Compound preparation of mofetidine and ritonavir and preparation method thereof

Abstract

The invention provides a compound preparation of mofetidine and ritonavir and a preparation method of the compound preparation. Specifically, the invention provides a compound preparation. In some embodiments of the invention, the compound preparation comprises active ingredients, and the active ingredients comprise the mofetidine and the ritonavir. Compared with single-prescription Murfisidine and single-prescription Ritonavir, the compound preparation has the advantages that the curative effect of the medicine can be improved, and the side effects of the medicine can be reduced; in addition, the compound preparation is convenient to take, and the two medicines are combined into one preparation, so that the medication process of a patient can be simplified, and the compliance of the patient and the treatment convenience are improved; in addition, manufacturing of one compound preparation is more economical, more convenient and more efficient than manufacturing of two independent medicines, and cost and trouble for purchasing and using multiple medicines by a patient are reduced at the same time.

Description

[0001] Priority Information

[0002] This invention claims the priority and benefits of the patent application with the patent application number 202311768248.8, which was filed with the China National Intellectual Property Administration on December 21, 2023, and incorporates the full text thereof herein by reference. Technical Field

[0003] This invention belongs to the field of pharmaceutical technology. Specifically, this invention relates to a compound preparation and its preparation method. More specifically, this invention relates to a compound preparation of morphethylbutadine and ritonavir and its preparation method. Background Art

[0004] Hepatitis B virus infection is a disease caused by the hepatitis B virus (HBV) after infecting the body. The hepatitis B virus is a hepatotropic virus that mainly exists in hepatocytes and damages hepatocytes, causing hepatitis, necrosis, and fibrosis of hepatocytes.

[0005] Morphethylbutadine is a new dihydropyrimidine antiviral drug that acts by interfering with the assembly of hepatitis B virus core particles. Data such as the master's thesis "Safety and Efficacy Trial of Morphethylbutadine Mesylate Combined with Ritonavir in Chronic Hepatitis B Patients" show that morphethylbutadine is rapidly metabolized in the human body, with strong first-pass elimination and a short half-life, and the time to maintain an effective antiviral blood drug concentration is short. Its main metabolic enzyme is CYP3A4. Ritonavir, as an inhibitor of the metabolic enzyme (CYP3A4) of morphethylbutadine mesylate, when combined with it, can inhibit the rapid metabolism of morphethylbutadine mesylate in the body, thereby increasing its exposure in the human body, reducing the dosing dose and frequency of use, and improving the antiviral effect. However, when the dose of ritonavir is relatively high, serious side effects will occur, such as high total cholesterol and high triglycerides.

[0006] Currently, the only available specification of the marketed ritonavir tablets is 100 mg. Clinical research data from the master's thesis "Exploratory Study on the Continuous Administration of Morphethylbutadine for 24 Weeks in Patients with Chronic Hepatitis B" show that the combination of 120 mg of morphethylbutadine and 100 mg of ritonavir administered continuously multiple times has good safety in hepatitis B patients. Administered three times a day continuously for 24 weeks, it can effectively inhibit the replication of hepatitis B virus DNA. However, a large number of side effects such as hypertriglyceridemia have occurred in clinical practice, and these side effects are likely related to the dose of ritonavir. In addition, when morphethylbutadine and ritonavir are taken simultaneously, it is easy for patients to take too much or miss one of the drugs, which brings inconvenience to patients and affects the treatment effect.

[0007] Therefore, there is an urgent need to develop a compound preparation for chronic adult hepatitis B to reduce the toxic and side effects caused by the high dose of ritonavir and facilitate drug administration. Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems existing in the prior art to at least a certain extent.

[0009] The inventors innovatively provide a compound preparation of mofetilide and ritonavir, in which the dosage of ritonavir is reduced from 100 mg to 50 mg, and the exposure of mofetilide is also increased. Therefore, the compound preparation of the present invention not only increases the exposure of mofetilide, but also reduces the dosage of ritonavir, thereby reducing the side effects caused by it, facilitating drug administration, and improving patient compliance. In addition, the compound preparation has good stability, is convenient to carry and use, and meets the clinical drug use options.

[0010] In addition, the inventors found that when mofetilide and ritonavir tablets are used in combination, the dissolution rates of mofetilide and ritonavir tablets are inconsistent, which will lead to the inability to fully exert the efficacy of the drugs. Specifically, when the two are used in combination (administered in the form of preparations respectively), mofetilide can be rapidly released (for example, it can be completely dissolved in 15 minutes), while ritonavir is released slowly during the dissolution process (for example, it takes 2 hours to be completely dissolved), and the inhibitory effect on CYP3A4 enzyme activity lags behind, that is, after mofetilide is partially metabolized in the body, ritonavir begins to exert its inhibitory effect on CYP3A4 enzyme, resulting in low bioavailability of mofetilide. To improve the bioavailability of mofetilide and ensure the efficacy of combined medication, it is necessary to ensure that the dissolution rates of mofetilide and ritonavir are consistent or similar, so that the two drugs can reach the expected drug concentration within an appropriate time. Through a large number of studies, the inventors found that the compound preparation of mofetilide and ritonavir of the present invention can basically achieve synchronous release of mofetilide and ritonavir, avoiding the premature release of one of the active ingredients and the inability to achieve the effect of combined treatment.

[0011] In addition, in addition to the above dissolution rate problem, the inventors also found during the research process that the main difficulty in making a compound preparation of mofetilide or its salt and ritonavir lies in: the problem of easy layering during the tabletting process due to the large density difference between mofetilide or its salt (such as mofetilide mesylate) and the ritonavir solid dispersion. To solve the above technical problems, after a large number of experiments, the inventors found that by using the dry granulation technology, mixing the mofetilide raw material drug with the ritonavir solid dispersion and excipients and granulating them together, the risk of tabletting layering can be effectively reduced.

[0012] Based on this, in one aspect of the present invention, the present invention proposes a compound preparation. In some embodiments of the present invention, the compound preparation includes active ingredients, and the active ingredients include mofetilide or its salt and ritonavir.

[0013] It should be noted that the "mofetilide mesylate" described in the present invention is the mesylate salt of mofetilide, which is a new type 1 anti-hepatitis C drug independently developed by the inventor, and "ritonavir" is a bioavailability enhancer.

[0014] In some embodiments of the present invention, the compound preparation may further include at least one of the following additional technical features:

[0015] In some embodiments of the present invention, the weight ratio of mofetilide to ritonavir is (1.68 - 5.05):1. In some embodiments of the present invention, the weight ratio of mofetilide to ritonavir is 1.68:1, 2.00:1, 2.50:1, 3.00:1, 3.50:1, 4.00:1, 4.50:1, 4.80:1, 5.00:1 or 5.05:1, etc.

[0016] In some embodiments of the present invention, the weight ratio of mofetilide to ritonavir is (1.68 - 2.53):1. In some embodiments of the present invention, the weight ratio of mofetilide to ritonavir is 1.68:1, 1.70:1, 1.80:1, 1.90:1, 2.00:1, 2.10:1, 2.20:1, 2.30:1, 2.40:1, 2.50:1 or 2.53:1, etc.

[0017] In some embodiments of the present invention, the mofetilide salt is mofetilide mesylate, and the weight ratio of mofetilide mesylate to ritonavir is (1.60 - 6):1. In some embodiments of the present invention, the weight ratio of mofetilide mesylate to ritonavir is 1.60:1, 1.65:1, 1.70:1, 1.75:1, 1.80:1, 1.85:1, 1.90:1, 1.95:1, 2.00:1, 2.40:1, 2.50:1, 3.00:1, 3.20:1, 3.50:1, 4.00:1, 4.50:1, 4.80:1, 5.00:1, 5.05:1, 5.10:1, 5.15:1, 5.20:1, 5.25:1, 5.30:1, 5.35:1, 5.40:1, 5.50:1, 5.55:1, 5.60:1, 5.65:1, 5.70:1, 5.75:1, 5.80:1, 5.85:1, 5.90:1, 6.00:1, etc.

[0018] In some embodiments of the present invention, the weight ratio of mofetilidine mesylate to ritonavir is (1.80 - 5.70):1. In some embodiments of the present invention, the weight ratio of mofetilidine mesylate to ritonavir is 1.80:1, 1.85:1, 1.90:1, 1.95:1, 2.00:1, 2.40:1, 2.50:1, 3.00:1, 3.20:1, 3.50:1, 4.00:1, 4.50:1, 4.80:1, 5.00:1, 5.05:1, 5.10:1, 5.15:1, 5.20:1, 5.25:1, 5.30:1, 5.35:1, 5.40:1, 5.50:1, 5.55:1, 5.60:1, 5.65:1, 5.70:1, etc.

[0019] In some embodiments of the present invention, the weight ratio of mofetilidine mesylate to ritonavir is (2 - 6):1. In some embodiments of the present invention, the mofetilidine salt is mofetilidine mesylate, and the weight ratio of mofetilidine mesylate to ritonavir is 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1 or 6:1, etc.

[0020] In some embodiments of the present invention, the weight ratio of mofetilidine mesylate to ritonavir is (2 - 3):1. In some embodiments of the present invention, the weight ratio of mofetilidine mesylate to ritonavir is 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1 or 3:1, etc.

[0021] In some embodiments of the present invention, the compound preparation further comprises pharmaceutically acceptable excipients, and the excipients include disintegrants.

[0022] In some embodiments of the present invention, the disintegrant is selected from at least one of crospovidone, croscarmellose sodium and sodium carboxymethyl starch. The inventors unexpectedly found during the experiment that crospovidone, croscarmellose sodium and / or sodium carboxymethyl starch can avoid the degradation of mofetilidine and ritonavir under the conditions of high temperature and adding water. Therefore, crospovidone, croscarmellose sodium and / or sodium carboxymethyl starch not only act as disintegrants in the compound preparation, but also have the effect of inhibiting the degradation of the active pharmaceutical ingredients.

[0023] In some embodiments of the present invention, the disintegrant is crospovidone.

[0024] In some embodiments, the crospovidone is selected from crospovidone CL, crospovidone CL-M, crospovidone XL or crospovidone XL-10, etc.

[0025] In some embodiments, the cross-linked povidone is selected from cross-linked povidone XL.

[0026] In some embodiments of the present invention, the excipients further include at least one of a filler, a plasticizer, a glidant, and a lubricant.

[0027] In some embodiments of the present invention, the filler is selected from at least one of lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, siliconized microcrystalline cellulose, mannitol, corn starch, sucrose, cellulose lactose, and pregelatinized starch.

[0028] In some embodiments, the lactose monohydrate is selected from lactose monohydrate Flowlac 100, lactose monohydrate Granulac200, lactose monohydrate Flowlac90, lactose monohydrate Pharma lose 200M, lactose monohydrate Pharma lose 100M, or lactose monohydrate Tablettose 70.

[0029] In some embodiments, the microcrystalline cellulose is selected from microcrystalline cellulose 101, microcrystalline cellulose 102, microcrystalline cellulose 112, microcrystalline cellulose 200, or microcrystalline cellulose 113, etc.

