Low-dose, high-drug-exposure oral sorafenib or donafenib and its applications

Abstract

The present invention provides an oral preparation of sorafenib or donafenib (TKI) containing a molecular mixture of TKIs and a self-assembling polymeric material, and the present application further provides an application of the oral TKI preparation. The synergistic adjustment of two kinds of self-assembling polymeric materials and TKI guest molecules in the oral TKI preparation provided in the present application reduces early degradation or excretion of the drug by CYP3A4 / A5, CYP2D6, CYP2C8, or P-gp, which are cytochrome P450s in epithelial cells of the gastrointestinal mucosa, during the absorption process of the oral preparation, and also reduces the decrease in absorption caused by rapid packing after the rapid release of the drug from the molecular composition, thereby achieving the same therapeutic effect at a lower dose, and C max , AUC 0-t It has lower variability in protein content, reducing the risk of ineffectiveness or toxicity, and is not affected by food when administered orally, while at the same time significantly reducing dose-related side effects and increasing patient compliance, and has good physical and chemical stability.

Description

[Technical field]

[0001] (cross reference) This application claims priority based on an international patent application bearing application number PCT / CN2022 / 077001 and entitled "Low-dose, high drug exposure oral sorafenib or donafenib preparation and its application" filed with the China Patent Office on February 21, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the fields of pharmaceutical formulation technology and material science, in particular, after a molecular-level pharmaceutical composition is released in the body, a new self-organizing system is reconstructed using a self-organizing polymer material, which destroys the molecular packing formed by the interaction between sorafenib or donafenib molecules, reduces the early metabolism of the drug by CYP3A4 / A5 / CYP2 / P-gp in the gastrointestinal tract, reduces the toxicity and side effects to the gastrointestinal tract before the drug is absorbed and enters the circulatory system, and adopts a lower dose of sorafenib or donafenib oral preparation to realize its application in treatment. [Background technology]

[0003] Nexavar (generic name: sorafenib tosylate tablets) is the first multi-targeted oral tumor molecular targeted drug developed jointly by Bayer and Onyx, Germany, to treat end-stage liver cancer, renal cell carcinoma, and thyroid cancer. Since its launch in 2007 as the first-line drug for systemic therapy of end-stage hepatocellular carcinoma, a remarkable change has occurred in systemic therapy for hepatocellular carcinoma. Sorafenib can act simultaneously on tumor cells and intratumoral blood vessels, and exerts its tumor growth inhibitory effect through mechanisms such as suppressing cell proliferation, promoting cell apoptosis, and inhibiting angiogenesis. On the one hand, sorafenib exerts its cell proliferation suppressive effect by suppressing c-Raf kinase and downstream signaling, inhibiting the phosphorylation process of MEK and ERK, and reducing the phosphorylation level of ERK. On the other hand, sorafenib exerts its anti-angiogenic effect by inhibiting vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3), and platelet-derived growth factor receptor-β (PDGFR-β), and inhibiting the autophosphorylation process of tyrosine kinase receptors. It has both anti-tumor effects, which can directly inhibit tumor cell proliferation by blocking the cell signaling pathway mediated by RAF / MEK / ERK, and also block tumor angiogenesis by inhibiting VEGFR and platelet-derived growth factor (PDGF) receptors, and also inhibit the phosphorylation process of initiation factor-4E (eIF4E), downregulating the level of the anti-apoptotic protein Mcl-1 in the body, and playing a pro-apoptotic role.

[0004] Sorafenib is an oral diaryl urea methyl kinase inhibitor with the chemical name 4-[4-[3-(4-chloro-3-trifluoromethyl-phenyl)ureido]-phenoxy]-N-methylpyridine-2-carboxamide and a relative molecular mass of 464.8. The active ingredient in sorafenib tablets (trade name Nexavar) has the molecular formula C 21 H 16 Sorafenib tosylate is ClF3N4O3·C7H8O3S, as shown in formula (2). The chemical structure of sorafenib is as follows:

[0005] [ka]

[0006] Donafenib is a heavy-duty drug of sorafenib developed by Suzhou Zekei Pharmaceutical Co., Ltd. in China. Its chemical name is 4-(-[3-[4-chloro-3-(trifluoromethyl)phenyl]ureido]phenoxy)-n-(methyl-d3)pyridine-2-formamide-4-tosylate. The differences in chemical structure from sorafenib and its physical and chemical properties are shown in Table 1 below.

[0007] [Table 1]

[0008] As shown in Table 1, both are exactly the same except for the methyl group linked by the amide bond. Moreover, since the deuterated group does not affect the intramolecular interactions of the drug, the intermolecular interactions, the drug pKa, the hydrophobicity (LogP), the number of hydrogen donors, the number of hydrogen acceptors, the number of rotatable chemical bonds, the site of action of metabolic enzymes in the body, etc., both are the same in all respects except for the methyl group or deuterated methyl group in the structure. Therefore, sorafenib will be explained below as an example. Donafenib tosylate tablets were published and approved by the China National Medical Products Administration in June 2021 as a Class 1 innovative drug in China in 2021. The launched product name is Zepusheng, the launched dosage form is a tablet, the standard is 100 mg, and the dosage is 2 tablets (200 mg) per dose, twice a day, for a total of 400 mg.

[0009] According to the Biopharmaceutical Classification System, sorafenib and donafenib are both classified as BCS class I. Belongs to VIt is a poorly soluble and poorly permeable drug. According to the package insert for sorafenib tosylate tablets (trade name DuoJimei in China), compared with oral solution, sorafenib tosylate tablets have an average relative bioavailability of only 38%-49%. Therefore, sorafenib tosylate tablets, trade name DuoJimei, are 200mg in weight, and should be administered at a dose of two tablets twice a day, with a maximum daily dose of 800mg. According to the package insert for sorafenib tablets, trade name Nexavar, healthy volunteers: 14 When 100mg of C radiolabeled sorafenib oral solution was orally administered, 77% of the dose was excreted in the feces, and the unchanged drug accounted for more than 51% of the excreted material. One of the reasons for the low oral bioavailability of Nexavar sorafenib tosylate tablets is the solubility problem of the drug itself, and more than half of the administered drug is directly excreted from the body through the feces due to its solubility. However, the actual clinical dose is 400mg per single dose, and currently there is no data on how much of the unchanged drug in the 400mg dose is directly excreted from the body through the feces.

[0010] AAPS J. 2019 Jan 9, 21(2):15, AAPS J. 2019 Oct 21;21(6):107, Chem Biol Interact. 2021 Apr 1;338:109401, Xenobiotica2016 Jul; 46(7): 651-658, and the package insert for sorafenib tosylate tablets, indicate that the metabolism of sorafenib is mediated by the cytochrome P450 enzymes CYP3A4 / A5 and CYP2C8 / D6, and the resulting metabolite is sorafenib N-oxide. Sorafenib is also a substrate for the efflux transporter P-gp. However, these CYP3A4 / A5, CYP2C8 / D enzymes and P-gp are widely distributed in the intestinal mucosal epithelial cells of humans, which is another reason why sorafenib is highly variable in absorption in the body and has low oral bioavailability. In a clinical trial of sorafenib disclosed in Clin Cancer Res 2005, the results showed that the pharmacokinetic parameters of sorafenib in humans showed high inter-individual variability, and the Cmax and AUC 0-12hThe coefficients of variation of the PK coefficients are 8.6% and 16.9% at 200 mg (Bid) and 106.7% and 90.5% at 400 mg (Bid), respectively. Therefore, for poorly soluble drugs, the patient's gastrointestinal environment (pH, food, enzymes, amount of digestive juices) and the process of the drug entering the intestinal tract from the stomach after oral administration have a significant effect on the absorption of sorafenib. Clinical high-dose administration may compensate for the high PK variability due to cytochrome P450 enzymes, but cannot compensate for the high PK variability due to solubility issues. In Oncotarget, 2017, Vol. 8, (26), pp: 43458-43469, in a clinical trial with 94 patients with renal cell carcinoma, group 1 (n=74) received sorafenib tablets 400mg (bid), group 2 (n=18) received sorafenib tablets 600mg (tid), and group 3 (n=2) received sorafenib tablets 400mg (qd). After 2 weeks of treatment, sorafenib steady-state blood drug (plasma) concentrations were 881-12,526ng / mL, and the incidence of major side effects was diarrhea (76.5%), hand-foot syndrome (68.99%), and fatigue (55.32%), all of which were related to sorafenib blood drug concentrations. The blood drug concentrations of patients who experienced serious side effects were all over 10,000ng / ml, and these serious side effects decreased with a reduction in dosage or discontinuation of medication, indicating that these serious side effects were all dose-related. Cancer Chemotherapy and Pharmacology (2020) 86:129-139 studied the effect of sorafenib systemic exposure on the response, efficacy, and safety of patients with advanced hepatocellular carcinoma. The results of the study showed that sorafenib tosylate tablets significantly increased grade 3 and 4 serious side effects when compared with a dose of 0.4g (twice daily) and a dose of 0.2g (twice daily), and many of these grade 3 and 4 serious side effects were due to the C-terminal cytotoxicity of sorafenib. throughThere is a significant correlation with trough concentration. When the trough concentration of sorafenib is more than 3.45μg / ml, the incidence of serious side effects of grade 3 or higher (ALT increase, AST increase, esterase increase, hand-foot syndrome, hypertension, etc.) is 72.7%, and when it is less than 3.45μg / ml, the incidence of serious side effects of grade 3 or higher is 26.7%. The high variability of PK of sorafenib tosylate tablets has a significant impact on the therapeutic effect of the drug [time to treatment failure (TTF), progression-free survival (PFS), and overall survival (OS)]. When the trough concentration of sorafenib is <1.40μg / mL, the TTF, PFS, and OS are 4.7 months, 4.7 months, and 5.3 months, respectively, and when the trough concentration of sorafenib is 1.40μg / mL or less, the TTF, PFS, and OS are 4.7 months, 4.7 months, and 5.3 months, respectively. through For sorafenib trough concentrations <3.45 μg / mL, the TTF, PFS, and OS were 13.1, 15.8, and 17.8 months, respectively (TTF, PFS, and OS for lenvatinib mesylate capsules (LENVIMA) were 8.9, 7.4, and 13.6 months, respectively), and for sorafenib trough concentrations ≥3.45 μg / mL, the TTF, PFS, and OS were 2.4, 8.9, and 9.5 months, respectively. It has been reported that insufficient therapeutic concentrations over a long period of time (trough concentration less than 1.40 μg / mL) result in poor therapeutic response, induce drug resistance, and are a common cause of failure of cancer chemotherapy, while excessively high therapeutic concentrations (≧3.45 μg / mL) lead to a doubling of serious side effects, ultimately leading to abandonment of treatment due to intolerance of serious side effects (TTF 2.4 months), and a significant decrease in overall survival (OS) and progression-free survival (PFS).

[0011] The above research results show that when sorafenib is used for treatment, reducing the high PK variability of the drug is of great significance to reducing serious toxicity and ineffectiveness, so the development of a new generation of sorafenib with low PK variability is of great clinical value.In the prior art, a large amount of experimental research and challenges have been carried out to improve the oral bioavailability of sorafenib preparations, reduce clinical doses, and solve the difficult global problems of high PK variability, but up to now, although the core patent of Nexavar sorafenib tosylate tablets has expired, no new products that surpass existing drugs on the market have been commercialized. US20090203709 discloses a pharmaceutical dosage form comprising a solid dispersion of at least one tyrosine kinase inhibitor, at least one pharma- ceutically acceptable polymer, and at least one pharma- ceutically acceptable solubilizer. Among them, the solubilizer is selected from polyol fatty acid ester, polyalkoxylated polyol fatty acid ester, polyalkoxylated fatty alcohol ether, tocopherol compounds, and mixtures thereof. At the same time, it discloses a method for preparing the pharmaceutical dosage form, which comprises preparing a homogeneous melt of at least one tyrosine kinase inhibitor, at least one pharma- ceutically acceptable polymer, and at least one pharma- ceutically acceptable solubilizer, and then hardening the melt to obtain a solid dispersion.

