherein the rifapentine is dissolved in a solvent and then mixed with a surfactant. The antioxidants are a mixture of one or more of sodium ascorbate, sodium pyrosulfite, disodium EDTA, tocopherol and butylated hydroxyanisole.

11. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 10, wherein the rifapentine is in the form of a rifapentine salt. The antioxidants are sodium ascorbate.

12. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 1, wherein The rifampicin is micronized rifampicin.

13. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 12, wherein the rifapentine is in the form of a rifapentine salt. The micronized rifampicin has a particle size D(90) of ≤10 μm.

14. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 12 or 13, wherein The micronized rifampicin is uniformly mixed with intragranular excipients except for lubricants, the lubricants are added, the mixture is added into a dry granulator to perform granulation.

15. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 1, wherein Further comprising: (2) mixing the prepared rifampicin-containing granules with extragranular excipients; the extragranular excipients comprise a mixture of one or more of fillers, disintegrants, lubricants and antioxidants.

16. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 15, wherein the rifapentine is in the form of a rifapentine salt. Further comprising: (3) preparing an isoniazid intermediate; (4) preparing the mixture of step (2) into a rifampicin-containing layer, adding the isoniazid intermediate of step (3) to press into a bilayer tablet; (5) coating.

17. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 1, wherein The rifampicin layer comprises the following ingredients: Rifampicin 50%-60% Fillers 20%-45% Binders 1%-8% Lubricants 0.5%-3%.

18. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 17, wherein The rifampicin layer further comprises solubilizers, and the content of the solubilizers is 0.1%-2%.

19. The method of preparing a rifapentine-containing pharmaceutical composition according to claim 17, wherein the rifapentine is in the form of a rifapentine salt. The rifampicin layer further comprises disintegrants, and the content of the disintegrants is 0.1%-8%.

20. The process for preparing a pharmaceutical composition containing rifapentine according to any one of claims 17 to 19, wherein The rifampicin layer further comprises antioxidants, and the content of the antioxidants is 1%-4%.

21. A pharmaceutical composition comprising rifapentine, wherein the composition is formulated for oral administration. The pharmaceutical composition contains not more than 4.0 ppm of 1-cyclopentyl-4-nitrosopiperazine in terms of the mass of rifampicin; and the pharmaceutical composition is prepared by the preparation method of any one of claims 1-20.

22. The rifapentine-containing pharmaceutical composition according to claim 21, wherein not more than 3.5 ppm of 1-cyclopentyl-4-nitrosopiperazine, based on the mass of rifapentine.

23. The rifapentine-containing pharmaceutical composition according to claim 22, wherein not more than 3.0 ppm of 1-cyclopentyl-4-nitrosopiperazine, based on the mass of rifapentine.

24. The rifapentine-containing pharmaceutical composition according to claim 23, wherein not more than 2.5 ppm of 1-cyclopentyl-4-nitrosopiperazine, based on the mass of rifapentine.

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