[0030] In some embodiments, the siliconized microcrystalline cellulose is selected from siliconized microcrystalline cellulose 50, siliconized microcrystalline cellulose 90, siliconized microcrystalline cellulose 50LD, siliconized microcrystalline cellulose HD 90, or siliconized microcrystalline cellulose 90LM.

[0031] In some embodiments, the pregelatinized starch is selected from pregelatinized starch 1500, pregelatinized starch SH-YJ-H, pregelatinized starch PREJEL PA5 PH, or pregelatinized starch LYCATAB PGS.

[0032] In some embodiments of the present invention, the filler is selected from lactose monohydrate and microcrystalline cellulose. The inventors have found through a large number of experiments that when the filler is selected as lactose monohydrate and microcrystalline cellulose, the dissolution and stability of the compound preparation are better.

[0033] In some embodiments of the present invention, the plasticizer is selected from at least one of polyethylene glycol, propylene glycol, glycerol, poloxamer, polysorbate 80, diethyl phthalate, triethyl citrate, octyl citrate, acetyltriethyl citrate, tributyl acetylcitrate, butyl stearate, glycerol monostearate, stearyl alcohol, dibutyl stearate, dibutyl phthalate, dioctyl phosphate, and vitamin E-TPGS.

[0034] In some embodiments of the present invention, the plasticizer is selected from polyethylene glycol.

[0035] In some embodiments, the polyethylene glycol is selected from polyethylene glycol 4000 (PEG4000), polyethylene glycol 6000 (PEG6000), polyethylene glycol 8000 (PEG8000), polyethylene glycol 3350 (PEG3350), etc.

[0036] In some embodiments, the polyethylene glycol is selected from polyethylene glycol 6000 (PEG6000).

[0037] In some embodiments of the present invention, the glidant is selected from at least one of anhydrous colloidal silica and talc powder.

[0038] In some embodiments of the present invention, the glidant is selected from anhydrous colloidal silica.

[0039] In some embodiments, the anhydrous colloidal silica is selected from colloidal silica (anhydrous) A200, colloidal silica HL-200 or colloidal silica CAB-O- M-5P.

[0040] In some embodiments of the present invention, the lubricant is selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated castor oil, glyceryl behenate and magnesium lauryl sulfate.

[0041] In some embodiments of the present invention, the lubricant is selected from at least one of magnesium stearate and sodium stearyl fumarate. Through a large number of experiments, the inventors found that when the lubricant is magnesium stearate or / and sodium stearyl fumarate, the dissolution and stability of the compound preparation are better.

[0042] In some embodiments of the present invention, the magnesium stearate is selected from magnesium stearate MF-2-V-MB, magnesium stearate SH-YM-M, magnesium stearate ZW-N or magnesium stearate ZW-D1.

[0043] In some embodiments of the present invention, the compound preparation further comprises a pharmaceutically acceptable carrier.

[0044] In some embodiments of the present invention, the carrier is selected from at least one of copovidone, povidone, hypromellose and hydroxypropyl cellulose.

[0045] In some embodiments of the present invention, the carrier is selected from copovidone.

[0046] In some embodiments, the copovidone is selected from copovidone VA64, copovidone VA 64Fine or copovidone S-630.

[0047] In some embodiments of the present invention, the weight ratio of the disintegrant to the compound preparation is (0 to 0.16):1. In some embodiments of the present invention, the weight ratio of the disintegrant to the compound preparation is 0.00:1, 0.01:1, 0.020:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, etc.

[0048] In some embodiments of the present invention, the weight ratio of the disintegrant to the compound preparation is (0.04 to 0.14):1. In some embodiments of the present invention, the weight ratio of the disintegrant to the compound preparation is 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1 or 0.14:1, etc.

[0049] In some embodiments of the present invention, the weight ratio of the disintegrant to the compound preparation is (0.04 to 0.07):1. In some embodiments of the present invention, the weight ratio of the disintegrant to the compound preparation is 0.04:1, 0.05:1, 0.06:1 or 0.07:1, etc.

[0050] In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is (0.00 to 0.65):1. In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is 0.00:1, 0.03:1, 0.05:1, 0.08:1, 0.10:1, 0.13:1, 0.15:1, 0.17:1, 0.20:1, 0.23:1, 0.25:1, 0.27:1, 0.30:1, 0.33:1, 0.35:1, 0.37:1, 0.40:1, 0.43:1, 0.45:1, 0.47:1, 0.50:1, 0.53:1, 0.55:1, 0.57:1, 0.60:1, 0.63:1 or 0.65:1, etc.

[0051] In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is (0.05 - 0.65):1. In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is 0.05:1, 0.08:1, 0.10:1, 0.13:1, 0.15:1, 0.17:1, 0.20:1, 0.23:1, 0.25:1, 0.27:1, 0.30:1, 0.33:1, 0.35:1, 0.37:1, 0.40:1, 0.43:1, 0.45:1, 0.47:1, 0.50:1, 0.53:1, 0.55:1, 0.57:1, 0.60:1, 0.63:1 or 0.65:1, etc.

[0052] In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is (0.08 - 0.55):1. In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is 0.08:1, 0.10:1, 0.15:1, 0.20:1, 0.25:1, 0.30:1, 0.35:1, 0.40:1, 0.45:1, 0.50:1 or 0.55:1, etc.

[0053] In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is (0.15 - 0.55):1. In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is 0.15:1, 0.20:1, 0.25:1, 0.30:1, 0.35:1, 0.40:1, 0.45:1, 0.50:1 or 0.55:1, etc.

[0054] In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is (0.23 - 0.33):1. In some embodiments of the present invention, the weight ratio of the filler to the compound preparation is 0.23:1, 0.25:1, 0.27:1, 0.3:1 or 0.33:1, etc.

[0055] In some embodiments of the present invention, the weight ratio of the plasticizer to the compound preparation is (0.01 - 0.06):1. In some embodiments of the present invention, the weight ratio of the plasticizer to the compound preparation is 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1 or 0.06:1, etc.

[0056] In some embodiments of the present invention, the weight ratio of the plasticizer to the compound preparation is (0.01 - 0.03):1. In some embodiments of the present invention, the weight ratio of the plasticizer to the compound preparation is 0.01:1, 0.02:1 or 0.03:1, etc.

[0057] In some embodiments of the present invention, the weight ratio of the glidant to the compound preparation is (0.00 to 0.04):1. In some embodiments of the present invention, the weight ratio of the glidant to the compound preparation is 0.00:1, 0.001:1, 0.003:1, 0.005:1, 0.007:1, 0.009:1, 0.01:1, 0.015:1, 0.02:1, 0.025:1, 0.03:1, 0.035:1 or 0.04:1, etc.

[0058] In some embodiments of the present invention, the weight ratio of the glidant to the compound preparation is (0.007 to 0.04):1. In some embodiments of the present invention, the weight ratio of the glidant to the compound preparation is 0.007:1, 0.009:1, 0.01:1, 0.015:1, 0.02:1, 0.025:1, 0.03:1, 0.035:1 or 0.04:1, etc.

[0059] In some embodiments of the present invention, the weight ratio of the glidant to the compound preparation is (0.01 to 0.03):1. In some embodiments of the present invention, the weight ratio of the glidant to the compound preparation is 0.01:1, 0.02:1, 0.03:1, etc.

[0060] In some embodiments of the present invention, the weight ratio of the lubricant to the compound preparation is (0.007 to 0.07):1. In some embodiments of the present invention, the weight ratio of the lubricant to the compound preparation is 0.007:1, 0.009:1, 0.01:1, 0.01:1, 0.015:1, 0.02:1, 0.025:1, 0.03:1, 0.035:1, 0.04:1, 0.045:1, 0.05:1, 0.055:1, 0.06:1, 0.065:1 or 0.07:1, etc.

[0061] In some embodiments of the present invention, the weight ratio of the lubricant to the compound preparation is (0.007 to 0.04):1. In some embodiments of the present invention, the weight ratio of the lubricant to the compound preparation is 0.007:1, 0.009:1, 0.01:1, 0.01:1, 0.015:1, 0.02:1, 0.025:1, 0.03:1, 0.035:1, 0.04:1, etc.

[0062] In some embodiments of the present invention, the weight ratio of the lubricant to the compound preparation is (0.02 - 0.07):1. In some embodiments of the present invention, the weight ratio of the lubricant to the compound preparation is 0.02:1, 0.025:1, 0.03:1, 0.035:1, 0.04:1, 0.045:1, 0.05:1, 0.055:1, 0.06:1, 0.065:1 or 0.07:1, etc.

[0063] In some embodiments of the present invention, the weight ratio of the lubricant to the compound preparation is (0.01 - 0.03):1. In some embodiments of the present invention, the weight ratio of the lubricant to the compound preparation is 0.01:1, 0.015:1, 0.02:1, 0.025:1, 0.03:1, etc.

[0064] In some embodiments of the present invention, the weight ratio of the carrier to the compound preparation is (0.05 - 0.4):1. In some embodiments of the present invention, the weight ratio of the carrier to the compound preparation is 0.05:1, 0.10:1, 0.15:1, 0.2:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, 0.25:1, 0.26:1, 0.27:1, 0.28:1, 0.29:1, 0.30:1, 0.31:1, 0.32:1, 0.33:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1 or 0.40:1, etc.

[0065] In some embodiments of the present invention, the weight ratio of the carrier to the compound preparation is (0.2 - 0.4):1. In some embodiments of the present invention, the weight ratio of the carrier to the compound preparation is 0.2:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, 0.25:1, 0.26:1, 0.27:1, 0.28:1, 0.29:1, 0.30:1, 0.31:1, 0.32:1, 0.33:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1 or 0.40:1, etc.

[0066] In some embodiments of the present invention, the weight ratio of the carrier to the compound preparation is (0.32 - 0.35):1. In some embodiments of the present invention, the weight ratio of the carrier to the compound preparation is 0.32:1, 0.33:1, 0.34:1, 0.35:1, etc.

[0067] In some embodiments of the present invention, the weight ratio of moricizine mesylate to the compound preparation is (0.15 - 0.25):1. In some embodiments of the present invention, the weight ratio of moricizine mesylate to the compound preparation is 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, 0.20:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, 0.25:1, etc.

[0068] In some embodiments of the present invention, the weight ratio of ritonavir to the compound preparation is (0.03 - 0.08):1. In some embodiments of the present invention, the weight ratio of ritonavir to the compound preparation is 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, etc.

[0069] In some embodiments of the present invention, the weight ratio of ritonavir to the compound preparation is (0.04 - 0.07):1.

[0070] In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is (0.00 - 0.16):1. In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is 0.00:1, 0.01:1, 0.020:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, etc.

[0071] In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is (0.04 - 0.14):1.

[0072] In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is (0.04 - 0.07):1.

[0073] In some embodiments of the present invention, the weight ratio of cross - linked sodium carboxymethyl cellulose to the compound preparation is (0.00 - 0.16):1, (0.04 - 0.14) or (0.04 - 0.07):1. In some embodiments of the present invention, the weight ratio of cross - linked sodium carboxymethyl cellulose to the compound preparation is 0.00:1, 0.01:1, 0.020:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, etc.