[0012] CN107115317 discloses a pharmaceutical composition comprising sorafenib, at least one polymer, and a solubilizer to form amorphous hybrid nanoparticles, further comprising at least one pharma- ceutically acceptable solubilizer selected from polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer, d-α-tocopherol polyethyleneglycol 1000 succinate (TPGS1000), and hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. The document discloses that the manufacturing method for producing the pharmaceutical composition is a supercritical fluid method. WO2006026501A1 discloses a composition containing sorafenib and / or its salts, hydrates, and solvates as an embodiment of a solid dispersion. The matrix of the solid dispersion is at least one polymer selected from povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and polyethylene oxide. CN105126111A discloses a molecular-level pharmaceutical composition of sorafenib, comprising at least one active ingredient selected from sorafenib, a sorafenib salt, a sorafenib derivative or a prodrug thereof, and a polymeric cosolvent having a vinyl acetate group, such as VA64, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0013] In the prior art, the in vitro dissolution rate of the molecular-level pharmaceutical composition of sorafenib or donafenib has been improved to some extent compared with sorafenib tosylate tablets (trade name in China: Duo Jimei), but there are the following problems: 1) The improvement in bioavailability in the human body is not as significant as the in vitro dissolution rate. For example, in WO2018211336A2, the oral bioavailability can be improved to about twice that of the reference formulation, sorafenib tosylate tablets (trade name in China: Duo Jime), in healthy volunteers (Cmax, AUC 72h , T / R are 194.32% and 199.58%, respectively.) The patent does not disclose the number of subjects and the dosages of the proprietary and reference formulations, and according to the package inserts of sorafenib tosylate tablets (trade name: Takichimi) or donafenib tosylate tablets (trade name: Sawafusa), this technology solves some of the solubility problems. 2) There is no data on the significant improvement of bioavailability in humans, only data on bioavailability in beagles or rats. For example, in CN106667916B, the AUC in rats is 2.24 times that of oral suspension in the example, and in CN105126111A, the Cmax and AUC distribution in beagles are improved by 85% and 78%, respectively, in its optimal formulation compared with the simulant of the commercial formulation. It is well known that bioavailability can be improved in rats or beagles, but not necessarily in the human body, and although a large number of tests have proven that there is no necessary connection between the two, it is necessary to conduct a large number of tests and spend a large amount of money to confirm whether it is feasible in the human body. On the other hand, the technology disclosed above can only improve it by about 2 times in the rat and beagles, which is still insignificant compared to the safety requirements for clinical administration of medicines.

[0014] 3) There is only in vitro dissolution rate data, but no in vivo data. For example, CN107115317, CN104888228A, and WO2006026501A1 all provide only in vitro dissolution rate data for sorafenib. However, pharmaceutical professionals can understand that in vitro dissolution tests, especially for poorly soluble drugs, the final measured dissolution behavior and dissolution results will vary greatly depending on the volume of the dissolution medium and the concentration of the surfactant added to the medium to increase the dissolution rate, and it cannot be proven that improving the in vitro dissolution rate can also significantly increase the bioavailability in vivo. 4) The commercially available sorafenib tosylate tablets have a standard of 200 mg and a recommended single dose of 400 mg. The standard is relatively large, and the dosage is also large. When preparing a solid dispersion, it is necessary to add a carrier several times the mass of the active ingredient. For example, in WO2006026501A1, when the polymer material povidone K25 is used in an amount 5 times the active ingredient, the dissolution rate only reaches 35%. In a dosage formulation manufactured with the desired standard of 100 mg, the mass of the solid dispersion composition alone reaches 600 mg. However, most of the carriers in ordinary solid dispersions act as binders or form gels, making it difficult to mold the formulation. For example, the disintegration time of tablets and capsules is greatly extended. In order to improve the disintegration, a large amount of additives for the formulation must be added, and the volume and weight of the tablet or capsule contents become large. The formulation prepared is unfavorable for patients to take, and compliance is poor, and at the same time, the cost of the improved product is also high. However, if the amount of carrier used in the solid dispersion is reduced, on the one hand, the effect of increasing dissolution is not significant, and the physical stability of the product is reduced; on the other hand, for example, in Patent WO2006026501A1, as shown in Example 2, it may lead to incomplete formation of the solid dispersion in terms of the manufacturing process (the crystalline drug cannot be converted to amorphous at all). In that case, if the crystalline drug core of sorafenib is present, the drug will rapidly crystallize and precipitate in a short time during subsequent storage, or the physical stability will be poor, which will affect the therapeutic effect of the drug, and thus it cannot be developed and released as a genuine product. Therefore, how to break through the limitations of the prior art, and how to develop a new generation sorafenib therapeutic drug with good stability, high bioavailability, and good patient compliance with the objective fact that the clinical dosage of sorafenib tosylate tablets is high and the amount of additives used per unit preparation is large, is not easy. This is also a serious limitation existing in the prior art.

[0015] 5) Solid dispersions, solid solutions, and nanocrystal formulations are sensitive to moisture, and high moisture content accelerates the nucleation, crystallization, and chemical decomposition of the drug, resulting in poor stability of the formulation. In addition, sorafenib itself has low stability and is prone to decomposition to produce the mutagenic impurity CTF-aniline, which is further prone to produce CTF-aniline after preparation of the solid dispersion. The structure of CTF-aniline is shown in formula (3).

[0016] [ka]

[0017] 6) The sorafenib solid dispersion pharmaceutical composition prepared with a polymer carrier can be rapidly dissolved in vitro or in vivo, but due to the intermolecular interactions between sorafenib and sorafenib and toluenesulfonic acid, molecular packing occurs in the solution through intermolecular non-covalent bonding actions such as hydrogen bonds and ionic actions, forming a supramolecular self-organized system, which rapidly precipitates from the solution or intestinal fluid, and ultimately the sorafenib molecule concentration in the solution becomes very low (pH 1.0: 0.0034 mg / ml, pH 4.5: In a dissolution test using a phosphate buffer solution of pH 6.8 containing 0.00013 mg / ml of sorafenib and 0.1% sodium dodecyl sulfate as a surfactant (at least 10 times less than the amount of surfactant used in the mass-controlled dissolution medium for sorafenib tosylate), the cumulative dissolution rate was basically the same as or lower than that of sorafenib tablets (trade name: Takichimi) at 37°C for 2 to 4 hours (the spring effect that is often referred to in conventional disclosed technology), and as a result, the improvement in the in vivo bioavailability of the pharmaceutical composition of the solid dispersion was not significant.

[0018] Acta Cryst. (2011). C67, o29-o32, ACS Omega. 2021 Mar 2; 6(8): 5532-5547 report the structure of a single crystal of sorafenib tosylate and the construction of a supramolecular self-organized system through intermolecular synergistic coordination of diaryl urea and dimethyl sulfoxide in the sorafenib molecular structure. The chemical structure of sorafenib contains diaryl urea, and the planarization of the two aryl planes in the diaryl urea contributes to strong π-π stacking interactions, hydrophobic effects, and hydrogen bonding between sorafenib molecules, so that sorafenib molecules are prone to rapid molecular packing through intermolecular interactions in solution, forming a stable solid supramolecular self-organized system, as shown in Figure 2. From the perspective of drug developers, the supramolecular self-assembly system due to its π-π stacking interaction is the most difficult to destroy, and although conventional technical means, such as dispersion technology, cocrystallization, salt formation, etc., can instantly destroy the supramolecular self-assembly structure involving its π-π stacking, they cannot maintain the stability over the time axis required for practical application. AAPS Pharm Sci Tech (2022) 23:16 reviewed conventional technologies to solve the solubility of poorly soluble drugs, but the adoption of these technologies at present cannot solve the pain points in the clinical application of sorafenib's currently marketed products. ACS Appl. Mater. Interfaces 2019, 11, 43996-44006, Molecular Pharmaceutics, 2015, 12 (3): 922-931, and Scientifc Reports | (2021) 11:874 reported that self-assembly systems constructed from sorafenib / curcumin / PEG-VES (PEG-vitamin E copolymer), sorafenib / indocyanine, and sorafenib and polypeptides, etc., improved the therapeutic effect and bioavailability of sorafenib, respectively. However, these studies remain academic research even at present, and there is still a long way to go before they can be translated into products. 7) If the solid dispersion further contains co-solvents or enzyme inhibitors such as tocopherol compounds, polyol fatty acid esters, polyalkoxylated fatty alcohol ethers, and hydrogenated castor oil, these co-solvents have low melting points, which dissipate heat during the preparation process, making the preparation process more difficult; on the other hand, the physical stability of the sorafenib solid dispersion is reduced, and amorphous sorafenib, which has poor thermodynamic stability during long-term storage, is easily induced by the co-solvents to accelerate the crystallization of nuclei and precipitate in large quantities, which makes it impossible to achieve the purpose of greatly increasing the bioavailability of the drug and reducing the dosage. In addition, hydrogenated castor oil and tocopherol have inhibitory effects on CYP3A4 or P-gp, but they are not very specific, and a large dose must be added to achieve a certain effect.

[0019] 8) Chinese patent CN103301066 B and CN103301067 B disclose a patent for a donafenib formulation made by Jiangsu Zekei Pharmaceutical, which uses solid dispersion technology to improve the solubility of donafenib and increase the oral bioavailability twice as much as sorafenib, so that the clinical dose is reduced to half that of sorafenib tosylate tablets (trade name: Tadayoshime). Deuterated intermediates are used in the preparation process of donafenib drug substance, but the price of deuterated intermediates is significantly higher than that of non-deuterated intermediates, so improving the oral absorption efficiency of donafenib formulations and reducing the amount of active ingredient (API) used in the unit formulation cost is of great significance in reducing the unit formulation cost and reducing the side effects of donafenib formulations. According to the patent, in preparing a solid dispersion of donafenibut tosylate, the ratio of active ingredient to polymer must be at least 2-4:1, i.e., the amount of active ingredient per unit dosage form must be 274 mg, and the mass of polymer used in preparing the solid dispersion must be at least 548 mg-1096 mg; otherwise, it is difficult to resolve the solubility, dissolution rate, and physical and chemical stability of the drug during shelf life. In addition, the method of taking Nexavar, a multi-drug drug currently available in China, is to take it twice a day on an empty stomach or with a low-fat or medium-fat meal, while the method of taking Nexavar in the US is to take it twice a day without food (at least 1 h before or 2 h after a meal). Taking it with a low-fat or medium-fat meal is difficult to judge during actual administration, and even those skilled in the art have difficulty in judging the difference between a low-fat, medium-fat meal and a high-fat meal, especially patients, so patients often take it on an empty stomach as required by the US package insert to take it at least 1 h before or 2 h after a meal. When taken on an empty stomach, the local drug concentration is high, so the incidence of toxicity and side effects in the upper part of the digestive tract is high, the severity of side effects is greater, and the incidence of serious side effects of grades 3 and 4 is higher [e.g., Seminars in Oncology, Vol 41, No S2, February 2014, pp S1-S16]. As mentioned above [Oncotarget, 2017, Vol. 8, (26), pp: 43458-43469], the incidence of diarrhea after taking sorafenib is as high as 76.5%. For example, as shown in the literature {Su Hua, Zhou Xiaodong, Ma Aihua, et al. Gastrointestinal side effects and prevention caused by commonly used drugs [J]. Journal of Drug Adverse Reactions, 2004, 6(1):5.}, taking drugs on an empty stomach is one of the main causes of gastrointestinal side effects. Taking a drug with food reduces the irritation of the drug to the gastrointestinal tract and reduces side effects. For example, the NMPA's "How to read drug package inserts: 12. There is knowledge about taking medicine with meals" (https: / / www.nmpa.gov.cn / xxgk / kpzhsh / kpzhshyp / 20160503170501830.html) explains that taking a drug with food can reduce the occurrence of drug side effects, because taking a drug with food or immediately after a meal can greatly reduce the irritation of the drug to the gastrointestinal tract. Therefore, the development of a sorafenib formulation that can be taken with food is of great significance in reducing the side effects of this drug and reducing the drug weight loss caused by gastrointestinal side effects.