[0074] In some embodiments of the present invention, the weight ratio of sodium carboxymethyl starch to the compound preparation is (0.00 to 0.16):1, (0.04 to 0.14), or (0.04 to 0.07):1. In some embodiments of the present invention, the weight ratio of sodium carboxymethyl starch to the compound preparation is 0.00:1, 0.01:1, 0.020:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, etc.

[0075] In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is (0.05 to 0.40):1. In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is 0.05:1, 0.10:1, 0.15:1, 0.20:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, 0.25:1, 0.26:1, 0.27:1, 0.28:1, 0.29:1, 0.30:1, 0.31:1, 0.32:1, 0.32:1, 0.33:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1, 0.40:1, etc.

[0076] In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is (0.20 to 0.40):1. In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is 0.20:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, 0.25:1, 0.26:1, 0.27:1, 0.28:1, 0.29:1, 0.30:1, 0.31:1, 0.32:1, 0.32:1, 0.33:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1, 0.40:1, etc.

[0077] In some embodiments of the present invention, the weight ratio of crospovidone to the compound preparation is (0.32 to 0.35):1.

[0078] In some embodiments of the present invention, the weight ratio of lactose monohydrate to the compound preparation is (0.00 - 0.39):1. In some embodiments of the present invention, the weight ratio of lactose monohydrate to the compound preparation is 0.00:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, 0.20:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, 0.25:1, 0.26:1, 0.27:1, 0.28:1, 0.29:1, 0.30:1, 0.31:1, 0.32:1, 0.33:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1, etc.

[0079] In some embodiments of the present invention, the weight ratio of lactose monohydrate to the compound preparation is (0.09 - 0.24):1.

[0080] In some embodiments of the present invention, the weight ratio of lactose monohydrate to the compound preparation is (0.14 - 0.22):1.

[0081] In some embodiments of the present invention, the weight ratio of microcrystalline cellulose to the compound preparation is (0.00 - 0.45):1. In some embodiments of the present invention, the weight ratio of microcrystalline cellulose to the compound preparation is 0.00:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, 0.20:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, 0.25:1, 0.26:1, 0.27:1, 0.28:1, 0.29:1, 0.30:1, 0.31:1, 0.32:1, 0.33:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1, 0.40:1, 0.41:1, 0.42:1, 0.43:1, 0.44:1, 0.45:1, etc.

[0082] In some embodiments of the present invention, the weight ratio of microcrystalline cellulose to the compound preparation is (0.05 - 0.45):1.

[0083] In some embodiments of the present invention, the weight ratio of the microcrystalline cellulose to the compound preparation is (0.05 - 0.32):1.

[0084] In some embodiments of the present invention, the weight ratio of the microcrystalline cellulose to the compound preparation is (0.07 - 0.15):1.

[0085] In some embodiments of the present invention, the weight ratio of the silicified microcrystalline cellulose to the compound preparation is (0.08 - 0.24):1. In some embodiments of the present invention, the weight ratio of the silicified microcrystalline cellulose to the compound preparation is 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, 0.20:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, etc.

[0086] In some embodiments of the present invention, the weight ratio of the silicified microcrystalline cellulose to the compound preparation is (0.08 - 0.12):1. In some embodiments of the present invention, the weight ratio of the silicified microcrystalline cellulose to the compound preparation is 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, etc.

[0087] In some embodiments of the present invention, the weight ratio of the silicified microcrystalline cellulose to the compound preparation is (0.12 - 0.24):1.

[0088] In some embodiments of the present invention, the weight ratio of the pregelatinized starch to the compound preparation is (0.08 - 0.10):1. In some embodiments of the present invention, the weight ratio of the pregelatinized starch to the compound preparation is 0.08:1, 0.09:1, 0.10:1, etc.

[0089] In some embodiments of the present invention, the weight ratio of the anhydrous calcium hydrogen phosphate to the compound preparation is (0.2 - 0.35):1. In some embodiments of the present invention, the weight ratio of the anhydrous calcium hydrogen phosphate to the compound preparation is 0.2:1, 0.22:1, 0.25:1, 0.27:1, 0.3:1, 0.32:1, 0.35:1, etc.

[0090] In some embodiments of the present invention, the weight ratio of the polyethylene glycol to the compound preparation is (0.01 - 0.06):1. In some embodiments of the present invention, the weight ratio of the polyethylene glycol to the compound preparation is 0.01:1, 0.013:1, 0.015:1, 0.017:1, 0.021:1, 0.025:1, 0.026:1, 0.03:1, 0.033:1, 0.035:1, 0.037:1, 0.04:1, 0.043:1, 0.045:1, 0.047:1, 0.05:1, 0.053:1, 0.055:1, 0.057:1, 0.06:1, etc.

[0091] In some embodiments of the present invention, the weight ratio of the polyethylene glycol to the compound preparation is (0.01 - 0.03):1.

[0092] In some embodiments of the present invention, the weight ratio of the anhydrous colloidal silica to the compound preparation is (0.00 - 0.04):1. In some embodiments of the present invention, the weight ratio of the anhydrous colloidal silica to the compound preparation is 0.00:1, 0.007:1, 0.009:1, 0.01:1, 0.014:1, 0.016:1, 0.019:1, 0.02:1, 0.024:1, 0.029:1, 0.03:1, 0.034:1, 0.036:1, 0.039:1, 0.04:1, etc.

[0093] In some embodiments of the present invention, the weight ratio of the anhydrous colloidal silica to the compound preparation is (0.007 - 0.04):1;

[0094] In some embodiments of the present invention, the weight ratio of the anhydrous colloidal silica to the compound preparation is (0.01 - 0.03):1.

[0095] In some embodiments of the present invention, the weight ratio of the anhydrous colloidal silica to the compound preparation is (0.0115 - 0.029):1.

[0096] In some embodiments of the present invention, the weight ratio of the anhydrous colloidal silica to the compound preparation is (0.01 - 0.02):1.

[0097] In some embodiments of the present invention, the weight ratio of sodium stearyl fumarate to the compound preparation is (0.02 - 0.07):1. In some embodiments of the present invention, the weight ratio of sodium stearyl fumarate to the compound preparation is 0.02:1, 0.027:1, 0.03:1, 0.032:1, 0.035:1, 0.037:1, 0.04:1, 0.045:1, 0.05:1, 0.055:1, 0.06:1, 0.065:1, 0.07:1, etc.

[0098] In some embodiments of the present invention, the weight ratio of sodium stearyl fumarate to the compound preparation is (0.03 - 0.05):1.

[0099] In some embodiments of the present invention, the weight ratio of magnesium stearate to the compound preparation is (0.007 - 0.04):1. In some embodiments of the present invention, the weight ratio of magnesium stearate to the compound preparation is 0.007:1, 0.009:1, 0.01:1, 0.014:1, 0.016:1, 0.019:1, 0.02:1, 0.024:1, 0.029:1, 0.03:1, 0.034:1, 0.036:1, 0.039:1, 0.04:1, etc.

[0100] In some embodiments of the present invention, the weight ratio of magnesium stearate to the compound preparation is (0.0075 - 0.035):1;

[0101] In some embodiments of the present invention, the weight ratio of magnesium stearate to the compound preparation is (0.01 - 0.03):1.

[0102] In some embodiments of the present invention, the weight ratio of magnesium stearate to the compound preparation is (0.01 - 0.023):1.

[0103] In some embodiments of the present invention, the dosage form of the compound preparation is selected from tablets, powders, granules, capsules or dripping pills.

[0104] In some embodiments of the present invention, the dosage form of the compound preparation is selected from tablets.

[0105] In some embodiments of the present invention, the compound preparation comprises: 15 - 25 parts by weight of mofetilidine mesylate; 3 - 8 parts by weight of ritonavir; 0 - 16 parts by weight of crospovidone; 20 - 40 parts by weight of copovidone; 0 - 39 parts by weight of lactose monohydrate; 5 - 45 parts by weight of microcrystalline cellulose; 1 - 6 parts by weight of polyethylene glycol; 0.7 - 4 parts by weight of anhydrous colloidal silica; 2 - 7 parts by weight of sodium stearyl fumarate.

[0106] In some embodiments of the present invention, the compound preparation comprises: 15 to 25 parts by weight of mofetilidine mesylate; 4 to 7 parts by weight of ritonavir; 4 to 14 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 9 to 24 parts by weight of lactose monohydrate; 5 to 32 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 3 parts by weight of anhydrous colloidal silicon dioxide; 3 to 5 parts by weight of sodium stearyl fumarate.

[0107] In some embodiments of the present invention, the compound preparation comprises: 15 to 25 parts by weight of mofetilidine mesylate; 3 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 20 to 35 parts by weight of copovidone; 14 to 20 parts by weight of lactose monohydrate; 9 to 25 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 3 to 5 parts by weight of sodium stearyl fumarate.

[0108] In some embodiments of the present invention, the compound preparation comprises: 15 to 25 parts by weight of mofetilidine mesylate; 5 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 18 to 21 parts by weight of lactose monohydrate; 9 to 11 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 3 to 5 parts by weight of sodium stearyl fumarate.

[0109] In some embodiments of the present invention, the compound preparation comprises: 20 to 25 parts by weight of mofetilidine mesylate; 3 to 6 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 20 to 22 parts by weight of copovidone; 14 to 17 parts by weight of lactose monohydrate; 22 to 25 parts by weight of microcrystalline cellulose; 1 to 2 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 3 to 5 parts by weight of sodium stearyl fumarate.

[0110] In some embodiments of the present invention, the compound preparation comprises: 15 to 25 parts by weight of mofetilidine mesylate; 3 to 8 parts by weight of ritonavir; 0 to 16 parts by weight of crospovidone; 20 to 40 parts by weight of copovidone; 0 to 39 parts by weight of lactose monohydrate; 5 to 45 parts by weight of microcrystalline cellulose; 1 to 6 parts by weight of polyethylene glycol; 0.7 to 4 parts by weight of anhydrous colloidal silicon dioxide; 0.7 to 4 parts by weight of magnesium stearate.

[0111] In some embodiments of the present invention, the compound preparation comprises: 15 to 25 parts by weight of mofetilidine mesylate; 4 to 7 parts by weight of ritonavir; 4 to 14 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 9 to 24 parts by weight of lactose monohydrate; 5 to 32 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 3 parts by weight of anhydrous colloidal silicon dioxide; 1 to 3 parts by weight of magnesium stearate.

[0112] In some embodiments of the present invention, the compound preparation comprises: 15 to 22 parts by weight of mofetilidine mesylate; 3 to 8 parts by weight of ritonavir; 4 to 8 parts by weight of crospovidone; 20 to 35 parts by weight of copovidone; 17 to 22 parts by weight of lactose monohydrate; 10 to 31 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 2.5 parts by weight of magnesium stearate.

[0113] In some embodiments of the present invention, the compound preparation comprises: 18 to 22 parts by weight of mofetilidine mesylate; 5 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 17 to 22 parts by weight of lactose monohydrate; 10 to 12 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 1.5 parts by weight of magnesium stearate.

[0114] In some embodiments of the present invention, the compound preparation comprises: 18 to 22 parts by weight of mofetilidine mesylate; 5 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 17 to 22 parts by weight of lactose monohydrate; 10 to 12 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 2.5 parts by weight of magnesium stearate.