[0020] Furthermore, according to the description in Variability of Sorafenib Toxicity and Exposure over Time: A Pharmacokinetic / Pharmacodynamic AnalysisThe Oncologist 2012;17:1204-1212, the current clinical therapeutic dose of sorafenib tosylate tablets is a fixed dose of 400 mg twice a day (800 mg daily). However, with the extension of the treatment time for currently available products, the drug exposure gradually decreases. For example, the drug exposure for 120 days is about 38% lower than that for 15 days. However, the drug exposure is directly related to the clinical treatment effect (overall survival, progression-free survival, time to treatment failure). If the disease progresses during clinical treatment of an existing product, the clinical dose will continue to increase, for example, from 400 mg orally administered each time to 600 mg each time. This is limited by the drug solubility and dissolution rate, and the drug exposure of sorafenib will only increase by 13%, which is not clinically significant [FDA]. Review Report Bio Pharmacology Review], serious side effects of grade 3 or 4 were significantly increased, including serious gastrointestinal toxicity and skin toxicity, in other words, when disease progression occurs during clinical treatment with existing commercially available products, drug titration cannot be performed based on the current treatment plan to maintain optimal therapeutic effect. Therefore, overcoming drug resistance of sorafenib / donafenib, facilitating titration, and exerting the therapeutic effect of the product are of great significance, and are a difficult problem that must be solved urgently in clinical practice. Therefore, the development of a new formulation of sorafenib that resolves the clinical drug resistance of sorafenib or donafenib, whose absorption is not affected by food, is not affected by gastrointestinal enzymes (such as CYP3A4 or P-gp), and has a stable therapeutic effect is clinically necessary and has significant clinical advantages over currently available formulations. Summary of the Invention [Problem to be solved by the invention]

[0021] The technical problem to be solved by the present invention is to provide an oral preparation of sorafenib or donafenib. The oral preparation of sorafenib or donafenib provided in the present application can be administered at a low dose, has good physical and chemical stability, and is C max , AUC 0-t It has low variability, absorption is not affected by food, and can be titrated to maintain optimal therapeutic efficacy when disease progression occurs in patients; it overcomes the resistance challenge, significantly prolongs patients' progression-free survival, improves patients' overall survival, delays the time to treatment failure, has more significant therapeutic efficacy and safety, and at the same time increases patient compliance. [Means for solving the problem]

[0022] The present application has been made in consideration of the above-mentioned circumstances, and provides a low-dose oral preparation of sorafenib or donafenib comprising a molecular-level pharmaceutical composition of sorafenib or donafenib, a polymeric material for self-assembly, and other pharma- ceutically acceptable additives, wherein an embodiment of the molecular-level pharmaceutical composition of sorafenib or donafenib is a molecular-level solid dispersion, solid solution, polymer nanoparticle, self-emulsifying microemulsion, nanoemulsion, or a molecular-level mixture. The self-organizing polymer material may be selected from the group consisting of povidone+hydroxypropyl cellulose, low-viscosity povidone+high-viscosity povidone, povidone+copovidone, povidone+polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone+hydroxypropyl methylcellulose acetate succinate, povidone+hydroxypropyl methylcellulose, povidone+cellulose acetate, povidone+crosslinked sodium carboxymethylcellulose, povidone+polyethylene glycol, povidone+low-substituted hydroxypropyl cellulose, povidone+hydroxypropyl methylcellulose phthalate, povidone+methacrylic acid-ethyl acrylate copolymer, povidone+methacrylic acid-methyl acrylate copolymer, copovidone+hydroxypropyl cellulose, copovidone+polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone+hydroxypropyl methylcellulose acetate succinate, copovidone+hydroxypropyl methylcellulose, copovidone+cellulose acetate, copovidone+crosslinked sodium carboxymethylcellulose, or calco sodium, copovidone + polyethylene glycol, copovidone + low-substituted hydroxypropyl cellulose, copovidone + hydroxypropyl methylcellulose phthalate, copovidone + methacrylic acid-ethyl acrylate copolymer, copovidone + methacrylic acid-methyl acrylate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose acetate succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + low-substituted hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + crosslinked sodium or calcium carboxymethylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + polyethylene glycol,The copolymer is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + methacrylic acid-ethyl acrylate copolymer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + methacrylic acid-methyl acrylate copolymer.

[0023] Preferably, the self-organizing polymer material is present in an amount of 10 to 50 wt % relative to the molecular-level pharmaceutical composition of sorafenib or donafenib. Preferably, the hydroxypropyl methylcellulose is HPMC E5 or HPMC CK100LV, the self-organizing polymer material is a composite self-organizing polymer material of HPMC E5 and one of povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and highly hydrophobic H grade hydroxypropyl methylcellulose acetate succinate, the composite ratio being (1 to 10):1, and the self-organizing polymer material is a composite self-organizing polymer material of HPMC CK100LV and one of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and highly hydrophobic H grade hydroxypropyl methylcellulose acetate succinate, the composite ratio being (1 to 10):1. Preferably, the hydroxypropyl methylcellulose acetate succinate has an acetyl group substitution rate of 6 to 16%, and a succinyl group substitution rate of 4 to 16%. Preferably, the povidone has an average molecular weight of 34,000 to 1,300,000, or is a complex of povidone having an average molecular weight of 34,000 and povidone having an average molecular weight of 1,300,000 in a ratio of 1:1 to 1:0.1. Preferably, the unit dose of the oral agent contains 20 to 69 mg of sorafenib or donafenib.

[0024] Preferably, the molecular pharmaceutical composition of sorafenib or donafenib comprises sorafenib or donafenib, or a salt, hydrate, solvate, hydrate or solvate of a salt thereof, and a carrier, the carrier being selected from the group consisting of copovidone, povidone, polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, povidone + hydroxypropylmethylcellulose acetate succinate, povidone + hydroxypropylmethylcellulose, low viscosity povidone + high viscosity povidone, povidone + copovidone, povidone + polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, copovidone + hydroxypropylmethylcellulose acetate succinate, copovidone + polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer,

[0033] The composition is selected from the group consisting of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone+hydroxypropyl methylcellulose, copovidone+polyethylene glycol, copovidone+hydroxypropyl cellulose, copovidone+cellulose acetate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer+hydroxypropyl methylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer+hydroxypropyl methylcellulose acetate succinate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer+povidone, or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer+copovidone. Preferably, the sorafenib or donafenib, or a salt, hydrate, solvate, hydrate or solvate of a salt thereof, is 30 to 60 wt% of the pharmaceutical composition at the molecular level of the sorafenib or donafenib.

[0025] Preferably, the dosage form of the oral sorafenib or donafenib is a tablet, suspension, granule or capsule. Preferably, the tablet additives include a filler, a disintegrant, a flow agent or a lubricant, the filler being one or two selected from microcrystalline cellulose and silicified microcrystalline cellulose, the disintegrant being cross-linked sodium carboxymethylcellulose, the flow agent being silica, and the lubricant being one or two selected from magnesium stearate and sodium stearyl fumarate. Preferably, the content of the filler is 30 to 45 wt% relative to the tablet, the content of the disintegrant is 5 to 15 wt% relative to the tablet, the content of the fluidizing agent is 3 to 5 wt% relative to the tablet, and the content of the lubricant is 1 to 5 wt% relative to the tablet.

[0026] The present application further relates to the use of said oral formulation of sorafenib or donafenib in the preparation of a medicament for the treatment or alleviation of hepatocellular carcinoma, breast cancer, primary malignant liver tumor, cholangiocarcinoma, renal cell carcinoma, recurrent or refractory solid tumors, central nervous system solid tumors, metastatic non-small cell lung cancer, hepatocellular carcinoma that cannot be removed by surgery, thyroid cancer, pancreatic cancer, salivary gland adenoid cystic carcinoma, anaplastic thyroid cancer, refractory differentiated thyroid cancer, adenoid cystic carcinoma, late stage endometrial cancer, thyroid anaplastic cancer, rectal cancer, colon cancer, unresectable stage III or IV melanoma, leukemia, acute myeloid leukemia, all solid tumors or various late stage solid tumors. Effect of the Invention

[0027] The present application provides an oral sorafenib or donafenib preparation comprising a molecular-level pharmaceutical composition of sorafenib or donafenib, a self-assembling polymeric material, and other additives, wherein the self-assembling polymeric material is a composite of two specific polymeric materials as a building block of composite self-assembly, and synergistically adjusts the two polymeric materials and sorafenib molecules to reconstruct a self-assembly system based on reversible weak intermolecular interactions, thereby improving the solubility and stability of sorafenib or donafenib, and reducing the early metabolism and excretion of the drug by CYP3A4 / 5, CYP2C8 / D6, and P-gp. The novel oral sorafenib or donafenib preparation obtained can be administered at a lower dose, obtain a higher drug exposure, and is safe, with a lower incidence of side effects and C. max , AUC 0-t It has low fluctuation, low weight / volume, rapid disintegration, good physical and chemical stability, and can maintain stable characteristics even when the moisture content is as high as 5%, and is not affected by food when taken. At the same time, when the patient experiences disease progression with the extension of treatment time, the optimal therapeutic effect can be achieved by titration administration, thereby overcoming the problem of drug resistance in the treatment process of existing commercially available sorafenib or donafenib products. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 is a schematic diagram of the three-dimensional structure of sorafenib of the present invention. [Diagram 2] FIG. 2 is a schematic diagram of the single crystal structure of sorafenib and donafenib of the present invention based on their intermolecular interactions. [Diagram 3] FIG. 3 is a graph showing the tuning curve of SLFN molecular packing by a high concentration of a single polymer self-assembly building block in an embodiment of the present invention. [Figure 4] FIG. 4 is a graph showing the synergistic adjustment curve of sorafenib molecular packing by copovidone complex polymer self-assembly building blocks in an embodiment of the present invention. [Diagram 5]FIG. 5 is a graph showing the synergistic adjustment curve of sorafenib molecular packing by low-viscosity povidone complex polymer self-assembly building blocks in an embodiment of the present invention. [Figure 6] FIG. 6 is a graph showing the synergistic tuning curve of sorafenib molecular packing by HPMC AS composite polymer self-assembly building blocks in an embodiment of the present invention. [Figure 7] FIG. 7 is a graph showing the synergistic tuning curve of sorafenib molecular packing by HPMC composite polymer self-assembly building blocks in an embodiment of the present invention. [Figure 8] FIG. 8 is a graph showing the synergistic tuning curve of sorafenib molecular packing by PEG-conjugated polymer self-assembly building blocks in an embodiment of the present invention. [Figure 9] FIG. 9 is a graph showing the synergistic tuning curve of sorafenib molecular packing by HPMCAS-H composite polymer self-assembly building block in an embodiment of the present invention. [Figure 10] FIG. 10 is a graph showing the synergistic tuning curve of sorafenib molecular packing by HPMCAS-L composite polymer self-assembly building block in an embodiment of the present invention. [Figure 11] FIG. 11 is a graph showing the synergistic tuning curve of sorafenib molecular packing by HPMCE5 complex polymer self-assembly building block in an embodiment of the present invention. [Figure 12] FIG. 12 is a bar graph showing the effect of self-assembling building blocks in which HPMC E5 is complexed with other polymers at different ratios in an embodiment of the present invention on the synergistic regulation of sorafenib molecular packing and stability-6h. [Figure 13] FIG. 13 is a graph of the blood drug concentration-time curves of healthy subjects for different formulations and a reference formulation in an embodiment of the present invention. [Figure 14] FIG. 14 is a comparison diagram of PK curves of the formulation T1 of the present invention and the reference formulation Takichimi in healthy subjects on an empty stomach and after a high-fat meal. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] In order to further understand the present invention, preferred embodiments of the present invention will be described below in combination with examples. However, it should be understood that these descriptions are intended to further explain the features and advantages of the present invention and are not intended to limit the claims of the present invention.

[0030] In view of the many problems existing in the prior art sorafenib or donafenib solid formulations, the present application provides an innovative solution and concept to maximize the efficacy and safety of the drug, addressing the problems of poor solubility of large doses, high variation in the body, molecular packing of the drug molecules themselves, and high variation or low bioavailability of oral pharmaceuticals caused by intestinal cytochrome P450 enzymes / P-gp in drug absorption, thereby specifically providing an oral sorafenib or donafenib formulation using a composite self-assembly building block and simultaneously combining molecular-level pharmaceutical composition technology, the resulting oral sorafenib or donafenib formulation can be taken at a low dose, that is, with only 10%-35% of the dosage of sorafenib tosylate tablets (Nexavar), which can achieve the same therapeutic effect as the ideal therapeutic effect, or with 40%-60% of the dosage of current donafenib tablets, which has better safety, less incidence of side effects, and C. max , AUC 0-t The present invention provides an oral preparation of sorafenib or donafenib that has the characteristics of low variation in viscosity, low weight / volume, rapid disintegration, good physical and chemical stability, and can maintain stability even with a moisture content as high as 5%, and is not affected by food when taken, and at the same time, when a patient experiences progression of the disease as the treatment time extends, can achieve an optimal therapeutic effect by titration administration, thereby overcoming the problem of drug resistance in the treatment process of existing commercially available products of sorafenib or donafenib. Specifically, an embodiment of the present invention provides a low-dose oral sorafenib or donafenib formulation comprising a molecular-level pharmaceutical composition of sorafenib or donafenib, a polymeric material for self-assembly, and other pharma- ceutically acceptable additives, and an embodiment of the molecular-level pharmaceutical composition of sorafenib or donafenib provides a low-dose oral sorafenib formulation that is a solid dispersion, a solid solution, a polymeric nanoparticle, a self-emulsifying microemulsion, a nanoemulsion, or a molecular-level mixture.