[0115] In some embodiments of the present invention, the compound preparation comprises: 18 to 22 parts by weight of mofetilidine mesylate; 3 to 6 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 20 to 25 parts by weight of copovidone; 17 to 20 parts by weight of lactose monohydrate; 25 to 30 parts by weight of microcrystalline cellulose; 1 to 2 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 2.5 parts by weight of magnesium stearate.

[0116] In some embodiments of the present invention, the compound preparation comprises: 15 to 20 parts by weight of mofetilidine mesylate; 3 to 6 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 20 to 25 parts by weight of copovidone; 17 to 22 parts by weight of lactose monohydrate; 29 to 31 parts by weight of microcrystalline cellulose; 1 to 2 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silica; 1 to 2.5 parts by weight of magnesium stearate.

[0117] In some embodiments of the present invention, the compound preparation comprises: 15 to 20 parts by weight of mofetilidine mesylate; 6 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 27 to 30 parts by weight of anhydrous calcium hydrogen phosphate; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silica; 3 to 4 parts by weight of sodium stearyl fumarate.

[0118] In some embodiments of the present invention, the compound preparation comprises: 15 to 20 parts by weight of mofetilidine mesylate; 6 to 8 parts by weight of ritonavir; 5 to 8 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 17 to 20 parts by weight of lactose monohydrate; 8 to 10 parts by weight of pregelatinized starch; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silica; 1 to 3 parts by weight of magnesium stearate.

[0119] In some embodiments of the present invention, the compound preparation comprises: 15 to 20 parts by weight of mofetilidine mesylate; 6 to 8 parts by weight of ritonavir; 5 to 8 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 10 to 24 parts by weight of lactose monohydrate; 8 to 24 parts by weight of siliconized microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silica; 1 to 3 parts by weight of magnesium stearate.

[0120] In some embodiments of the present invention, the compound preparation comprises: 15 to 20 parts by weight of mofetilidine mesylate; 6 to 8 parts by weight of ritonavir; 5 to 8 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 17 to 20 parts by weight of lactose monohydrate; 8 to 10 parts by weight of siliconized microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silica; 1 to 3 parts by weight of magnesium stearate.

[0121] In some embodiments of the present invention, the compound preparation comprises: 15 to 20 parts by weight of mofetilidine mesylate; 6 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of crospovidone; 32 to 35 parts by weight of copovidone; 18 to 21 parts by weight of lactose monohydrate; 9 to 11 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silica; 1 to 2 parts by weight of magnesium stearate.

[0122] In some embodiments of the present invention, the compound preparation comprises: 15-20 parts by weight of mofetilidine mesylate; 6-8 parts by weight of ritonavir; 4-6 parts by weight of sodium carboxymethyl starch; 32-35 parts by weight of copovidone; 18-21 parts by weight of lactose monohydrate; 9-11 parts by weight of microcrystalline cellulose; 1-3 parts by weight of polyethylene glycol; 1-2 parts by weight of anhydrous colloidal silica; 1-2 parts by weight of magnesium stearate.

[0123] In some embodiments of the present invention, the compound preparation further comprises a coating, such as Opadry II 85F620048-CN, etc.

[0124] In a second aspect of the present invention, the present invention provides a method for preparing the compound preparation described in the first aspect. In some embodiments of the present invention, the method comprises: performing a first mixing treatment on mofetilidine or mofetilidine mesylate, a ritonavir solid dispersion, and a first auxiliary material to obtain a first mixed product; performing a second mixing treatment on the first mixed product and a lubricant 1 to obtain a second mixed product; performing a first dry granulation treatment on the second mixed product to obtain a first dry granulation treatment product; and mixing the first dry granulation treatment product with a second auxiliary material to obtain the compound preparation.

[0125] The preparation method of the present invention has a simple process, avoiding the problem of easy delamination during tabletting caused by the large density difference between mofetilidine or mofetilidine mesylate and the ritonavir solid dispersion, thereby reducing the delamination risk during tabletting; in addition, the compound preparation prepared by the method of the present invention is more efficient than manufacturing two separate drugs, which can simplify the medication process of patients, improve the compliance and convenience of treatment of patients, and at the same time reduce the cost and trouble of patients purchasing and using multiple drugs; furthermore, the inventors found that the compound preparation prepared by the method of the present invention not only increases the exposure of mofetilidine in vivo under the condition of reducing the dosage of ritonavir, but also can reduce the toxic and side effects of ritonavir, and the two active ingredients can basically achieve synchronous release, avoiding the phenomenon that one active ingredient is released completely early while the other active ingredient is not released completely.

[0126] In some embodiments of the present invention, the method for preparing the compound preparation described in the first aspect may further include at least one of the following additional technical features:

[0127] In some embodiments of the present invention, the feeding weight ratio of moricizine or moricizine mesylate to the ritonavir solid dispersion is 1:(1-3). In some embodiments of the present invention, the feeding weight ratio of moricizine or moricizine mesylate to the ritonavir solid dispersion is 1:1, 1:1.2, 1:1.3, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.3, 1:2.5, 1:2.8, 1:3, etc.

[0128] It should be noted that the "feeding ratio" described in the present invention is the mass ratio of two substances.

[0129] In some embodiments of the present invention, the first excipient includes a disintegrant.

[0130] In some embodiments of the present invention, the disintegrant is selected from at least one of crospovidone, sodium carboxymethyl starch and sodium carboxymethylcellulose crosslinked. The inventors unexpectedly found during the experiment that during the preparation of the compound preparation, after adding the disintegrant such as crospovidone, sodium carboxymethyl starch or sodium carboxymethylcellulose crosslinked to the compound preparation, the degradation of moricizine and ritonavir under high temperature and water addition conditions can be avoided. Therefore, the crospovidone, sodium carboxymethyl starch and / or sodium carboxymethylcellulose crosslinked has the effect of inhibiting degradation.

[0131] In some embodiments of the present invention, the disintegrant is crospovidone.

[0132] In some embodiments of the present invention, the lubricant 1 is selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated castor oil, glyceryl behenate and magnesium lauryl sulfate.

[0133] In some embodiments of the present invention, the lubricant 1 is selected from at least one of magnesium stearate and sodium stearyl fumarate. The inventors found through a large number of experiments that when the lubricant is selected as magnesium stearate or sodium stearyl fumarate, the dissolution and stability of the compound preparation are better.

[0134] In some embodiments of the present invention, the ritonavir solid dispersion is obtained by the following method: mixing ritonavir, a carrier, a plasticizer and a glidant 1 for the third time to obtain a third mixed product; performing the second dry granulation treatment on the third mixed product, and performing hot melt extrusion treatment on the product obtained by the second dry granulation treatment to obtain the ritonavir solid dispersion. The solubility and bioavailability of ritonavir pure compound are extremely low. By using the method described in the present invention, the solubility and bioavailability of ritonavir can be improved, laying a foundation for the subsequent preparation of a stable compound preparation.

[0135] In some embodiments of the present invention, the first dry granulation treatment and the second dry granulation treatment are carried out in a dry granulator.

[0136] In some embodiments of the present invention, the hot melt extrusion treatment is carried out in a hot melt extruder.

[0137] In some embodiments of the present invention, the carrier is selected from at least one of copovidone, povidone, hypromellose, and sucrose.

[0138] In some embodiments of the present invention, the carrier is selected from copovidone.

[0139] In some embodiments of the present invention, the plasticizer is selected from at least one of polyethylene glycol, propylene glycol, glycerol, poloxamer, polysorbate 80, diethyl phthalate, triethyl citrate, octyl citrate, acetyltriethyl citrate, tributyl acetylcitrate, butyl stearate, glyceryl monostearate, stearyl alcohol, dibutyl stearate, dibutyl phthalate, dioctyl phosphate, and vitamin E-TPGS.

[0140] In some embodiments of the present invention, the plasticizer is selected from polyethylene glycol.

[0141] In some embodiments of the present invention, the glidant 1 is selected from anhydrous colloidal silica or talc powder.

[0142] In some embodiments of the present invention, the glidant 1 is selected from anhydrous colloidal silica.

[0143] In some embodiments of the present invention, the weight feeding ratio of ritonavir, the carrier, the plasticizer, and the glidant 1 is (3 - 8):(20 - 40):(1 - 6):(0.1 - 0.6). In some embodiments of the present invention, the weight feeding ratio of ritonavir, the carrier, the plasticizer, and the glidant 1 is (4 - 7):(20 - 40):(1 - 6):(0.1 - 0.6), (4 - 7):(32 - 35):(1 - 6):(0.1 - 0.6), (4 - 7):(32 - 35):(1 - 3):(0.1 - 0.6), (4 - 7):(32 - 35):(1 - 3):(0.2 - 0.5), etc.

[0144] In some embodiments of the present invention, the first excipient further includes at least one of a filler and a glidant 2.

[0145] In some embodiments of the present invention, the second excipient includes at least one of a lubricant 2 and colloidal silica hydrate.

[0146] In some embodiments of the present invention, the second excipient includes a lubricant 2.

[0147] In some embodiments of the present invention, the filler is selected from at least one of lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, siliconized microcrystalline cellulose, mannitol, corn starch, sucrose, cellulose lactose, and pregelatinized starch.

[0148] In some embodiments of the present invention, the filler is selected from at least one of lactose monohydrate and microcrystalline cellulose. Through a large number of experiments, the inventors found that when the filler is lactose monohydrate and / or microcrystalline cellulose, the dissolution and stability of the compound preparation are better.

[0149] In some embodiments of the present invention, the glidant 2 is selected from at least one of anhydrous colloidal silica and talc.

[0150] In some embodiments of the present invention, the lubricant 1 and the lubricant 2 are respectively selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated castor oil, glyceryl behenate, and magnesium lauryl sulfate.

[0151] In some embodiments of the present invention, the lubricant 1 and the lubricant 2 are respectively selected from at least one of magnesium stearate and sodium stearyl fumarate. Through a large number of experiments, the inventors found that when the lubricant is magnesium stearate or sodium stearyl fumarate, the dissolution and stability of the compound preparation are better.

[0152] In some embodiments of the present invention, the feeding ratio of the disintegrant, the filler, and the glidant 2 in the first excipient is (0 - 16):(8 - 55):(0.7 - 3). In some embodiments of the present invention, the feeding ratio of the disintegrant, the filler, and the glidant 2 in the first excipient is (4 - 16):(8 - 55):(0.7 - 3), (4 - 7):(8 - 55):(0.7 - 3), (4 - 16):(15 - 55):(0.7 - 3), (4 - 16):(23 - 33):(0.7 - 3), (4 - 7):(15 - 55):(0.7 - 3), (4 - 7):(23 - 33):(0.7 - 3), (4 - 16):(8 - 55):(1 - 3), (4 - 7):(15 - 55):(1 - 3), (4 - 7):(23 - 33):(1 - 3), etc.

[0153] In the third aspect of the present invention, the present invention provides a compound preparation. In some embodiments of the present invention, the compound preparation is obtained by the method described in the second aspect. The compound preparation prepared by the method of the present invention can improve the therapeutic effect of the drug and reduce the risk of treatment recurrence and relapse; in addition, the compound preparation is convenient for administration. Combining two drugs into one preparation can simplify the medication process of patients, improve patient compliance and treatment convenience; furthermore, the compound preparation reduces the dosage of ritonavir, reduces the toxic and side effects of ritonavir while increasing the exposure of mofetilide; and, the two active ingredients in the compound preparation can be basically released synchronously, avoiding the phenomenon that one of the active ingredients is released prematurely and the combined treatment cannot be achieved.

[0154] In the fourth aspect of the present invention, the present invention provides a method for improving the dissolution of ritonavir. In some embodiments of the present invention, the method includes preparing mofetilide or mofetilide mesylate and ritonavir into a compound preparation according to the method described in the second aspect.

[0155] In the fifth aspect of the present invention, the present invention provides the use of the compound preparation described in the first aspect or the third aspect in the preparation of a drug for treating and / or preventing hepatitis B virus infection.

[0156] In the sixth aspect of the present invention, the present invention provides a method for determining the dissolution rate of the compound preparation described in the first aspect or the third aspect. In some embodiments of the present invention, the method includes placing the compound preparation in a first container and placing hydrochloric acid solution in a second container; after placing the first container in the second container, stirring treatment is carried out to obtain a dissolution solution; the peak area of the dissolution solution is detected by HPLC, and the dissolution rate of the compound preparation is calculated.

[0157] When the dissolution rate of the compound preparation is determined by the method of the present invention, the dissolution rates of the two active ingredients in the compound preparation are appropriate, and they can be basically completely dissolved in 120 min, and the phenomenon that the RSD of the dissolution rate in the first 60 min is relatively large is improved.

[0158] In some embodiments of the present invention, the method may further include at least one of the following additional technical features:

[0159] In some embodiments of the present invention, the stock solution concentration of the hydrochloric acid solution is 0.05 - 0.15 mol / L. In some embodiments of the present invention, the stock solution concentration of the hydrochloric acid solution is 0.05 mol / L, 0.07 mol / L, 0.1 mol / L, 0.12 mol / L, 0.15 mol / L, etc.

[0160] In some embodiments of the present invention, the dosage of the compound preparation is 1 tablet, and the tablet weight is the weight described in the present invention, that is, 600 mg to 900 mg, such as 600 mg, 750 mg, 850 mg, 900 mg.

[0161] In some embodiments of the present invention, the dosage of the hydrochloric acid solution is 500 - 1000 mL, such as 500 mL, 600 mL, 700 mL, 800 mL, 900 mL, 1000 mL, etc.

[0162] In some embodiments of the present invention, the dosage of the hydrochloric acid solution is 800 - 1000 mL, such as 800 mL, 850 mL, 900 mL, 950 mL, 1000 mL.

[0163] In some embodiments of the present invention, the first container is a rotating basket, and the second container is a dissolution cup.

[0164] In some embodiments of the present invention, the aperture of the rotating basket is 10 - 40 mesh, such as 10 mesh, 20 mesh, 30 mesh or 40 mesh, etc.

[0165] In some embodiments of the present invention, the aperture of the rotating basket is 10 mesh.

[0166] In some embodiments of the present invention, the rotation speed of the stirring is 75 - 110 rpm, such as 75 rpm, 95 rpm, 100 rpm, 105 rpm or 110 rpm, etc.

[0167] In some embodiments of the present invention, the rotation speed of the stirring is 90 - 110 rpm, such as 90 rpm, 95 rpm, 100 rpm, 105 rpm or 110 rpm, etc. In some embodiments of the present invention, the rotation speed of the stirring is 100 rpm.

[0168] Beneficial effects:

[0169] 1. The compound preparation of the present invention can increase the blood drug concentration of mofetilide after administration, and at the same time can solve the problem of decreased exposure caused by the induction effect of long-term administration; in addition, by reducing the dosage of ritonavir, the compound preparation can reduce the toxic and side effects brought by ritonavir in combination therapy while increasing the exposure of mofetilide.

[0170] 2. When mofetilide and ritonavir are taken simultaneously, it is easy for patients to take too much or miss one of the drugs, which brings inconvenience to patients and affects the treatment effect. The present invention innovatively provides a mofetilide-ritonavir compound preparation, which is convenient for administration and can improve patient compliance.

[0171] 3. When mofetilide and ritonavir are formulated into the compound preparation of the present invention, the two active ingredients (mofetilide and ritonavir) can basically achieve synchronous release, avoiding the phenomenon that one of the active ingredients is released prematurely and unable to be used for combined treatment.

[0172] 4. Mofetilide and ritonavir will interact with each other and degrade under the conditions of high temperature and adding water. Through a large amount of creative work, the present invention has screened excipients such as crospovidone, croscarmellose sodium, and sodium carboxymethyl starch, which can all effectively inhibit the degradation of the active ingredients, and crospovidone has the best effect.

[0173] 5. The present invention adopts the dry granulation technology to granulate the mofetilide raw material drug, the ritonavir solid dispersion and the excipients together after mixing, which can effectively reduce the risk of tablet lamination.

[0174] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention. Detailed Description of the Invention

[0175] The embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as a limitation of the present invention.

[0176] It should be noted that the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include one or more of such features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0177] Detailed Description of the Present Invention

[0178] Definitions and General Terms

[0179] Before describing the present invention in more detail, it should be understood that the present invention is not limited to the specific embodiments described herein, as such embodiments may vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not used to limit. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications and patents referred to herein are incorporated herein by reference in their entirety.

[0180] Where a numerical range is provided, it is understood that, unless the context clearly indicates otherwise, to one tenth of the unit of the lower limit, the intervening values between the upper and lower limits of the range and any other stated or intervening values within the said range are covered by the present invention. The upper and lower limits of these smaller ranges may independently be included within the smaller range and are also covered by the present invention, subject to any specific exclusionary limitations within the said range. Where the range includes one or both of the said limits, ranges excluding either or both of those included limits are also included in the present invention.

[0181] The terms “optionally”, “optional” or “option” mean that the subsequent recited event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, the composition according to the present invention contains an optional binder, which means that the composition may or may not contain a binder.

[0182] The term “comprising” or “including” is an open-ended expression, i.e., it includes what is specified in the present invention but does not exclude other aspects.

[0183] The term “pharmaceutically acceptable” means that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith. Preferably, “pharmaceutically acceptable” as used in the present invention means approved by a federal regulatory agency or a national government or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, particularly in humans.

[0184] TID administration: Administer 3 times a day.

[0185] BID administration: Administer 2 times a day.

[0186] For these and other pharmaceutically acceptable excipients or processes mentioned herein, reference may be made to the extensive literature on this subject, specifically see Handbook of Pharmaceutical Excipients, 3rd edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, edited by H.P. Fiedler, 4th edition, edited by Cantor, Aulendorf and earlier editions.

[0187] The term "parts by weight" refers to the number of parts by mass obtained by comparing the mass of a certain component of a composition with the masses of other components.

[0188] Mofetilidine mesylate was prepared by the inventors themselves. The synthesis process can be found in Patent WO2008 / 154817, and the crystal form patent is WO2014 / 048355.

[0189] The embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as a limitation of the present invention. For those not specified in the embodiments regarding specific technologies or conditions, they shall be carried out according to the technologies or conditions described in the literature in this field or according to the product specifications. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0190] In addition, it should be noted that the "mofetilidine mesylate - ritonavir combination" described in Embodiments 1 - 6 of the present invention is also abbreviated as the "mofetilidine - ritonavir combination", that is, the "mofetilidine mesylate - ritonavir combination" and the "mofetilidine - ritonavir combination" refer to the same drug. In addition, the mofetilidine - ritonavir combination without mesylate salt is also within the protection scope of the present invention. That is, whether it contains mesylate salt or not, the mofetilidine - ritonavir combination can achieve the technical effects of the present invention.

[0191] Example 1: Compatibility test of disintegrant and excipients

[0192] Experimental method:

[0193] The mofetilidine mesylate raw material (the specific synthesis process can be found in Patent WO2008 / 154817) is denoted as API 1 (calculated as mofetilidine, the molecular weight ratio of mofetilidine to mofetilidine mesylate is 0.8413), and the ritonavir solid dispersion (the specific synthesis process can be found in Example 2) is denoted as API 2 (calculated as ritonavir, the absolute content is 15.68%, components: ritonavir, copovidone, polyethylene glycol 6000, and colloidal silicon dioxide (anhydrous) A200 ①).

[0194] The ratio (w:w) of the two raw materials is set as: API 1:API 2 = 1:2.2 (According to the target specification of 120 mg mofetilidine and 50 mg ritonavir in the prescription, the material ratio is converted, and it is specifically calculated according to the ratio of mofetilidine mesylate and ritonavir solid dispersion in Prescription 1).

[0195] The ratio ((w:w):w) of the raw material and the disintegrant is set as; (API 1:API 2):disintegrant = (1:2.2):1

[0196] Accurately weigh the active pharmaceutical ingredient and the corresponding excipients, place them in vials. For each group of samples, 16 vials are weighed in parallel for content and related substances detection. Among them, 8 vials are added with ultrapure water accounting for 5% of the content weight, and the other 8 vials are not added with water. After all samples are stirred evenly with a glass capillary, break the capillary and keep the end in contact with the sample inside the vial, and seal it by a suitable method.

[0197] Place the prepared samples at room temperature in the dark and at high temperature (50 °C) for 7 days and 21 days respectively, take samples and use a high-performance liquid chromatograph to detect the content and related substances.

[0198] The experimental results are shown in Table 1. Among them, Group 1 is Mofetilide Mesylate API 1 + Ritonavir Solid Dispersion API 2; Group 2 is Mofetilide Mesylate API 1 + Ritonavir Solid Dispersion API 2 + Sodium Carboxymethyl Starch; Group 3 is Mofetilide Mesylate API 1 + Ritonavir Solid Dispersion API 2 + Cross-linked Carboxymethylcellulose Sodium; Group 4 is Mofetilide Mesylate API 1 + Ritonavir Solid Dispersion API 2 + Cross-linked Povidone.

[0199] Table 1: Results of Compatibility Test of Disintegrants with Active Pharmaceutical Ingredients and Excipients

[0200]

[0201]

[0202] ND indicates that no impurities are detected.

[0203] The experimental results show that: under the conditions of room temperature, room temperature with water added, high temperature and high temperature with water added, after mofetilide and ritonavir are mixed with the disintegrants described in the present invention, the stability is good. Cross-linked povidone, cross-linked carboxymethylcellulose sodium and sodium carboxymethyl starch all have the effect of inhibiting degradation. Among them, cross-linked povidone has the strongest ability to inhibit degradation.