[0031] The self-assembling polymeric materials described in the present application may also be referred to as composite self-assembling building blocks, and may be selected from the group consisting of povidone + hydroxypropyl cellulose, low viscosity povidone + high viscosity povidone, povidone + copovidone, povidone + polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone + hydroxypropyl methylcellulose acetate succinate, povidone + hydroxypropyl methylcellulose, povidone + cellulose acetate, povidone + cross-linked sodium carboxymethylcellulose, povidone + polyethylene glycol, povidone + low-substituted hydroxypropyl cellulose, povidone + hydroxypropyl methylcellulose phthalate, povidone + methacrylic acid-ethyl acrylate copolymer, povidone + methacrylic acid-methyl acrylate copolymer, copovidone + hydroxypropyl cellulose, copovidone + polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone + hydroxypropyl methylcellulose acetate succinate, copovidone + hydroxypropyl methylcellulose, copovidone + cellulose acetate, copovidone + cross-linked sodium or calcium carboxymethylcellulose, copovidone + polyethylene glycol, copovidone + low-substituted hydroxypropylcellulose, copovidone + hydroxypropyl methylcellulose phthalate, copovidone + methacrylic acid-ethyl acrylate copolymer, copovidone + methacrylic acid-methyl acrylate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose acetate succinate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl cellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + low-substituted hydroxypropylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + cross-linked sodium or calcium carboxymethylcellulose,The copolymer is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer+polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer+hydroxypropyl methylcellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer+methacrylic acid-ethyl acrylate copolymer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer+methacrylic acid-methyl acrylate copolymer. The present application provides an oral preparation of sorafenib or donafenib, in which a composite self-assembling building block is present in an amount of 10 to 50 wt % relative to a molecular-level pharmaceutical composition of sorafenib, more specifically, the composite self-assembling building block is present in an amount of 20 to 40 wt % relative to a molecular-level pharmaceutical composition of sorafenib or donafenib.

[0032] The molecular level pharmaceutical composition of sorafenib or donafenib is present as a solid dispersion, solid solution, polymeric nanoparticle, self-emulsifying microemulsion, nanoemulsion or molecular level mixture, and the molecular level pharmaceutical composition of sorafenib or donafenib comprises sorafenib or donafenib, or a salt, hydrate, solvate, hydrate or solvate of a salt thereof, and a carrier. In the present application, the sorafenib or donafenib, or a salt, hydrate, solvate, salt hydrate or solvate thereof is present in an amount of 30 to 60 wt % relative to the molecular level pharmaceutical composition of sorafenib or donafenib, and more specifically, the sorafenib, or a salt, hydrate, solvate, salt hydrate or solvate thereof is present in an amount of 35 to 55 wt % relative to the molecular level pharmaceutical composition of sorafenib or donafenib.

[0033] In the molecular pharmaceutical composition of sorafenib or donafenib, the carrier is selected from a polymer carrier that can provide hydrogen acceptors and has a certain ratio of hydrophobic groups and / or a combination carrier of at least two polymer carriers, specifically, copovidone, povidone, polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer (Soluplus), povidone and hydroxypropylmethylcellulose acetate succinate (HPMCAS), povidone and hydroxypropylmethylcellulose, low viscosity povidone and high viscosity povidone, povidone and copovidone, povidone and polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, copovidone and hydroxypropylmethylcellulose acetate succinate, copovidone and polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, copovidone and hydroxypropylmethylcellulose acetate succinate, copovidone and polyvinylcaprolactam-polyacetate The carrier is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone and hydroxypropyl methylcellulose (HPMC), copovidone and polyethylene glycol (PEG), copovidone and hydroxypropyl cellulose, copovidone and cellulose acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and hydroxypropyl methylcellulose acetate succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and povidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and copovidone, and more specifically, the carrier is selected from PVP K30, HPC LF, HPMC E5, VA64, PVP K25+K90, PVP K25+VA64, PVP K30+HPMC AS, PVP K90+HPMC AS, Soluplus, or VA64+HPMC AS. In a specific embodiment, the mass ratio of the sorafenib or donafenib, or a salt, hydrate, solvate, hydrate or solvate of a salt thereof to the carrier is 1:1.

[0034] In the present application, the hydroxypropyl methylcellulose of the composite self-assembling building blocks is preferably the E series or K series, the E series is more preferably a low viscosity type, and the K series is more preferably K100LV. The composite self-assembling building blocks are composite self-assembling building blocks of one of povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and highly hydrophobic hydroxypropyl methylcellulose acetate succinate, and HPMC E, and the composite ratio is (1 to 10):1. The composite self-assembling building blocks are composite self-assembling building blocks of one of the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and highly hydrophobic hydroxypropyl methylcellulose acetate succinate, and HPMC K100LV, and the composite ratio is (1 to 10):1. The hydroxypropyl methylcellulose acetate succinate has an acetyl group substitution rate of 6 to 16%, and a succinyl group substitution rate of 4 to 16%, more specifically, an acetyl group substitution rate of 10 to 14%, and a succinyl group substitution rate of 4 to 8%. In the crystallization inhibitor, the povidone has an average molecular weight of 34000 to 1300000, or is a complex of povidone having an average molecular weight of 34000 and povidone having an average molecular weight of 1300000 in a ratio of 1:1 to 1:0.1. In a specific embodiment, the composite self-assembly building block is specifically selected from PVP VA64+HPMCAS H grade, PVP VA64+HPMCAS M grade, PVP VA64+Soluplus, PVP VA64+HPMC, PVP K90+HPMCAS, PVP K90+HPMC, PVP K25+PVP K90, PVP K30+PVP K90, low-viscosity HPMC+PVP VA64, PVP K90+HPMC K100LV, +Povidone, HPMCAS H grade+Soluplus, HPMCAS M grade+, HPMCAS L type+Soluplus, HPMC(low viscosity)+Povidone, HPMC(low viscosity)+Copovidone or HPMC(low viscosity)+HPMCAS(high hydrophobicity). In the present application, the addition manner of the composite self-assembling building blocks can be internal addition, external addition, or one is internal addition and the other is external addition, and the composite self-assembling building blocks can be added to a coating, for example, a powder coating, a micropellet coating, or a tablet coating.

[0035] In the sorafenib oral preparation described in the present application, the single dose of the molecular level pharmaceutical composition of sorafenib is 10% to 35% of the dosage of Nexavar, preferably 12.5 to 30%, and the unit dose of the oral preparation contains 20 mg to 69 mg of sorafenib or donafenib, equivalent to 200 mg of Nexavar, preferably 25 mg, 30 mg, 50 mg or 60 mg, and the standard of the unit preparation is 50 to 140 mg, equivalent to a single dose of 400 mg of Nexavar, preferably 50 mg, 60 mg, 100 mg or 120 mg. In the donafenib oral preparation described in the present application, the dosage of the molecular level pharmaceutical composition of donafenib per administration is 40%-60% of the dosage of Sawafenib donafenib tosylate tablet, preferably 45%-55%, and the standard of the unit preparation is preferably 25mg, 30mg, 40mg, 45mg, 50mg and 55mg, which is equivalent to taking a single dose of 100mg of Sawafenib donafenib tosylate tablet, preferably 50mg, 60mg, and equivalent to taking a single dose of 200mg of Sawafenib donafenib tosylate tablet, preferably 80mg, 90mg, 100mg or 110mg. The dosage form of the sorafenib or donafenib oral preparation is a tablet, a suspension, a granule, or a capsule, and the additives of the tablet include a filler, a disintegrant, a flow agent, or a lubricant, and the filler is one or two selected from microcrystalline cellulose and silicified microcrystalline cellulose, the disintegrant is one or two selected from crosslinked sodium carboxymethylcellulose, the flow agent is one or two selected from silica, and the lubricant is one or two selected from magnesium stearate and sodium stearyl fumarate. The content of the filler is 30 to 45 wt% and preferably 30 to 40 wt% relative to the tablet, the content of the disintegrant is 5 to 15 wt% and preferably 5 to 10 wt% relative to the tablet, the content of the flow agent is 3 to 5 wt% relative to the tablet, and the content of the lubricant is 1 to 5 wt% relative to the tablet. In the present application, the disintegration time of the tablet is ≦5 min.

[0036] The present invention further provides the use of a formulation containing the above-mentioned sorafenib composition in the preparation of a therapeutic drug for tumors, specifically, hepatocellular carcinoma, breast cancer, primary malignant liver tumor, cholangiocarcinoma, renal cell carcinoma, recurrent or refractory solid tumors, central nervous system solid tumors, metastatic non-small cell lung cancer, hepatocellular carcinoma that cannot be removed by surgery, thyroid cancer, pancreatic cancer, salivary gland adenoid cystic carcinoma, anaplastic thyroid cancer, refractory differentiated thyroid cancer, adenoid cystic carcinoma, late-stage endometrial cancer, thyroid anaplastic cancer, rectal cancer, colon cancer, unresectable stage III or IV melanoma, leukemia, acute myeloid leukemia, and all solid tumors, various late-stage solid tumors. The preparations provided by the present invention can be used for the treatment of the above-mentioned tumors as a single agent or in combination with other drugs, such as PD-1 inhibitors, venetoclax and / or decitabine, combination treatment with TACE and / or I-125 seeds brachytherapy, combination treatment with drug-eluting bead transarterial chemoembolization, combination with pembrolizumab, combination with toripalimab, combination with atezolizumab, combination with atezolizumab+bevacizumab, combination with TACE+tilelizumab, combination with recombinant human adenovirus type 5 injection, combination with PD-1 inhibitors, venetoclax and / or decitabine, combination with TACE and / or I-125 seeds brachytherapy, combination ... combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 inhibitors, combination with PD-1 injection), combination with MTL-CEBPA, combination with Vemurafenib, combination with Oxaliplatin and 5-fluorouracil, combination with Eribulin and Toripalimab, Gemox or Everolimus, combination with Doxorubicin and Lipiodol, combination with Oxaliplatin, Raltitrexed and Epirubicin, combination with Toripalima, combination with PD-1 mAb, combination with Hydroxychloroquine, combination with CVM-1118, Hepatic Artery Infusion Chemotherapy(Oxaliplatin, Hepatic Artery Infusion Chemotherapy (Irinotecan, Oxaliplatin, Fluorouracil, and Leucovorin)and leucovorin, YIV-906, or Tislelizumab.

[0037] Furthermore, it will broaden the clinical application of sorafenib or donafenib as a single agent, in combination with other agents, or in combination therapy in each disease treatment field. For example, the low-dose sorafenib or donafenib oral preparation studied in the present invention can be used as a first-line therapeutic drug for terminal liver cancer, and can be combined with a PD-1 inhibitor, such as camrelizumab. On the first day, 200 mg of camrelizumab is intravenously injected once every two weeks, and from the next day, 50 mg to 120 mg of the pharmaceutical composition sorafenib or donafenib is orally administered twice a day. The present invention studies low-dose sorafenib or donafenib oral preparations and combines them with TACE therapy to treat hepatocellular carcinoma. TACE therapy involves injecting chemotherapy drugs (doxorubicin and lipiodol) and orally administering 50 to 120 mg of sorafenib or donafenib twice a day. The present invention includes the low-dose oral sorafenib or donafenib in combination with toripalimab for the treatment of unresectable hepatocellular carcinoma and portal vein tumor thrombosis. Sorafenib or donafenib is administered at 50-120mg once or twice daily according to the patient's cohort A or cohort B.

[0038] The present invention is based on the study of low-dose sorafenib or donafenib oral preparations, and sequential treatment with SBRT+TACE is used to treat unresectable hepatocellular carcinoma and portal vein tumor thrombosis. Sorafenib or donafenib is orally administered at a dose of 100-120 mg twice a day. The low-dose oral sorafenib or donafenib studied in this invention is used in combination with hydroxychloroquine (HCQ) to treat hepatocellular carcinoma, with sorafenib or donafenib being orally administered at 100-120 mg twice a day, and hydroxychloroquine (HCQ) being orally administered at 400 mg once a day. The low-dose sorafenib or donafenib oral preparation studied in this invention is used in combination with pembrolizumab monoclonal antibody to treat adult patients with advanced hepatocellular carcinoma. On the first day of treatment, pembrolizumab is intravenously injected and the injection is completed within 30 minutes. On the 1st to 21st days of treatment, sorafenib or donafenib is orally administered at 100 to 120 mg twice a day, with one course repeated every 3 weeks. The present invention includes the low-dose sorafenib or donafenib oral preparation studied in this invention, which is combined with CVM-1118 for the treatment of end-stage hepatocellular carcinoma. CVM-1118 is orally administered at 150 mg or 200 mg twice a day, and sorafenib or donafenib is orally administered at 50 to 120 mg twice a day, with one treatment cycle lasting 28 days. The low-dose oral sorafenib or donafenib studied in this invention is used in combination with hepatic arterial infusion chemotherapies (oxaliplatin, fluorouracil, and leucovorin) to treat hepatocellular carcinoma, with sorafenib or donafenib being orally administered at 50-120 mg twice a day.

[0039] The present invention is directed to the treatment of hepatocellular carcinoma by combining the oral low-dose sorafenib or donafenib with hepatic arterial infusion chemotherapy (irinotecan, oxaliplatin, fluorouracil, and leucovorin), and administering sorafenib or donafenib orally at 50-120 mg twice a day. The present invention includes the low-dose sorafenib or donafenib oral preparation studied in the present invention, which is used in combination with DEB-TACE to treat hepatocellular carcinoma, and sorafenib or donafenib is orally administered at 50-120 mg twice a day. The present invention includes the low-dose sorafenib or donafenib oral preparation studied in the present invention, which is used in combination with YIV-906 to treat patients with end-stage hepatocellular carcinoma infected with Hepatitis B virus (HBV). One treatment cycle is 28 days, in which sorafenib or donafenib is orally administered at 50-120 mg twice daily for 28 consecutive days, and YIV-906 is orally administered at 600 mg twice daily for 4 days each week, followed by a 3-day break. The low-dose oral sorafenib or donafenib studied in this invention is used in combination with TACE and Tislelizumab to treat inoperable hepatocellular carcinoma. On the 3rd to 7th day after the first TACE treatment, oral sorafenib or donafenib is orally administered at 100-120mg twice a day, and Tislelizumab is intravenously injected at 200mg each time once every 3 weeks. The number of times TACE treatment is repeated is determined according to the clinical results, and Tislelizumab treatment can last up to 24 months. The present invention includes the low-dose sorafenib or donafenib oral preparation studied in the present invention, which is used in combination with vemurafenib to treat pancreatic cancer. Vemurafenib is orally administered at 720 mg twice a day, and sorafenib or donafenib is orally administered at 100-120 mg every morning, and sorafenib is orally administered at 50-60 mg every afternoon. The present invention is a low-dose oral sorafenib or donafenib combination with MTL-CEBPA for the treatment of hepatocellular carcinoma caused by viral infection. MTL-CEBPA is administered at 130 mg / m every week. 2 This is administered intravenously for three consecutive weeks, followed by one week of rest, and then sorafenib or donafenib is orally administered at 100 to 120 mg each time, twice a day. The present invention uses the low-dose sorafenib or donafenib oral preparation in combination with TACE and tilelizumab to treat BCLC stage C hepatocellular carcinoma. First, TACE treatment is started, and within one week of TACE treatment, 240 mg of tilelizumab is intravenously administered once every three weeks, and within one week of TACE treatment, sorafenib or donafenib is orally administered at 100 to 120 mg each time, twice a day.

[0040] The low-dose sorafenib or donafenib oral preparation studied in this invention is used in combination with atezolizumab to treat inoperable late-stage hepatocellular carcinoma. Atezolizumab is administered intravenously at 1200 mg on days 1 and 21 of the treatment cycle, and sorafenib or donafenib is orally administered at 100-120 mg twice a day every day during the treatment cycle. If the treatment is effective, multiple treatment courses can be repeated until the condition progresses or becomes intolerable. The present invention includes the low-dose sorafenib or donafenib oral preparations studied in the present invention, which are used in combination with TACE therapy to treat hepatocellular carcinoma. TACE therapy involves the injection of chemotherapy drugs (Oxaliplatin 200mg, Raltitrexed 4mg, Epirubicin 20mg for cTACE, or 70mg for dTACE), and sorafenib or donafenib is orally administered at 50-120mg twice a day. The present invention is designed to treat inoperable hepatocellular carcinoma by combining the low-dose sorafenib or donafenib oral preparation with TACE therapy, and sorafenib or donafenib is orally administered at 100-120 mg twice a day for 3-7 days after the first TACE treatment. The number of repeat TACE and sorafenib treatment are determined based on the results of clinical treatment, until the disease progresses or the patient is unable to tolerate it.

[0041] The present invention is a low-dose oral sorafenib or donafenib preparation that is used in combination with venetoclax and decitabine to treat adult acute myeloid leukemia (FLT3-ITD allele ratio is relatively high). Decitabine 20 mg / m was administered on days 1 to 5 of each treatment cycle. 2 is administered intravenously, and Venetoclax is gradually increased from 100 mg to 400 mg (for 28 days) and administered orally until one treatment cycle is completed. If the patient has a high FLT3-ITD allele ratio, sorafenib or donafenib is administered at 100-120 mg twice a day from the third day of each treatment cycle until one treatment cycle is completed. The low-dose oral sorafenib or donafenib formulation studied in this invention is applicable to the attack, recurrence, and hematopoietic stem cell transplantation of acute leukemia. Sorafenib or donafenib is orally administered at 100-120 mg twice a day, and if intolerable, the dose can be reduced to 50 mg-240 mg daily. The low-dose sorafenib or donafenib oral preparations studied in this study were included in the HAIC (130 mg / m 2 Oxaliplatin, 2400 mg / m 2 5-fu or 85 mg / m 2 Oxaliplatin, and 2400 mg / m 2 In combination with 5-fu, it is used to treat terminal, inoperable hepatocellular carcinoma, with sorafenib or donafenib administered at 100 to 120 mg twice daily. In the event that any of the above treatment methods cause disease progression with the extension of treatment time, the low-dose sorafenib or donafenib oral preparation studied in the present invention can be titrated based on clinical treatment results, for example, from 100-120 mg per oral administration to 125-150 mg per oral administration, or 150-210 mg per oral administration, or 175-240 mg per oral administration, or 200-270 mg per oral administration, or 225-300 mg per oral administration, or 250-330 mg per oral administration, or 275-360 mg per oral administration, or 300-400 mg per oral administration, twice a day.

[0042] The low-dose sorafenib or donafenib oral preparation studied in the present invention, when used alone or in combination with any one of the above other treatments, can extend the overall survival and progression-free survival of patients, reduce side effects caused by high drug exposure, and improve patient tolerance and compliance. The drug exposure is related to the therapeutic effect, but also has a certain correlation with certain side effects, and the higher the exposure, the more severe the hand-foot skin reaction (HFS) is. In the case where the patient has severe Hepatitis B Reaction (HFSR), first, based on the patient's tolerance, 50mg-60mg of the low-dose sorafenib or donafenib oral preparation of the present invention is orally administered for a certain period of time, and then titrated to 50mg-60mg, twice a day. After maintaining the dose for a certain period of time, based on the patient's tolerance, the dose is adjusted to 50mg-60mg once a day for each treatment for a certain period of time. If the patient has serious side effects that cannot be tolerated, the administration plan is adjusted to 50mg-60mg, once every other day, or periodically adjusted based on the progression of the disease and the patient's tolerance. The present invention includes the low-dose sorafenib or donafenib oral preparations studied herein, which may be used in combination with any one of the other treatments listed above or as monotherapy, to extend patient overall survival and progression-free survival, reduce side effects from high drug exposure, and increase patient tolerance and compliance, with sorafenib or donafenib being administered at 50-240 mg once daily. The self-assembling polymeric material in the sorafenib or donafenib oral preparation provided in the present application is composited as a composite self-assembling building block using two specific polymeric materials, and the two self-assembling polymeric materials and the sorafenib guest molecule are synergistically adjusted to prevent molecular packing due to the original intermolecular interaction of sorafenib or donafenib molecules, and reconstruct a composite self-assembling building block and a new self-assembly system in a new microenvironment, thereby reducing the early decomposition or excretion of the drug caused by cytochrome P450 enzymes CYP3A4 / A5, CYP2D6, CYP2C8 or P-gp in the epithelial cells of the gastrointestinal mucosa during the absorption process of the obtained oral preparation, and also reducing absorption by the rapid molecular packing caused by the interaction between sorafenib molecules after the drug is rapidly released from the molecular-level composition. Therefore, it can be taken at a lower dose, is safe, has a lower incidence of side effects, and has a low C max , AUC 0-t It has low variation in mass, low weight / volume, rapid disintegration, good physical and chemical stability, and can maintain good physical and chemical stability even when the moisture content is as high as 5%. EXAMPLES

[0043] In order to further understand the present invention, the low-dose sorafenib or donafenib oral preparation provided by the present invention and its application are described in detail below in combination with examples, but the scope of protection of the present invention is not limited to the following examples. In the chemical structure of sorafenib, the possible groups through which biomolecular interactions can occur are not related to the methyl group linked to the amide, as shown in Figure 2. Therefore, whether it is sorafenib or donafenib, the intermolecular interactions, the interaction type between sorafenib or donafenib and the effective groups of the polymer material in the self-assembly building blocks, the strength of action, and molecular recognition are all consistent. Therefore, the following description will be given using sorafenib as an example, but the same applies to donafenib.

[0044] Example 1 Screening of self-assembling building blocks An appropriate amount of sorafenib or sorafenib tosylate was weighed out, dissolved in a small amount of dimethyl sulfoxide, and diluted with acetonitrile to prepare a highly concentrated stock solution containing approximately 50 mg of sorafenib per ml, ensuring that sorafenib was dispersed in the solution at the molecular level. The pH 6.8 phosphate buffer solution containing 0.1% sodium dodecyl sulfate (SDS) was used as the base medium (pH 6.8 phosphate + 0.1% SDS). The base medium was prepared according to the guidelines for oral solid preparation dissolution testing, and the polymer materials used were povidone (PVP) PVP K25, PVP K30, PVP K90; copovidone (a copolymer of vinylpyrrolidone and vinyl acetate), e.g., PVP VA64; hydroxypropyl methylcellulose acetate succinate (HPMCAS), e.g., HPMCAS H grade (methoxy group content is 22% to 26%, hydroxypropoxy group content is 6% to 10%, acetyl group content is 10% to 14%, succinyl group content is 4% to 8%) (or equivalent model number), HPMCAS Granular or powdered form of MG (methoxy group content 21%-25%, hydroxypropoxy group content 5%-9%, acetyl group content 7%-11%, succinyl group content 10%-14%) (or equivalent model number), HPMCAS LG (methoxy group content 20%-24%, hydroxypropoxy group content 5%-9%, acetyl group content 5%-9%, succinyl group content 14%-18%) (or equivalent model number); hydroxypropyl methylcellulose, e.g., HPMCE5, K100LV; polyethylene glycol, e.g., PEG 8000, Soluplus, etc., were weighed out in appropriate amounts and dissolved in phosphate + 0.1% SDS at pH 6.8 to prepare different media of the same concentration. 50ml of the above base medium or base medium containing a certain mass% of polymeric material as a self-organizing building block was weighed out, placed in a 100ml stoppered Erlenmeyer flask, shaken on a shaker at 37°C and incubated until 37°C. 1.0ml (1000μg / mL) of sorafenib stock solution was added to each stoppered Erlenmeyer flask, and ultrasonically dispersed at 37°C until uniform. Then, the flask was transferred to a thermostatic shaker at 37°C and sampled at 0.5h, 1h, 2h, 3h, 4h, and 6h. The mixture was centrifuged at 37°C and 13000rpm. An appropriate amount of the supernatant was taken and diluted with 50%-acetonitrile as a diluent. The concentration of sorafenib present as molecules in the systems constructed with the medium containing different self-organizing building blocks was detected by HPLC. The results are shown in Table 1 below.

[0045] As shown in Figure 1, the three-dimensional structure and single crystal structure of the sorafenib molecule are such that the N4 hydrogen in the carboxamide and the N3 hydrogen in the pyridine are likely to form intramolecular hydrogen bonds, while the hydrogens on N1 and N2 of the ureido group are likely to form intermolecular hydrogen bonds, hydrophobic effects, and π-π stacking interactions with the O1 of the carboxamide on other molecules. Therefore, after the sorafenib molecule is dissolved in solution, it quickly forms molecular packing through intermolecular interactions, and finally precipitates from the solution to form a solid supramolecular self-organized system, as shown in Figure 2.

[0046] [Table 2]

[0047] As shown by the above results and Figure 1, compared with the base medium (not including self-assembly building blocks), the sole use of other polymer materials as building blocks other than 0.5%-HPMC K100LV has a certain regulating effect on the occurrence of sorafenib molecular packing in solution, but as the incubation time is extended, the thermal motion of the molecules increases, increasing the opportunity for intermolecular hydrogen bond formation, and the molecular packing increases over time. 0.5%-povidone (PVP K25-K90, polymer of N-vinylpyrrolidone), 0.5%-copovidone (PVPVA64), 0.5%-Soluplus, and 0.5%-HPMCAS H grade (acetyl group 10%-14%, succinyl group 4%-8%) all had good adjustment effects on sorafenib molecular packing. The sorafenib concentrations in the self-assembled systems measured after 6 h were 208.61 μg / mL-759.31 μg / mL, both of which were significantly higher than the concentration (5.61 μg / mL) measured after 6 h in the base medium. Compared with the base medium, the self-assembled systems constructed with 0.5% Soluplus and 0.5% HPMCAS H grade had higher sorafenib encapsulation rates, 75.9% and 63.4%, respectively, which could be increased by at least 100 times. 0.5% The self-assembly system constructed with Soluplus and 0.5% HPMCAS H grade tended to show a gradual increase in the encapsulated drug over time, which is due to the fact that Soluplus and HPMCAS H grade not only have the opportunity to competitively form hydrogen bonds with sorafenib molecules, but also play a decisive role in terms of their strong hydrophobic effect. In other povidone series and copovidone series, as the incubation time is extended, sorafenib molecules gradually generate molecular packing, but the concentration of sorafenib in the self-assembly system measured at 6h is still 34-55 times that of the base medium, and the adjustment effect of high molecular weight K90 on sorafenib molecular packing is better than K25, K30 and VA64, so it is speculated that the high viscosity K90 restricts the thermal motion of sorafenib molecules themselves and reduces the opportunity to form hydrogen bonds between molecules.