[0204] Example 2: Prescription and Preparation of Mofetilide Ritonavir Compound

[0205] 1. Preparation Method of Mofetilide Ritonavir Compound Tablets

[0206] The inventors found during the preparation of the compound preparation that the main difficulty in making mofetilide or its salt and ritonavir into compound tablets lies in the problem of easy layering during the tabletting process due to the large density difference between mofetilide or its salt and ritonavir solid dispersion. After trying various different preparation methods (such as direct compression, etc.), the inventors found that by using the dry granulation technology, the active pharmaceutical ingredient of mofetilide, ritonavir solid dispersion and excipients are mixed and granulated together, reducing the risk of tabletting layering. The specific method is as follows:

[0207] (1) Preparation of Ritonavir Solid Dispersion

[0208] Mix the weighed ritonavir, carrier (such as copovidone), plasticizer (such as polyethylene glycol 6000), and glidant (such as colloidal silicon dioxide (anhydrous) A200①), sieve them, and then mix again to evenly disperse the materials to obtain a pre-mixed material after sieving. Granulate the pre-mixed material after sieving by dry granulation to obtain dry granules. Use a hot melt extruder to obtain an amorphous hot melt extrudate from the dry granules, and then pulverize it to obtain a ritonavir solid dispersion.

[0209] (2) Preparation of mofetilide ritonavir tablets

[0210] Mix the ritonavir solid dispersion, mofetilide or its salt, filler (such as lactose monohydrate Flowlac100 and microcrystalline cellulose 102), disintegrant (such as crospovidone XL), and glidant (such as colloidal silicon dioxide (anhydrous) A200②), sieve them, and then mix again to obtain a first mixture. Take about 3 times the first mixture of the lubricant (added internally) and mix it with the lubricant (added internally) (such as sodium stearyl fumarate) to obtain a second mixture. Granulate the second mixture by dry granulation to obtain dry granules. Take about 3 times the dry granules of the externally added excipients (externally added) and mix them with the externally added excipients (externally added) (the externally added excipients such as sodium stearyl fumarate or colloidal silicon dioxide (anhydrous) A200②) to obtain a total mixed granule. Compress the total mixed granule into tablets and coat them to obtain coated tablets.

[0211] Note: The colloidal silicon dioxide (anhydrous) A200① and colloidal silicon dioxide (anhydrous) A200② in the present invention are the same substance, that is, colloidal silicon dioxide (anhydrous) A200. The ① and ② therein are only used to distinguish the colloidal silicon dioxide (anhydrous) added in the preparation of the ritonavir solid dispersion and the colloidal silicon dioxide (anhydrous) added in the preparation of mofetilide ritonavir tablets.

[0212] 2. Information on the prescriptions of mofetilide ritonavir compound tablets

[0213] The ingredient information of prescriptions 1 - 38 of the mofetilide ritonavir compound prepared in the present invention is shown in Table 2 - 11 below, where "proportion %" is the weight percentage of each prescription ingredient, and the total is 100. The prescription weights are in specifications such as 850 mg, 750 mg, 600 mg, etc. Prescriptions without the prescription weight information written in the table are all 750 mg in weight. The coating material is not included in the prescription ingredients, and it accounts for 3.0% ± 1.0% of the core weight of the prescription.

[0214] Table 2: Prescription information table of copovidone and polyethylene glycol 6000 in different proportions

[0215]

[0216] Table 3: Prescription information table of different types of fillers

[0217]

[0218]

[0219] Table 4: Prescription Information Table with Different Filler Proportions

[0220]

[0221]

[0222] Table 5: Prescription Information Table with Different Disintegrant Types

[0223]

[0224]

[0225] Table 6: Prescription Information Table with Different Disintegrant Proportions

[0226]

[0227] Table 7: Prescription Information Table with Different Glidant Proportions

[0228]

[0229]

[0230] Table 8: Prescription Information Table for Investigating Different Glidant Proportions

[0231]

[0232]

[0233] Table 9: Prescription Information Table with Different Lubricant (Sodium Stearyl Fumarate, Internal Addition) Proportions

[0234]

[0235] Table 10: Prescription Information Table with Different Lubricant (Sodium Stearyl Fumarate, External Addition) Proportions

[0236]

[0237]

[0238] Table 11: Specific Prescription Information for Prescriptions 36, 37 and 38

[0239]

[0240]

[0241] Example 3: Investigation of the properties of the formulation of mofetilide and ritonavir combination

[0242] 1. Investigation of the dissolution of the formulation

[0243] Dissolution test method:

[0244] The dissolution test was carried out according to the dissolution test method (Method 1 in General Chapter 0931 of Chinese Pharmacopoeia 2020 Edition). Using 0.1M HCl as the dissolution medium, the basket method (10-mesh basket), 900 mL, 100 rpm. The dissolution of Formulations 1-38 of the present invention (or the formulation of the coated tablets) and ritonavir tablets was measured successively at 15 min, 30 min, 45 min, 60 min, 90 min and 120 min. The acceptable standard for dissolution was ≥ 80% at 120 min.

[0245] Using 0.1 mol / L hydrochloric acid as the dissolution medium, the device was tentatively the basket method, 75 rpm, the volume of the dissolution curve medium was 900 ml, and the medium temperature was 37 °C. Sampling was carried out at 5, 10, 15, 30, 45, and 60 min respectively, and the subsequent filtrate was taken. The samples were quantitatively analyzed by high performance liquid chromatography (HPLC). The dissolution of mofetilide mesylate capsules was investigated.

[0246] Experimental results:

[0247] The results of the dissolution test showed that:

[0248] 1) The dissolution of mofetilide and ritonavir in Formulations 1-38 of the present invention at 120 min was greater than 80%; the dissolution of mofetilide and ritonavir in most formulations at 120 min was greater than 95%; the dissolution of mofetilide and ritonavir in most formulations at 90 min was greater than 90%; in some formulations, the dissolution of mofetilide and ritonavir reached more than 80% at 60 min; in some other formulations, the dissolution of mofetilide and ritonavir reached more than 80% at 45 min. The dissolution results of some formulations of the present invention are shown in Table 12.

[0249] 2) The comparative dissolution data of mofetilide mesylate capsules, ritonavir tablets and mofetilide and ritonavir tablets (Formulation 1) are shown in Table 13. The data show that in the same medium, for mofetilide mesylate capsules using the basket method, 75 rpm, the dissolution rate is relatively fast, and the dissolution at 10 min can reach more than 90%. While for the single-component ritonavir tablets using the basket method (10-mesh basket), 100 rpm, a higher rotation speed, the dissolution rate is still significantly slower than that of mofetilide mesylate capsules, and the dissolution at 60 min reaches 90%. In the compound tablets of the present invention, the dissolution rates of mofetilide and ritonavir can be basically the same, and the synchronous release of mofetilide and ritonavir can be achieved.

[0250] Table 12: Dissolution results of some formulations of the present invention

[0251]

[0252]

[0253] Table 13: Dissolution comparison data of mofetilidine mesylate capsules, ritonavir tablets, and mofetilidine ritonavir tablets (Prescription 1)

[0254]

[0255] 2. Investigation of prescription stability

[0256] Prescription stability test method

[0257] Experimental method:

[0258] Long-term test: Place the double aluminum plates containing mofetilidine ritonavir tablets under the conditions of temperature 30±2°C, relative humidity 65±5%RH and temperature 25±2°C, 60±5%RH for 12 months. Samples are taken at the end of the 0th month, 3rd month, 6th month, 9th month, and 12th month during the test to detect appearance, moisture, dissolution, content, related substances, etc.

[0259] Accelerated test: Place the double aluminum plates containing mofetilidine ritonavir tablets under the conditions of temperature 40±2°C and relative humidity 75±5%RH for 6 months. Samples are taken at the end of the 0th month, 1st month, 2nd month, 3rd month, and 6th month during the test to detect appearance, moisture, dissolution, content, related substances, etc.

[0260] Stress test - high temperature test: Place mofetilidine ritonavir tablets in a suitable open container. Place them at 60°C for 30 days, and take samples on the 30th day to detect related substances, etc.

[0261] The dissolution test results show that the stabilities of the prescriptions of the present invention are all good in high temperature and high humidity environments.

[0262] Example 4: Effects of surfactants, antioxidants, and coatings on the prescription

[0263] The inventors also investigated the effects of surfactants, antioxidants, and coatings on the prescription in the experiment:

[0264] 1) The inventors studied the effect of adding surfactants such as adding and externally adding sodium dodecyl sulfate (both accounting for 1.00% of the prescription weight) to the prescription on the dissolution of the prescription. The results show that adding and externally adding sodium dodecyl sulfate (both accounting for 1.00% of the prescription weight) have no obvious effect on the dissolution of the prescription. That is, the dissolution of the prescriptions with added surfactants can all reach more than 80%, meeting the standards.

[0265] 2) The inventors studied the antioxidant and dissolution effects of butylated hydroxytoluene (0.13 weight ratio of the prescription), EDTA-2Na (0.10 weight ratio of the prescription) or BHT (0.02 weight ratio of the prescription) in the prescription. The results showed that the antioxidant butylated hydroxytoluene, EDTA-2Na or BHT had no obvious inhibitory effect on the growth of impurities in the prescription, and had no obvious effect on dissolution. The dissolution of the prescription with the addition of antioxidant butylated hydroxytoluene, EDTA-2Na or BHT can reach more than 80% in 120 minutes, which meets the standard.

[0266] 3) The inventors investigated the effects of different coatings (such as Opadry II 85F620048-CN, Opadry 321A120020-CN, etc.) on dissolution. For example, Opadry II 85F620048-CN (composition: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and yellow iron oxide) was used as the coating material, and the coating solution concentration was 15.00% (W / W). The coating weight gain of the target hardness tablets was investigated, and the effect of the theoretical coating weight gain of 2.0%, 3.0%, and 4.0% on the dissolution of the coated tablets was investigated. The results of the investigation of different coating weight gain showed that there was no significant difference in the dissolution rate when the coating weight gain was 2.05% to 4.14%, and the obtained coated tablets had a good appearance. The dissolution of the prescription with the coating reached more than 80% in 120 minutes, which met the standard.

[0267] Example 5: PK experiment of compound administration of murfecidin (GLS4) and ritonavir (RTV)

[0268] 1. Test method 1:

[0269] The effects of different doses of ritonavir on the PK absorption of mofetil were compared in beagle dogs (weight 7-11 kg, male, age 10-12 months, oral administration, 3 dogs per group, three-way cross-administration):

[0270] Beagles were orally administered with a combination of ritonavir (100, 50, 25 mg / dog) and mofecillin (120 mg / dog), as well as the ritonavir-mofecillin compound preparation of the present invention, BID administration with an interval of 8 hours.

[0271] After administration, venous blood was collected at time points (0.25, 0.5, 1, 2, 4, 6, 8, 8.5, 9, 10, 12, and 24 hours) and collected in anticoagulant tubes with EDTA-K2. After liquid-liquid extraction, plasma samples were quantitatively analyzed on a triple quadrupole tandem mass spectrometer using multiple reaction ion monitoring (MRM). Pharmacokinetic parameters were calculated using WinNonlin 6.3 software using the non-compartmental model method.