[0048] 0.5%-copovidone (e.g., PVP VA64) is a copolymer of vinyl acetate and N-vinylpyrrolidone, in which N-vinylpyrrolidone accounts for about 60% and vinyl acetate accounts for about 40% in the copolymer, so that the hydrophobicity of copovidone at the same mass fraction is superior to that of the povidone series, and the density of hydrogen acceptors that copovidone can donate is different from that of povidone. The oil-water partition coefficient LogP of sorafenib molecules is about 5.6, which increases the hydrophobicity. Therefore, the adjusting effect of 0.5%-PVP VA64 on sorafenib molecular packing is superior to that of the low-viscosity K25 and K30 of the povidone series, but its ability to maintain the stability of the self-organized system in the later stage is slightly inferior to that of K90. Compared with copovidone, 0.5% polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) not only has an increased hydrophilic group (PEG6000) of 13%, but also has a hydrophobicity of 59% vinyl lactam group and 30% vinyl acetate ester group that is superior to povidone and copovidone, i.e., it provides hydrophobic interaction and competitively forms hydrogen bonds with the hydrophilic group and sorafenib molecules. Therefore, the supramolecular self-assembly system constructed with the involvement of Soluplus has the strongest synergistic adjustment ability for sorafenib molecular packing, and the constructed supramolecular self-assembly system is the most stable and has the highest encapsulation rate. 0.5%-Hydroxypropyl methylcellulose acetate succinate (HPMC AS) is a hydroxypropyl methylcellulose Hydroxypropyl methylcellulose acetate succinate is a mixture of acetate and succinate, with the succinyl group gradually increasing and the acetyl group gradually decreasing, and its hydrophobicity gradually weakens. According to the amount of succinyl and acetyl groups substituted, there are three general standards for sale, such as H grade (succinyl group is 4%-8%, acetyl group is 10%-14%), L type (succinyl group is 14%-18%, acetyl group is 5%-9%), and M grade is between them. Hydroxypropyl methylcellulose acetate succinate can provide hydrogen acceptor and hydrogen donor, and its succinyl group can also have ionic interaction with weakly basic drugs, and hydrophobic action occurs with hydrophobic drugs, and forms a stable supramolecular self-organized system with aqueous solution under appropriate pH conditions. Therefore, its H grade has a stronger synergistic adjustment effect on sorafenib molecular packing than L or M grade, and can maintain stability for a long time. Specifically, as shown in Figure 3.

[0049] In view of the above, in molecular-level pharmaceutical compositions prepared with sorafenib, such as solid dispersions, solid solutions, polymer nanoparticles, self-emulsifying microemulsions, nanoemulsions or molecular-level mixtures, the structure of the sorafenib molecule itself is likely to form a supramolecular self-organized system and become solid, which affects the absorption of the drug; the polymer material selected as the supramolecular self-organized building block should, apart from a group having a certain number of hydrogen acceptors and hydrogen donors, have the special structure and strong hydrophobic properties of the sorafenib molecule, and as long as sufficient hydrophobic and ionic effects are given, the balance between the subsystem and the entire supramolecular system can be maintained, and more sorafenib molecules can be stably encapsulated in the newly constructed supramolecular self-organized system for a long period of time. However, as pharmaceutical additives, various polymeric materials have a maximum daily safe dose, especially for drugs taken for a long period of time. If the content of a certain polymeric material in a prescription is too high (0.5% mass fraction, calculated as 250mL intestinal fluid, the amount of additive contained in a unit preparation is about 125mg, and if two preparation units are required to be taken twice a day, the amount of the carrier taken daily is 500mg, which is not achievable for most additives), it will also lead to changes in the preparation process, dissolution, disintegration behavior, physical stability, and chemical stability, and the desired results are often not achieved. Therefore, based on the above research, the inventor has found that an unexpected effect can be obtained by combining two or more polymeric materials with different properties to form the building blocks of a supramolecular self-organized system. The specific embodiments and experimental results are as follows:

[0050] [Table 3-1]

[0051] [Table 3-2]

[0052] From the above results, when the dose of copovidone, povidone or Soluplus was reduced by half and used in combination with other polymeric materials in a mass ratio of 1:1, in addition to significantly reducing the daily dose of a single polymeric material, an unexpected synergistic adjusting effect was also found, which is specifically shown in Figures 4 to 7.

[0053] Copovidone, for example, PVP VA64, has a lack of hydrophilic groups and hydrogen donor groups compared with Soluplus or HPMCAS H grade, and its hydrophobic effect is weaker than that of Soluplus compared with sorafenib. The povidone series, except for having the characteristics of copovidone, has a hydrophobic effect inferior to copovidone. When 0.25%-(PVP-VA64) was used in combination with 0.25% HPMCAS H grade, HPMCAS M grade, or Soluplus, it was possible to significantly compensate for the deficiency of PVP VA64 alone, and the sorafenib concentration in the self-assembly system measured after 6 h was 700 μg / mL in all cases. Similarly, the combination of 0.25%-(PVP-VA64) with hydrophilic HPMC also had a significant adjusting effect on sorafenib molecular packing, and the sorafenib concentration in the self-assembly system measured after 6 h was maintained at 335-458 μg / mL, which was significantly higher than the effect achieved by any single polymer material in the composite carrier. The complex of 0.25% PVPVA64 and 0.25% PEG8000 had a significantly reduced synergistic regulatory effect on sorafenib molecular packing compared with 0.5%-PVPVA64 due to the highly hydrophilic nature of PEG8000. For the povidone series, PVP K25 is used as an example for low viscosity, and PVP K90 is used as an example for high viscosity. The 0.25% (PVP+HPMCAS) and 0.25% (PVP+HPMC) series are all superior to any single polymer material with a high mass fraction, especially 0.5%-HPMCAS M and L, 0.5%-PVP VA64, 0.5%-PVP, 0.5% HPMCE5, 0.5% HPMC K100LV. The hydrophilic and hydrophobic groups in the structure of each polymer material and their ability to provide hydrogen acceptors and donors can be used to complex the self-organizing building blocks, which can compensate for the limitations of single polymer materials and commercially available polymer materials, and can be rationally complexed based on the classification of the drug's own structure and intermolecular interactions. Even more unexpectedly, the use of the low-viscosity PVPK25, K30 and high-viscosity PVP K90 in combination demonstrated a synergistic adjustment effect on the molecular packing of sorafenib that was superior to the effect of either polymer alone. In 0.25%-PVP (K25+K90), sorafenib was maintained at 718-630μg / mL in both systems from 0.5h to 6h, whereas in the systems using 0.5%-PVPK25 and 0.5%-PVP K90 as self-assembly building blocks, the sorafenib concentration was 209-310μg / mL measured at 6h. The effect of the composite self-assembly building blocks of the 0.25%-(PVP-VA64 / PVP+HPMC) series was also significantly better than that of any single polymer material with a high mass fraction alone. 0.5% HPMC had poor synergistic adjustment ability for sorafenib molecular packing, and was basically the same as the basic medium. However, the effect after the 0.25%-(PVP-VA64 / PVP+HPMC) composite was significantly better than that of 0.5%-PVP VA64, 0.5%-PVP, and 0.5%-HPMC. In the 0.25%(PVP-VA64+HPMC) group, the composite of low-viscosity HPMC, high-viscosity HPMC, and copovidone was significantly better than that of the single application, but the synergistic adjustment effect of the composite of low-viscosity HPMC and PVP VA64 on sorafenib molecular packing was significantly better than that of high-viscosity HPMC K100 LV. In the 0.25% (PVP+HPMC) group, the synergistic adjusting effect of PVP K25 on high and low viscosity HPMC was basically consistent.

[0054] However, not all polymer composite applications have a synergistic regulatory effect on sorafenib molecular packing. For example, the composites of povidone, copovidone, and Soluplus with PEG8000 correspond to basic mediators, as shown in Figure 8. Soluplus is a supramolecular self-assembly building block that is compounded with povidone, copovidone, HPMCAS series, and HPMC series, and while reducing the mass fraction of each by half, maintains the synergistic effect that can be achieved by the high mass fraction of Soluplus. It provides a new concept to solve problems such as the large dosage of Soluplus, poor moldability, and its effect on the stability of active ingredients. In the composite application of 0.25%-PVP K90 with the HPMCAS series or HPMC with low hydrophobic groups, a remarkable synergistic adjustment effect was also found. The succinyl group (L-type, M-grade) with high hydrophilic group content of the HPMCAS series can provide ionic action to sorafenib and can destroy its original self-organization system by competing with the groups that are likely to form hydrogen bonds between sorafenib molecules. PVP K90 can compensate for the defects caused by the lack of hydrophobicity of HPMCAS (L-type, M-grade) and HPMC, and reduce the opportunity for mutual contact due to thermal motion of molecules, thereby reducing the formation of intermolecular hydrogen bonds. This is also supported by the effect of 0.25%-PVP K90 + 0.25%-HPMC K100LV, and the competition of hydrogen bonds between the hydrogen donor or acceptor on the polymer material and the sorafenib molecules and the hydrophobic effect are even more remarkable.

[0055] Table 4 shows performance data for supramolecular self-assembly systems constructed by the composite application of the HPMCAS series (which differ in the content of hydrophobic acetyl groups and hydrophilic succinyl groups) with other polymer materials.

[0056] [Table 4]

[0057] As can be seen from Table 4, the composite application of the HPMCAS series with other polymer materials showed remarkable selectivity. When 0.25%-HPMCAS grade H (succinyl group 4%-8%, acetyl group 10%-14%) was used with povidone, copovidone, and Soluplus after reducing the mass fraction, it still maintained the high solubilization and crystallization inhibition effect at the original high mass fraction. The concentration of sorafenib in the self-assembled system measured after 6 hours was approximately 793-818 μg / mL, and the encapsulation rate was high at 81.8%. When 0.25%-HPMCAS grade H was composited with hydrophilic polymer materials of equal mass fraction, the synergistic adjustment ability gradually decreased over time. After combining HPMCAS L-type with the same mass fraction of HPMCAS M-type, the hydrophobic acetyl group in the constructed composite self-assembly building block is about 6%-10%, and the hydrophilic succinyl group is about 12%-16%, and the synergistic adjustment effect that can be achieved is equivalent to HPMCAS H-type, far exceeding the application of 0.5%-HPMCAS L-type or 0.5%-HPMCAS M-type alone, which is very important for the development of formulation products, and the in vivo dissolution and release properties of the product can be adjusted based on the different mixing ratios of the two. When HPMCAS L-type is combined with copovidone and povidone, the two can take advantage of each other's advantages and compensate for each other's disadvantages, and act synergistically, the results are greater than the effect of the application of any one polymer material alone. When 0.25% HPMCAS L-type is combined with 0.25% Soluplus, the dosage of each can be reduced, the feasibility of the formulation technology can be improved, and the release can be adjusted based on the designed release behavior of the drug in vivo. Hydroxypropyl methylcellulose E series generally has a methoxy group content of about 29% and a hydroxypropyl group content of about 12%, and the number of hydrogen donors and acceptors in its structure is higher than that of HPMCAS. Therefore, it is more hydrophilic than HPMCAS, and therefore has no ability to adjust the formation of sorafenib molecular packing when used alone.However, after HPMCAS was complexed with povidone, copovidone, and Soluplus, which have stronger hydrophobicity, the number of hydrogen donors and acceptors in the system was changed, and the system was further hydrophobized. However, as the incubation time was extended, for example, sorafenib slowly packed in the supramolecular system constructed by complexing low-viscosity povidone, copovidone, and HPMC during 6 hours of incubation, but high-viscosity povidone slowly grew by 6 hours. When 0.25%-HPMC (low viscosity) was complexed with the same mass fraction of povidone, copovidone, and medium- and high-hydrophobic types of HPMCAS, all showed a significant synergistic adjustment effect, and the effect was better than that achieved by either one alone. The details are shown in Figures 9 and 10.

[0058] HPMC, taking the E series as an example, has an average methoxy group content of about 29% and an average hydroxypropyl group content of 10%, and has more hydrophilic groups and poorer hydrophobicity than HPMCAS. Therefore, when the mass fraction of the hydrophobic composite crystallization inhibitor is increased to 1:2, its solubilization and crystallization inhibition ability can be significantly improved. In particular, when 0.5% povidone, HPMCAS-H and 0.25% HPMCE5 are combined and more hydrophobic additives are added, the solubilization and crystallization inhibition effect for sorafenib can be enhanced, but 0.5% copovidone and Soluplus do not show obvious advantages, as shown in Figures 11 and 12. The HPLC analysis method was as follows. High-performance liquid chromatography using an Agilent 1260, a four-liquid gradient low-pressure pump, a column oven, an autosampler, an ultraviolet detector, and an online degasser were used, and the parameters are shown in Table 5.

[0059] [Table 5]

[0060] Example 2 Preparation of low carrier dose molecular level pharmaceutical composition Sorafenib (SLFN) / sorafenib tosylate (TSSLFN) was added to a mixed solvent of methanol-dichloromethane (1:3) and dissolved by stirring at 30-33°C. The ratio of the active ingredient to the mixed solvent was 1:100. A carrier was then added and dissolved, so that the ratio of the active ingredient to the carrier was 1:1 as the carrier dosage. The mixture was spray-dried, and the inlet air temperature was set to 120°C, the outlet air temperature to 60°C, and nitrogen gas was used as the carrier gas.

[0061] [Table 6]

[0062] The above results show that under the condition of low carrier ratio, molecular level pharmaceutical compositions can be formed using copovidone, povidone, copovidone + HPMCAS, HPMC E5, and Soluplus as carriers.

[0063] Example 3 Preparation of tablet samples Preparation process: A molecular-level pharmaceutical composition (SD) was prepared according to Example 2. SD, self-assembly building blocks, half the prescribed amount of filler, disintegrant, and half the prescribed amount of lubricant were mixed uniformly, dry granulated, and the remaining half the prescribed amount of filler, glidant, and half the prescribed amount of lubricant were added, mixed uniformly, and compressed into tablets. The formulation of the tablet sample is shown in Table 7.

[0064] [Table 7-1]

[0065] [Table 7-2]

[0066] [Table 7-3]

[0067] [Table 7-4]

[0068] [Table 8]

[0069] In the dissolution test, the following conditions were used: 900 mL of 0.1% sodium dodecyl sulfate (SDS) pH 6.8 phosphate buffer, 100 rpm, 37°C, using the paddle method. In the sampling and sample processing method, 10 mL was sampled and filtered through a PES filtration membrane (diameter 25 mm, pore size 0.45 μm), 8 mL of the filtrate was discarded, 1-2 mL of the filtrate was continuously collected, and 10 mL of the medium was added to the dissolution cup. After filtration, the sample was submitted for analysis and measured after dilution. One tablet (200 mg) of the reference formulation (RLD) and four tablets (200 mg) of the self-control formulation were administered. The detection of the dissolution rate was performed by the HPLC method, and the dissolution results are shown in the table below.

[0070] [Table 9-1]

[0071] [Table 9-2]

[0072] The above results show that the cumulative dissolution rates of formulations F1 to F42 are all much higher than those of RLD, F43 (a molecular-level pharmaceutical composition with a low active ingredient content) and DB1, and that the composite self-assembly building blocks in the formulation have a better synergistic adjustment effect on sorafenib molecular packing.

[0073] Example 4: Consideration of tablet hardness, disintegration, and formulation stability due to tablet additives and moisture Preparation process: Prepare solid dispersion (SD) according to Example 2, uniformly mix SD, crystallization inhibitor, half the prescribed amount of filler, disintegrant, and half the prescribed amount of lubricant, dry granulate, add the remaining half the prescribed amount of filler, glidant, and half the prescribed amount of lubricant, uniformly mix, and tablet. Moisture content was measured according to Method 1 of Part 4 General Provisions 0831 of the Pharmacopoeia of the People's Republic of China, 2020 Edition. The tablet formulation is shown in the table below.

[0074] [Table 10-1]

[0075] [Table 10-2]

[0076] Hardness was tested using a tablet hardness tester, 6 tablets were measured and the average value was taken, disintegration time was tested using a disintegration tester, 6 tablets were measured and the average value was taken, CTF-aniline and total impurities were detected by HPLC, and crystalline content was measured by Raman spectroscopy, the results are shown in Table 10, and stability experimental conditions were examined in an accelerated test box at 40℃±2℃ / RH75%±5%. Tablets examined for stability were wrapped in double aluminum foil in addition to aluminum-plastic composite film.

[0077] [Table 11]

[0078] From the above data, the tablet fillers microcrystalline cellulose and silicified microcrystalline cellulose are obviously superior to lactose and mannitol, and the dosage range is 30-45% based on the total weight of the tablet. The disintegrant is preferably cross-linked sodium carboxymethylcellulose, and the dosage is 5-15% based on the total weight of the tablet. The tablet also contains a lubricant, preferably magnesium stearate, sodium stearyl fumarate, more preferably magnesium stearate. Preferably, the formulation prepared by the formula can be rapidly disintegrated within 5 min. Based on the above data, under high moisture conditions, tablets were used with fillers of microcrystalline cellulose and silicified microcrystalline cellulose and a disintegrant of cross-linked sodium carboxymethylcellulose. The sorafenib tablets were left in their packaging for 90 days under conditions of 40°C / RH75%, and no molecular packing occurred.

[0079] Example 5 Preparation of coated tablets The polymeric material of the self-organizing building block may be added during the production of the core tablet, or may be added to the coating material, or may be added simultaneously. In the preparation process, the molecular level pharmaceutical composition (SD) was prepared according to Example 2, and the SD, the polymeric material of the self-organizing building block, half the prescribed amount of filler, disintegrant, and half the prescribed amount of lubricant were uniformly mixed, dry granulated, and the remaining half the prescribed amount of filler, glidant, and half the prescribed amount of lubricant were added, uniformly mixed, tableted, and coated. The tablets were prepared according to the formula in the table below.

[0080] [Table 12-1]

[0081] [Table 12-2]

[0082] In the dissolution test, the following conditions were used: 900 mL of 0.1% sodium dodecyl sulfate (SDS) pH 6.8 phosphate buffer, 100 rpm, 37°C, using the paddle method. In the sampling and sample processing method, 10 mL was sampled and filtered through a PES filtration membrane (diameter 25 mm, pore size 0.45 μm), 8 mL of the filtrate was discarded, 1-2 mL of the filtrate was continued to be collected, and 10 mL of the medium was added to the dissolution cup. After filtration, the sample was diluted in the same proportion and then detected. For the reference formulation (RLD), one tablet (200 mg) was administered, and for the self-administered formulation, four tablets (200 mg) were administered. The dissolution results are shown in the table below.

[0083] [Table 13]

[0084] The above results demonstrate that there is a significant effect whether the polymer material constructed by self-organization inside the tablet core, during coating, or both are added simultaneously.

[0085] Example 6 Preparation of Micropellets In the preparation process, sorafenib and VA64 were dissolved in a mixture of dichloromethane and methanol (3:1), and the drug was layered on the micropellets by fluidized bed, and then a coating layer was sprayed, and the resulting micropellets were encapsulated, each capsule containing 50 mg of sorafenib. The micropellets were prepared according to the formula in the table below.

[0086] [Table 14]

[0087] In the dissolution test, the following conditions were used: 900 mL of 0.1% sodium dodecyl sulfate (SDS) pH 6.8 phosphate buffer, 100 rpm, 37 °C, using the paddle method. In the sampling and sample processing method, 10 mL was sampled and filtered through a PES filtration membrane (diameter 25 mm, pore size 0.45 μm), 8 mL of the filtrate was discarded, 1-2 mL of the filtrate was continued to be collected, and 10 mL of the medium was added to the dissolution cup. After filtration, the sample was diluted in the same proportion and then detected. For the reference formulation (RLD), one tablet (200 mg) was administered, and for the self-administered formulation, four tablets (200 mg) were administered. The dissolution results are shown in the table below.

[0088] [Table 15]

[0089] From the above results, the micropellets were prepared as a molecular-level pharmaceutical composition by coprecipitation, and the addition of a polymer material coating containing self-organizing building blocks clearly had a synergistic effect on adjusting the sorafenib molecular packing after dissolution.

[0090] Example 7 Powder Coating A molecular level pharmaceutical composition of sorafenib was prepared by spray drying according to Example 2, and the pharmaceutical composition SD was powder coated according to the recipe in the table below, and further additives were added according to the recipe in Table 8 to prepare tablets. The powder coating was prepared according to the recipe in the table below.

[0091] [Table 16]

[0092] Dissolution and dissolution tests were performed using the paddle method, with 900 mL of 0.1% sodium dodecyl sulfate (SDS) pH 6.8 phosphate buffer, 100 rpm, and 37°C. Sampling and sample processing methods: 10 mL was sampled and filtered through a PES filtration membrane (diameter 25 mm, pore size 0.45 μm), 8 mL of the filtrate was discarded, 1-2 mL of the filtrate was continued to be collected, and 10 mL of the medium was added to the dissolution cup. After filtration, the sample was submitted for analysis and measured after dilution. For the reference formulation (RLD), one tablet (200 mg) was administered, and for the self-administered formulation, four tablets (200 mg) were administered. The dissolution results are shown in the table below.

[0093] [Table 17]

[0094] From the above results, in SD, powder coating is performed using a coating material containing self-organizing building blocks, and then it is placed in solution after sorafenib is dissolved. The self-organizing polymer material in the coating layer is already in the system at the outermost layer, and still has a good synergistic adjusting effect on sorafenib molecular packing.

[0095] Example 7 Preparation of self-emulsifying microemulsion Ethyl oleate, polyoxyethylene castor oil, and ethanol were mixed uniformly in the ratio to form a blank self-emulsifying microemulsion, sorafenib was added and dissolved, and the self-assembly building block was added and mixed uniformly. The self-emulsifying microemulsion was prepared according to the table below.

[0096] [Table 18]

[0097] Lipolysis Test: The lipolysis buffer was prepared by adding Tris-maleate buffer (0.474 g / L), calcium chloride anhydrous (0.208 g / L), aqueous NaCl solution (8.766 g / L, ultrapure water), and 5 mol / L NaOH to adjust the pH to 6.5. The lipolysis medium was L-α-phosphatidylcholine (PC) (0.576 g / L), and sodium ursodeoxycholate (1.565 g / L) was added to the buffer, and the medium was stirred overnight to ensure complete dissolution of PC. The trypsin solution was prepared by adding 3 g of polished porcine pancreatic juice to 15 ml of lipolysis buffer, adjusting the pH to 6.5 using 5 mol / L NaOH, and stirring the mixture for 10 min using a magnetic stirrer. The mixture was aliquoted and centrifuged (5°C, 10 min), and the supernatant was collected for lipolysis experiments. For the detection of trypsin enzyme activity, before the start of the lipolysis experiment, trypsin enzyme activity was detected using tributyrin as an enzyme substrate. An excess of tributyrin was added so that the reaction rate was proportional to the enzyme concentration. For this purpose, 500 μl of tributyrin in 35 ml of lipolysis medium (without phosphatidylcholine) can be lipolyzed with 1.5 μl of trypsin. The enzyme activity should be more than 900 U / mg. For the lipolysis test, a formulation sample equivalent to 50 mg of SLFN was taken and added to a lipolysis medium with a volume of 36 ml at 37°C. After stirring for 10 minutes, 4 ml of trypsin solution was added. Samples (approximately 1 ml) were taken periodically throughout the entire test process (approximately 1 hour), and the samples were mixed with 4-bromophenylboronic acid (a lipase inhibitor). The samples were centrifuged at 37°C, and the supernatant was collected and diluted before detection. Sampling times were 10 min and 0 min before enzyme addition (dispersion step), and 5, 15, 30 and 60 min after enzyme addition (digestion step).

[0098] [Table 19]

[0099] These results indicate that the self-emulsifying microemulsions containing self-assembling building block materials can still maintain synergistic regulation of sorafenib molecular packing during the lipase digestion process, while in formulation F75 without added crystallization inhibitor, the sorafenib molecular packing gradually increased over time.

[0100] Example 8 Formulation of Donafenib In the preparation process, molecular level pharmaceutical composition SD (replace sorafenib in Example 2 with donafenib) was prepared according to Example 2, and SD, self-assembly building block, half the prescribed amount of filler, disintegrant, and half the prescribed amount of lubricant were mixed uniformly, dry granulated, and the remaining half the prescribed amount of filler, glidant, and half the prescribed amount of lubricant were added, mixed uniformly, and compressed into tablets. The formulation of the tablet sample is shown in Tables 20 and 21.

[0101] [Table 20]

[0102] [Table 21]

[0103] In the dissolution test, the following conditions were used: 900 mL of 0.1% sodium dodecyl sulfate (SDS) pH 6.8 phosphate buffer, 100 rpm, 37 °C, using the paddle method. In the sample processing method, 10 mL was sampled and filtered through a PES filtration membrane (diameter 25 mm, pore size 0.45 μm), 8 mL of the filtrate was discarded, 1 to 2 mL of the filtrate was continued to be collected, and 10 mL of the medium was added to the dissolution cup. After filtration, the sample was submitted for analysis and measured after dilution. For the reference formulation (RLD), one tablet (200 mg) was administered, and for the self-control formulation, four tablets (200 mg) were administered. The detection of the dissolution rate was performed by the HPLC method, and the dissolution results are shown in the table below.

[0104] [Table 22]

[0105] F76 is a comparative example prepared with reference to Example 1 of Patent CN103301067 B. From the above results, it was found that the elution of samples F77, F78, and F79 prepared according to the present invention was significantly higher than that of F76.