[0272] The experimental results are as follows:

[0273] Data 1 is the canine PK data of the combined administration of mofetilide and ritonavir; Data 2 and Data 3 are the canine PK data of the administration of the compound preparation mofetilide ritonavir tablets respectively. The drug specification information is shown in Table 14. The amounts in the mofetilide specifications in the table do not include the amount of mesylate. For example, 120 mg / tablet of mofetilide refers to the content of mofetilide, not the content of mofetilide mesylate. Another example is that 100 mg / capsule of mofetilide mesylate, 240 mg / animal in the combined administration of mofetilide capsules + ritonavir tablets or the administration of mofetilide ritonavir tablets refers to the content of mofetilide, not the content of mofetilide mesylate.

[0274] Table 14: PK Experimental Information of Mofetilide and Ritonavir in Beagle Dogs in Combination / Tablets

[0275]

[0276] Note: All mofetilide mesylate capsules used in the experiment are samples for Phase IIb clinical trials, with the same prescription and process; the ritonavir tablets are samples used in Phase IIb clinical trials and are produced by AbbVie.

[0277] Table 15: PK Parameters of Mofetilide (GLS4) and Ritonavir (RTV) in Beagle Dogs after Combined Administration

[0278]

[0279] The experimental results show that: compared with the combined use of mofetilide mesylate capsules and ritonavir tablets (Data 1), the mofetilide ritonavir compound tablets can increase the exposure of mofetilide in dogs (Data 2 and Data 3); after the dosage of ritonavir (RTV) is reduced from 50 mg to 25 mg, mofetilide (GLS4) can still maintain a relatively high exposure. Therefore, the mofetilide ritonavir compound of the present invention can reduce the dosage of ritonavir, thereby reducing the toxic and side effects caused by ritonavir and increasing the exposure of mofetilide.

[0280] 2. Test Method 2:

[0281] Compare the effects of mofetilide at different doses on PK absorption in Beagle dogs (body weight 7 - 11 kg, male, age 10 - 12 months, 4 animals per group orally, three - cross administration):

[0282] Compare the combined use of ritonavir (100, 25 mg / animal) and mofetilide (120, 100, 80 mg / animal) administered orally to Beagle dogs respectively, and the mofetilide ritonavir compound preparation of the present invention, with BID administration and an 8 - h dosing interval.

[0283] Venous blood samples were collected at time points (0.5, 1, 2, 4, 6, 8, 8.5, 9, 10, 12, and 24 hours) after administration and collected in anticoagulant tubes containing EDTA-K2. After liquid-liquid extraction of the plasma samples, quantitative analysis was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode. Pharmacokinetic parameters were calculated using WinNonlin 6.3 software with the non-compartmental model method.

[0284] The experimental results are as follows:

[0285] Data 1 is the PK data of dogs administered with mofetilide and ritonavir in combination; Data 2-1 and Data 3-1 are the PK data of dogs administered with the compound preparation mofetilide ritonavir tablets, both administered BID with an 8-hour dosing interval. The drug specification information is shown in Table 16. The blood drug concentrations and pharmacokinetic parameters of mofetilide and ritonavir in Beagle dogs are shown in Table 17.

[0286] Table 16: Special PK Information of Mofetilide and Ritonavir in Beagle Dogs

[0287]

[0288] Note: All mofetilide mesylate capsules used in the experiment were samples for Phase IIb clinical trials, with the same prescription and process; the ritonavir tablets were samples used in Phase IIb clinical trials and were produced by AbbVie.

[0289] Table 17: PK Parameters in Beagle Dogs after Administration of Mofetilide and Ritonavir

[0290]

[0291] The experimental results show that the exposure of mofetilide in dogs in the combination of high-dose mofetilide (120 mg * 2 / animal) and ritonavir (100 mg * 2 / animal) (Data 1) is similar to the exposure of mofetilide in dogs in the low-dose mofetilide ritonavir compound tablets (80 mg / 25 mg) (Data 3-1), indicating that a reduced dose of mofetilide in the present invention's compound can also achieve a good exposure.

[0292] Example 6: Development of the Dissolution Test Method of the Present Invention

[0293] In order to enable the better dissolution of each active ingredient in the mofetilide and ritonavir compound tablets, the inventors studied the dissolution method. The inventors studied the dissolution medium, dissolution device, and rotation speed, and selected 0.1 mol / L hydrochloric acid or water + 0.06 M / L AEO (aliphatic alcohol polyoxyethylene ether) as the dissolution medium, with the dissolution curve medium volume being 900 ml. The dissolution device was selected as the basket method (10 / 40 mesh basket) or the paddle method, the rotation speed was selected as 100 rpm or 75 rpm, and the medium temperature was 37°C. Sampling was carried out at 15, 30, 45, 60, 90, and 120 min respectively, and the subsequent filtrate was taken. The samples were quantitatively analyzed using a high performance liquid chromatograph (HPLC). The dissolution degree and RSD value of the mofetilide and ritonavir tablets (such as 120 mg / 50 mg, formulation 23) were investigated. The test results are shown in Table 18.

[0294] The experimental results show that: compared with other methods, under the conditions of the basket method (10-mesh basket), 100 rpm, and 0.1 mol / L hydrochloric acid solution, the RSD of the dissolution degree at 60 min is relatively small. Therefore, using this method to measure the dissolution results of the compound preparation of the present invention is more accurate.

[0295] Table 18: Dissolution curve results of formulation 23 in different devices

[0296]

[0297]

[0298] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0299] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound preparation, characterized in that: The invention comprises active ingredients, wherein the active ingredients include mufesiden or its salt and ritonavir.

2. The compound preparation according to claim 1, characterized in that: The methanesulfonate salt is methanesulfonate, The weight ratio of mofecillin mesylate to ritonavir is (1.60-6):1; Optionally, the weight ratio of the mofetil mesylate to the ritonavir is (1.80-5.70):1; Optionally, the weight ratio of the mofetil mesylate to the ritonavir is (2-6):1; Preferably, the weight ratio of the mofetil mesylate to the ritonavir is (2-3):

1.

3. The compound preparation according to claim 2, characterized in that: Further comprising a pharmaceutically acceptable excipient, wherein the excipient comprises a disintegrant; Preferably, the disintegrant is selected from at least one of crospovidone, croscarmellose sodium and sodium carboxymethyl starch; More preferably, the disintegrant is cross-linked polyvinylpyrrolidone; Optionally, the auxiliary material further comprises: at least one of a filler, a plasticizer, a glidant, and a lubricant; Optionally, the filler is selected from at least one of lactose monohydrate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, silicified microcrystalline cellulose, mannitol, corn starch, sucrose, cellulose lactose and pregelatinized starch; Preferably, the filler is selected from at least one of lactose monohydrate and microcrystalline cellulose; Optionally, the plasticizer is selected from at least one of polyethylene glycol, propylene glycol, glycerol, poloxamer, polysorbate 80, diethyl phthalate, triethyl citrate, octyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, butyl stearate, glyceryl monostearate, stearyl alcohol, dibutyl stearic acid, dibutyl phthalate, dioctyl phosphate and vitamin E-TPGS; Preferably, the plasticizer is selected from polyethylene glycol; Optionally, the glidant is selected from at least one of anhydrous colloidal silicon dioxide and talc; Preferably, the glidant is selected from anhydrous colloidal silicon dioxide; Optionally, the lubricant is selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated castor oil, glyceryl behenate and magnesium lauryl sulfate; Preferably, the lubricant is selected from at least one of magnesium stearate and sodium stearyl fumarate; Optionally, the compound preparation further comprises a pharmaceutically acceptable carrier; Preferably, the carrier is selected from at least one of copovidone, povidone, hypromellose and hydroxypropyl cellulose; More preferably, the carrier is selected from copovidone.

4. The compound preparation according to claim 3, characterized in that: The weight ratio of the disintegrant to the compound preparation is (0-0.16):1; Optionally, the weight ratio of the disintegrant to the compound preparation is (0.04-0.14):1; Optionally, the weight ratio of the disintegrant to the compound preparation is (0.04-0.07):1; Optionally, the weight ratio of the filler to the composite preparation is (0.00-0.65):1; Optionally, the weight ratio of the filler to the composite preparation is (0.05-0.65):1; Optionally, the weight ratio of the filler to the composite preparation is (0.08-0.55):1; Optionally, the weight ratio of the filler to the composite preparation is (0.15-0.55):1; Optionally, the weight ratio of the filler to the composite preparation is (0.23-0.33):1; Optionally, the weight ratio of the plasticizer to the compound preparation is (0.01-0.06):1; Optionally, the weight ratio of the plasticizer to the compound preparation is (0.01-0.03):1; Optionally, the weight ratio of the glidant to the compound preparation is (0.00-0.04):1; Optionally, the weight ratio of the glidant to the compound preparation is (0.007-0.04):1; Optionally, the weight ratio of the glidant to the compound preparation is (0.01-0.03):1; Optionally, the weight ratio of the lubricant to the compound preparation is (0.007-0.07):1; Optionally, the weight ratio of the lubricant to the compound preparation is (0.007-0.04):1; Optionally, the weight ratio of the lubricant to the compound preparation is (0.02-0.07):1; Optionally, the weight ratio of the lubricant to the compound preparation is (0.01-0.03):1; Optionally, the weight ratio of the carrier to the composite preparation is (0.05-0.40):1; Optionally, the weight ratio of the carrier to the composite preparation is (0.2-0.4):1; Optionally, the weight ratio of the carrier to the compound preparation is (0.32-0.35):

1.

5. The compound preparation according to claim 4, characterized in that: The weight ratio of the mofetil mesylate to the compound preparation is (0.15-0.25):1; Optionally, the weight ratio of the ritonavir to the compound preparation is (0.03-0.08):1; Optionally, the weight ratio of the ritonavir to the compound preparation is (0.04-0.07):1; Optionally, the weight ratio of the cross-linked polyvinylpyrrolidone to the composite preparation is (0.00-0.16):1; Optionally, the weight ratio of the cross-linked polyvinylpyrrolidone to the composite preparation is (0.04-0.14):1; Optionally, the weight ratio of the cross-linked polyvinylpyrrolidone to the compound preparation is (0.04-0.07):1; Optionally, the weight ratio of the cross-linked sodium carboxymethyl cellulose to the compound preparation is (0.04-0.07):1; Optionally, the weight ratio of the sodium carboxymethyl starch to the compound preparation is (0.04-0.07):1; Optionally, the weight ratio of the copovidone to the composite preparation is (0.05-0.40):1; Optionally, the weight ratio of the copovidone to the composite preparation is (0.20-0.40):1; Optionally, the weight ratio of the copovidone to the composite preparation is (0.32-0.35):1; Optionally, the weight ratio of the lactose monohydrate to the compound preparation is (0.00-0.39):1; Optionally, the weight ratio of the lactose monohydrate to the compound preparation is (0.09-0.24):1; Optionally, the weight ratio of the lactose monohydrate to the compound preparation is (0.14-0.22):1; Optionally, the weight ratio of the microcrystalline cellulose to the compound preparation is (0.00-0.45):1; Optionally, the weight ratio of the microcrystalline cellulose to the compound preparation is (0.05-0.45):1; Optionally, the weight ratio of the microcrystalline cellulose to the compound preparation is (0.05-0.32):1; Optionally, the weight ratio of the microcrystalline cellulose to the compound preparation is (0.07-0.15):1; Optionally, the weight ratio of the silicified microcrystalline cellulose to the compound preparation is (0.08-0.12):1; Optionally, the weight ratio of the silicified microcrystalline cellulose to the compound preparation is (0.12-0.24):1; Optionally, the weight ratio of the pregelatinized starch to the compound preparation is (0.08-0.10):1; Optionally, the weight ratio of the anhydrous calcium hydrogen phosphate to the compound preparation is (0.2-0.35):1; Optionally, the weight ratio of the polyethylene glycol to the compound preparation is (0.01-0.06):1; Optionally, the weight ratio of the polyethylene glycol to the compound preparation is (0.01-0.03):1; Optionally, the weight ratio of the anhydrous colloidal silicon dioxide to the composite preparation is (0.00-0.04):1; Optionally, the weight ratio of the anhydrous colloidal silicon dioxide to the composite preparation is (0.007-0.04):1; Optionally, the weight ratio of the anhydrous colloidal silicon dioxide to the composite preparation is (0.01-0.03):1; Optionally, the weight ratio of the sodium stearyl fumarate to the compound preparation is (0.02-0.07):1; Optionally, the weight ratio of the sodium stearyl fumarate to the compound preparation is (0.03-0.05):1; Optionally, the weight ratio of the magnesium stearate to the compound preparation is (0.007-0.04):1; Optionally, the weight ratio of the magnesium stearate to the compound preparation is (0.01-0.03):

1.