[0106] Example 9 PK study in beagle dogs A fasting PK study was conducted in beagle dogs using the sample of Example F44 (50 mg x 4 tablets, T1), the sample of Example F33 (50 mg x 4 tablets, T2), the sample of DB1 (50 mg x 4 tablets, T3), and the reference formulation Takichimi (standard 200 mg x 1 tablet, R). The animals used were adult male beagle dogs (8-11 kg), non-naive, and were divided into three groups, with two beagles per group. Regarding the route and frequency of administration, a single dose of 200 mg was orally administered into the stomach. Subjects were fasted for 16 hours or more before administration, and were allowed to eat freely 4 hours after administration. There was a 4-day washout period, and the administration was performed in a 4-cycle cross-administration. Blood was drawn at the following times: 0, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 48 hours. Blood drug concentrations were detected using an LC / MS / MS method, and pharmacokinetic parameters (AUC 0-t , AUC 0- ∞, C max , T 1 / 2 , T max The arithmetic mean (±SD) and geometric mean of these parameters were calculated.

[0107] [Table 23]

[0108] From the above results, it was found that the bioavailability of F33 and F44 of the present invention was much higher than that of the reference preparation and also much higher than that of comparative example DB1. The test confirmed that the addition of a self-assembling polymeric material significantly improved the bioavailability of sorafenib.

[0109] Example 10 PK Study in Healthy Volunteers Fasting PK studies were conducted using samples of Example F44 (50 mg, T1), Example F33 (50 mg, T2), and Takichimi (standard 200 mg, R) as a reference preparation. The subjects were 12 healthy Chinese men or women (5 women) aged 18-65 years. Single-center, randomized, 3-formulation, 3-cycle, 3-crossover design. Regarding the route and frequency of administration, subjects fasted overnight for at least 10 hours, then took one tablet of the reference formulation, two tablets each of T1 and T2 in 240 mL of aqueous solution the next morning on an empty stomach. There was a 10-day washout period. Blood was collected at the following times: before administration (0 h), 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h, 72 h, and 96 h after administration. Blood drug concentrations were detected by LC / MS / MS, and pharmacokinetic parameters (AUC 0-t , AUC 0- ∞, C max , T 1 / 2 , T max The arithmetic means (±SD) and geometric means) of these parameters were calculated and an analysis of relative bioavailability was performed, the results of which are shown in Tables 24, 25 and FIG. 13 below.

[0110] [Table 24]

[0111] [Table 25]

[0112] From the above results, 50mg of T1 is equivalent to 200mg of the reference formulation, Takumi, and 60mg of T2 is equivalent to 200mg of the reference formulation, Takumi. It was also found that the variability of Cmax and AUC of the T1 and T2 formulations was lower than that of the reference formulation. This means that the product developed using the technical solution provided by the present invention can be used in future clinical applications instead of Takumi sorafenib tosylate tablets and generic drugs 800mg (Bid), or instead of donafenib tablets 400mg (Bid), 200mg (Bid).

[0113] Example 11 High Fat Meal PK Study in Healthy Volunteers A high-fat, high-calorie diet PK test was conducted using a sample of Example F44 (50 mg, T1) and the reference preparation Takichimi (standard 200 mg, R). The subjects were 12 healthy Chinese men or women (5 women) aged 18-55 years. Single-center, randomized, open-label, postprandial, single-dose, two formulations, two cycles, double crossover design Regarding the route of administration and frequency of administration, all subjects fasted overnight but did not abstain from water (at least 10 h), started a high-fat, high-calorie meal 30 minutes before administration on the administration day of each cycle, finished the meal within 30 minutes, and administered the test drug 30 minutes (± 30 s) after the start of the meal. They took 100 mg of the test formulation T1 (sorafenib tablet) or 200 mg of the reference formulation (R, Takichimi / Nexavar) with 240 mL of water, with a washout period of 10 days between cycles. Blood was collected from the cubital vein at approximately 4 mL before administration (0 h) and at 1.0 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h, 4.0 h, 4.5 h, 5.0 h, 6.0 h, 8.0 h, 12.0 h, 16.0 h, 24.0 h, 36.0 h, 48.0 h, 72.0 h, and 96.0 h after administration. Blood drug concentrations were detected by LC / MS / MS, and pharmacokinetic parameters (AUC 0-t , AUC 0- ∞, Cmax , T 1 / 2 , T max The arithmetic mean (±SD) and geometric mean of these parameters were calculated and an analysis of relative bioavailability was performed, the results of which are shown in Table 26, Table 27 and FIG. 14 below.

[0114] [Table 26]

[0115] [Table 27]

[0116] According to the package insert of Takimi / Nexavar, the bioavailability of sorafenib was reduced by 29% when a high-fat, high-calorie meal was consumed compared to the fasting state. Therefore, the method of administration prescribed in the package insert of Takimi / Nexavar is to be taken on an empty stomach (without food (at least 1 hour before or 2 hours after a meal)). According to Examples 9 and 10, the relative bioavailability of T1-100 mg and RLD-200 mg was 200.98% when fasted, and the relative bioavailability was 268% when a high-fat, high-calorie meal was consumed. The postprandial / preprandial Cmax and AUC0-∞ ratios of the test formulation T1 were 1.1 and 1.3, respectively, while the AUC0-∞ of the reference formulation was reduced by about 30% after a meal. From the above, it was shown that the formulation of the present invention can eliminate the effect of a high-fat meal on bioavailability and realize postprandial administration. When taken with food, it can significantly reduce gastrointestinal side effects such as nausea and diarrhea. At the same time, Examples 9 and 10 show that the CV of the formulations of the present invention is significantly lower than that of the reference formulation, Takumi. This also contributes to further improving the therapeutic effect and reducing side effects. Therefore, the formulation of the present invention has significant clinical advantages and can bring significant benefits to patients. From the above data and analysis, it can be seen that the formulation of the present invention solves the problems of sorafenib dissolution and absorption, and therefore when drug resistance occurs with long-term administration and the dosage needs to be increased, effective exposure can be maintained through convenient titration, thereby solving the problem of drug resistance.

[0117] The above description of the embodiments is only used to help the understanding of the method and gist of the present invention. Those skilled in the art can make some improvements and modifications to the present invention without departing from the principle of the present invention, and these improvements and modifications are also included in the protection scope of the claims. The description set forth in the disclosed embodiments may be practiced or used by those skilled in the art. Various modifications to these embodiments will be apparent to those skilled in the art, and the generic principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Thus, the present invention is not intended to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A low-dose oral preparation of sorafenib or donafenib comprising a molecular-level pharmaceutical composition of sorafenib or donafenib, a self-assembling polymeric material, and other pharma- ceutically acceptable additives, wherein the state of the molecular-level pharmaceutical composition of sorafenib or donafenib is a molecular-level solid dispersion, a solid solution, a polymer nanoparticle, a self-emulsifying microemulsion, a nanoemulsion, or a molecular-level mixture; The self-organizing polymer material is povidone + hydroxypropyl cellulose, low viscosity povidone + high viscosity povidone, povidone + Copovidone, povidone + polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, povidone + hydroxypropyl methylcellulose acetate succinate, povidone + hydroxypropyl methylcellulose, povidone + cellulose acetate, povidone + cross-linked sodium carboxymethylcellulose, povidone + polyethylene glycol, povidone + low-substituted hydroxypropylcellulose, povidone + hydroxypropyl methylcellulose phthalate, povidone + methacrylic acid-ethyl acrylate copolymer, povidone + methacrylic acid-methyl acrylate copolymer, copovidone + hydroxypropylcellulose, copovidone + polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, copovidone + hydroxypropyl methylcellulose acetate succinate, copovidone + hydroxypropyl methylcellulose, copovidone + cellulose acetate, copovidone + cross-linked sodium or calcium carboxymethylcellulose, copovidone + polyethylene glycol, copovidone + low-substituted hydroxypropyl cellulose, copovidone + hydroxypropyl methylcellulose phthalate, copovidone + methacrylic acid-ethyl acrylate copolymer, copovidone + methacrylic acid-methyl acrylate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose acetate succinate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl cellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + low-substituted hydroxypropyl cellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + crosslinked sodium or calcium carboxymethylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + polyethylene glycol,A low-dose sorafenib or donafenib oral preparation selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose phthalate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + methacrylic acid-ethyl acrylate copolymer, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + methacrylic acid-methyl acrylate copolymer.

2. The oral formulation of sorafenib or donafenib according to claim 1, characterized in that the self-organizing polymer material is 10 to 50 wt % of the molecular-level pharmaceutical composition of sorafenib or donafenib.

3. The sorafenib or donafenib oral preparation according to claim 1, characterized in that the hydroxypropyl methylcellulose is HPMC E5 or HPMC K100LV, the self-organizing polymer material is a composite self-organizing polymer material of povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, one of highly hydrophobic hydroxypropyl methylcellulose acetate succinate grade H, and HPMC E5, the composite ratio being (1-10):1, and the self-organizing polymer material is a composite self-organizing polymer material of the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, one of highly hydrophobic hydroxypropyl methylcellulose acetate succinate grade H, and HPMC K100LV, the composite ratio being (1-10):

1.

4. The sorafenib or donafenib oral preparation according to claim 1 or 3, characterized in that the hydroxypropyl methylcellulose acetate succinate has an acetyl group substitution rate of 6 to 16% and a succinyl group substitution rate of 4 to 16%.

5. The sorafenib or donafenib oral preparation according to claim 1 or 3, characterized in that the povidone is a povidone having an average molecular weight of 34,000 to 1,300,000 or a povidone complex of povidone having an average molecular weight of 34,000 and povidone having an average molecular weight of 1,300,000 in a ratio of 1:1 to 1:0.

1.

6. The oral formulation of claim 1, wherein the oral formulation contains 20 to 69 mg of sorafenib or donafenib per unit dose.

7. The molecular pharmaceutical composition of sorafenib or donafenib comprises sorafenib or donafenib, or a salt, hydrate, solvate, hydrate or solvate of a salt thereof, and a carrier, the carrier being selected from the group consisting of copovidone, povidone, polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, povidone + hydroxypropylmethylcellulose acetate succinate, povidone + hydroxypropylmethylcellulose, low viscosity povidone + high viscosity povidone, povidone + copovidone, povidone + polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, copovidone + hydroxypropylmethylcellulose acetate succinate, copovidone + polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, 2. The oral preparation of sorafenib or donafenib according to claim 1, characterized in that the sorafenib or donafenib is selected from the group consisting of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose, copovidone + polyethylene glycol, copovidone + hydroxypropyl cellulose, copovidone + cellulose acetate; polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + hydroxypropyl methylcellulose acetate succinate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + povidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer + copovidone.

8. The oral formulation of sorafenib or donafenib according to claim 7, characterized in that the sorafenib or donafenib, or a salt, hydrate, solvate, hydrate or solvate of a salt thereof is 30 to 60 wt% of the molecular level pharmaceutical composition of sorafenib or donafenib.

9. The sorafenib or donafenib oral preparation according to claim 1, characterized in that the dosage form of the sorafenib or donafenib oral preparation is a tablet, a suspension, a granule or a capsule.

10. The oral formulation of sorafenib or donafenib according to claim 9, characterized in that the tablet additives include a filler, a disintegrant, a glidant or a lubricant, the filler being one or two selected from microcrystalline cellulose and silicified microcrystalline cellulose, the disintegrant being selected from cross-linked sodium carboxymethylcellulose, the glidant being selected from silica, and the lubricant being one or two selected from magnesium stearate and sodium stearyl fumarate.

11. The sorafenib or donafenib oral formulation of claim 10, wherein the filler content is 30-45 wt% of the tablet, the disintegrant content is 5-15 wt% of the tablet, the glidant content is 3-5 wt% of the tablet, and the lubricant content is 1-5 wt% of the tablet.

12. The sorafenib or donafenib oral formulation according to any one of claims 1 to 11, characterized in that the sorafenib or donafenib oral formulation is a formulation to be taken with food or a formulation not to be taken with food.

13. Use of the oral formulation of sorafenib or donafenib according to any one of claims 1 to 12 in the preparation of a medicament for treating or alleviating hepatocellular carcinoma, breast cancer, primary malignant liver tumor, cholangiocarcinoma, renal cell carcinoma, recurrent or refractory solid tumors, central nervous system solid tumors, metastatic non-small cell lung cancer, hepatocellular carcinoma that cannot be removed by surgery, thyroid cancer, pancreatic cancer, salivary gland adenoid cystic carcinoma, anaplastic thyroid cancer, refractory differentiated thyroid cancer, adenoid cystic carcinoma, late stage endometrial cancer, thyroid anaplastic cancer, rectal cancer, colon cancer, unresectable stage III or IV melanoma, leukemia, acute myeloid leukemia, all solid tumors or various late stage solid tumors.

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