6. The compound preparation according to claim 1, characterized in that: The dosage form of the compound preparation is selected from tablets, powders, granules, capsules or pills; Optionally, the dosage form of the compound preparation is selected from tablets.

7. The compound preparation according to any one of claims 1 to 6, characterized in that: include: 15-25 parts by weight of mofetil mesylate; 3 to 8 parts by weight of ritonavir; 0 to 16 parts by weight of cross-linked polyvinylpyrrolidone; 20 to 40 parts by weight of copolyvidone; 0 to 39 parts by weight of lactose monohydrate; 5 to 45 parts by weight of microcrystalline cellulose; 1 to 6 parts by weight of polyethylene glycol; 0.7 to 4 parts by weight of anhydrous colloidal silicon dioxide; 2 to 7 parts by weight of sodium stearyl fumarate; or, including: 15-25 parts by weight of mofetil mesylate; 4 to 7 parts by weight of ritonavir; 4 to 14 parts by weight of cross-linked polyvinylpyrrolidone; 32-35 parts by weight of copolyvidone; 9 to 24 parts by weight of lactose monohydrate; 5 to 32 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 3 parts by weight of anhydrous colloidal silicon dioxide; 3 to 5 parts by weight of sodium stearyl fumarate; or, including: 15-25 parts by weight of mofetil mesylate; 3 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of cross-linked polyvinylpyrrolidone; 20 to 35 parts by weight of copolyvidone; 14 to 20 parts by weight of lactose monohydrate; 9 to 25 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1-2 parts by weight of anhydrous colloidal silicon dioxide; 3-5 parts by weight of sodium stearyl fumarate; or, including: 15 to 25 parts by weight of mofetil mesylate; 3 to 8 parts by weight of ritonavir; 0 to 16 parts by weight of cross-linked polyvinylpyrrolidone; 20 to 40 parts by weight of copolyvidone; 0 to 39 parts by weight of lactose monohydrate; 5 to 45 parts by weight of microcrystalline cellulose; 1 to 6 parts by weight of polyethylene glycol; 0.7 to 4 parts by weight of anhydrous colloidal silicon dioxide; 0.7 to 4 parts by weight of magnesium stearate; or, including: 15 to 25 parts by weight of mofecillin mesylate; 4 to 7 parts by weight of ritonavir; 4 to 14 parts by weight of cross-linked polyvinylpyrrolidone; 32-35 parts by weight of copolyvidone; 9 to 24 parts by weight of lactose monohydrate; 5 to 32 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 3 parts by weight of anhydrous colloidal silicon dioxide; 1 to 3 parts by weight of magnesium stearate; or, including: 15 to 20 parts by weight of mofecillin mesylate; 3 to 8 parts by weight of ritonavir; 4 to 8 parts by weight of cross-linked polyvinylpyrrolidone; 20 to 35 parts by weight of copolyvidone; 17-22 parts by weight of lactose monohydrate; 10 to 31 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 2.5 parts by weight of magnesium stearate; or, including: 15-20 parts by weight of mofetil mesylate; 6-8 parts by weight of ritonavir; 4 to 6 parts by weight of cross-linked polyvinylpyrrolidone; 32-35 parts by weight of copolyvidone; 27-30 parts by weight of anhydrous calcium hydrogen phosphate; 1-3 parts by weight of polyethylene glycol; 1-2 parts by weight of anhydrous colloidal silicon dioxide; 3-4 parts by weight of sodium stearyl fumarate; or, including: 15-20 parts by weight of mofetil mesylate; 6-8 parts by weight of ritonavir; 5 to 8 parts by weight of cross-linked polyvinylpyrrolidone; 32-35 parts by weight of copolyvidone; 17-20 parts by weight of lactose monohydrate; 8 to 10 parts by weight of pregelatinized starch; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 3 parts by weight of magnesium stearate; or, including: 15-20 parts by weight of mofetil mesylate; 6-8 parts by weight of ritonavir; 5 to 8 parts by weight of cross-linked polyvinylpyrrolidone; 32-35 parts by weight of copolyvidone; 17-20 parts by weight of lactose monohydrate; 8 to 10 parts by weight of silicified microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 3 parts by weight of magnesium stearate; or, including: 15-20 parts by weight of mofetil mesylate; 6-8 parts by weight of ritonavir; 5 to 8 parts by weight of cross-linked polyvinylpyrrolidone; 32-35 parts by weight of copolyvidone; 10 to 24 parts by weight of lactose monohydrate; 8 to 24 parts by weight of silicified microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 3 parts by weight of magnesium stearate; or, including: 15-20 parts by weight of mofetil mesylate; 6 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of cross-linked sodium carboxymethyl cellulose; 32-35 parts by weight of copolyvidone; 18-21 parts by weight of lactose monohydrate; 9 to 11 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 2 parts by weight of magnesium stearate; or, including: 15-20 parts by weight of mofetil mesylate; 6 to 8 parts by weight of ritonavir; 4 to 6 parts by weight of sodium carboxymethyl starch; 32-35 parts by weight of copolyvidone; 18-21 parts by weight of lactose monohydrate; 9 to 11 parts by weight of microcrystalline cellulose; 1 to 3 parts by weight of polyethylene glycol; 1 to 2 parts by weight of anhydrous colloidal silicon dioxide; 1 to 2 parts by weight of magnesium stearate.

8. A method for preparing the compound preparation according to any one of claims 1 to 7, characterized in that: include: Performing a first mixing process on mfcetin or mfcetin mesylate, ritonavir solid dispersion and a first auxiliary material to obtain a first mixed product; Performing a second mixing process on the first mixed product and lubricant 1 to obtain a second mixed product; subjecting the second mixed product to a first dry granulation treatment to obtain a first dry granulation treatment product; The first dry granulation product is mixed with the second auxiliary material to obtain the compound preparation.

9. The method according to claim 8, characterized in that The weight ratio of the mofecillin or mofecillin mesylate to the ritonavir solid dispersion is 1:(1-3); Optionally, the first excipient comprises a disintegrant; Preferably, the disintegrant is selected from at least one of crospovidone, croscarmellose sodium and sodium carboxymethyl starch; More preferably, the disintegrant is cross-linked polyvinylpyrrolidone; Optionally, the lubricant 1 is selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated castor oil, glyceryl behenate and magnesium lauryl sulfate; Preferably, the lubricant 1 is selected from at least one of magnesium stearate and sodium stearyl fumarate; Optionally, the ritonavir solid dispersion is prepared by the following method: Performing a third mixing process on ritonavir, the carrier, the plasticizer and the glidant 1 to obtain a third mixed product; subjecting the third mixed product to a second dry granulation process to obtain a second dry granulation process product; The product of the second dry granulation process is subjected to hot melt extrusion to obtain the ritonavir solid dispersion; Optionally, the carrier is selected from at least one of copovidone, povidone, hypromellose and sucrose; Preferably, the carrier is selected from copovidone; Optionally, the plasticizer is selected from at least one of polyethylene glycol, propylene glycol, glycerol, poloxamer, polysorbate 80, diethyl phthalate, triethyl citrate, octyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, butyl stearate, glyceryl monostearate, stearyl alcohol, dibutyl stearic acid, dibutyl phthalate, dioctyl phosphate and vitamin E-TPGS; Preferably, the plasticizer is selected from polyethylene glycol; Optionally, the glidant 1 is selected from anhydrous colloidal silicon dioxide or talc; Preferably, the glidant 1 is selected from anhydrous colloidal silicon dioxide; Optionally, the weight ratio of the ritonavir, the carrier, the plasticizer and the glidant 1 is (3-8):(20-40):(1-6):(0.1-0.6); Optionally, the first auxiliary material further comprises at least one of a filler and a glidant 2; Optionally, the second auxiliary material includes at least one of lubricant 2 and anhydrous colloidal silicon dioxide; Optionally, the filler is selected from at least one of lactose monohydrate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, silicified microcrystalline cellulose, mannitol, corn starch, sucrose, cellulose lactose and pregelatinized starch; Preferably, the filler is selected from at least one of lactose monohydrate and microcrystalline cellulose; Optionally, the glidant 2 is selected from at least one of anhydrous colloidal silicon dioxide and talc; Optionally, the lubricant 2 is selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated castor oil, glyceryl behenate and magnesium lauryl sulfate; Preferably, the lubricant 2 is selected from at least one of magnesium stearate and sodium stearyl fumarate; Optionally, the feeding ratio of the disintegrant, the filler and the glidant 2 in the first auxiliary material is (0-16):(8-55):(0.7-3).

10. A compound preparation, characterized in that: The method is prepared by the method according to any one of claims 8 to 9.

11. A method for improving the dissolution of ritonavir, characterized in that: Murfesiden or Murfesiden mesylate and ritonavir are prepared into a compound preparation according to the method described in any one of claims 8 to 9.

12. Use of the compound preparation according to any one of claims 1 to 7 or 10 in the preparation of a medicament for treating and / or preventing hepatitis B virus infection.

13. A method for determining the dissolution rate of the compound preparation according to any one of claims 1 to 7 or 10, characterized in that: include The compound preparation is placed in a first container, and the hydrochloric acid solution is placed in a second container; placing the first container in a second container and stirring the container to obtain a dissolving solution; HPLC is used to detect the peak area of ​​the dissolution solution, and the dissolution rate of the compound preparation is calculated; Optionally, the stock concentration of the hydrochloric acid solution is 0.05 to 0.15 mol / L; Optionally, the compound preparation is added in an amount of 600 to 900 mg; Optionally, the amount of the hydrochloric acid solution added is 500-1000 mL; Optionally, the first container is a rotating basket, and the second container is a dissolution cup; Optionally, the pore size of the rotating basket is 10 to 40 mesh; Optionally, the stirring speed is 75 to 110 rpm.

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