Paclitaxel drug oral pharmaceutical composition, preparation, and preparation method and application of paclitaxel drug oral pharmaceutical composition

Abstract

The invention discloses a paclitaxel drug oral pharmaceutical composition, a paclitaxel drug preparation, and a preparation method and application of the paclitaxel drug oral pharmaceutical composition. The paclitaxel drug oral pharmaceutical composition comprises the following components: a paclitaxel drug, a lipid substance, a solubilizer and a glycoprotein inhibitor, wherein the lipid substance comprises a polyglycerol oleate mixture, and the HLB (Hydrophile-Lipophile Balance) value of the polyglycerol oleate mixture is 8 to 9. The oral pharmaceutical composition of the paclitaxel drugs can significantly increase the solubility of the paclitaxel drugs and improve the oral bioavailability, and has the advantages of small side effect, good tolerance and safety, and excellent tumor inhibition and treatment effects.

Description

Technical Field

[0001] The present invention relates to an oral pharmaceutical composition and preparation of paclitaxel drugs and a preparation method and application thereof. Background Art

[0002] Paclitaxel is an anti-microtubule drug and a cytotoxic anti-tumor drug. It can bind to cellular tubulin and stabilize microtubules by promoting the combination of tubulin dimers and preventing their depolymerization, thereby inhibiting the normal dynamic reorganization of microtubules that is essential for cell function during interphase and mitosis. Paclitaxel drugs block the cell cycle at the G2 / M phase, causing abnormal or stopped mitosis, hindering tumor cell replication, and making cancer cells unable to continue dividing and die, thereby inhibiting cancer cell growth. In addition, paclitaxel also has a radiosensitizing effect, which can promote cell damage caused by ion irradiation. Paclitaxel drugs are widely used in the clinical treatment of ovarian cancer, breast cancer, lung cancer, head and neck tumors, esophageal cancer, gastric cancer, and soft tissue sarcoma.

[0003] Paclitaxel injection is mainly used in clinical practice. Paclitaxel injection must be added with excipients such as high-content polyoxyethyl castor oil, Tween 80, anhydrous ethanol and micellar polymers to aid solubilization. Polyoxyethyl castor oil (Cremophor EL or Kolliphor EL) can cause allergic reactions to varying degrees when it enters the systemic circulation after injection. The micelles formed by high-concentration polyoxyethyl castor oil affect the diffusion of drug molecules into tissues and affect the anti-tumor effect. In addition, polyoxyethyl castor oil can dissolve divinyl ethyl phthalate in the PVC infusion set during intravenous infusion, causing serious adverse reactions. In order to prevent the occurrence of allergic reactions to paclitaxel injection, complex medical pretreatment is required before paclitaxel treatment, including oral administration of dexamethasone 20 mg at 12 hours and about 6 hours, intramuscular injection of diphenhydramine 50 mg 30 to 60 minutes before treatment, and intravenous injection of cimetidine 300 mg or ranitidine 50 mg.

[0004] Docetaxel (also known as docetaxel) is suitable for the treatment of locally advanced or metastatic breast cancer, locally advanced or metastatic non-small cell lung cancer, hormone-refractory metastatic prostate cancer, advanced gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) that has not received chemotherapy before, etc. Similar to paclitaxel, docetaxel has low water solubility and must be added with high-content polysorbate 80 and anhydrous ethanol to aid solubilization, both of which can increase the occurrence of adverse reactions. Ethanol can inhibit the central nervous system and pass through the human red blood cell membrane to cause red blood cell denaturation or hemolysis. Polysorbate 80 is a non-ionic surfactant that can cause allergic reactions and hemolytic reactions. In order to reduce the occurrence and severity of fluid retention of docetaxel injection and reduce the severity of allergic reactions, all patients must take glucocorticoids before receiving docetaxel treatment. Dexamethasone is usually taken one day before docetaxel administration, twice a day, 8 mg each time, for 3 days.

[0005] New intravenous paclitaxel formulations such as albumin paclitaxel, micellar paclitaxel and liposomal paclitaxel can only reduce side effects, but cannot change the route of administration or completely overcome the inherent shortcomings of intravenous preparations. Paclitaxel injections generally produce side effects such as phlebitis and peripheral neurotoxicity. Symptoms of peripheral neurotoxicity include numbness at the extremities similar to wearing gloves and socks, symptoms and signs of sensory nerve involvement, including paresthesia, dysesthesia, hypoesthesia, hyperesthesia and pain; burning sensation, decreased vibration sensation, disappearance of tendon reflexes, and even affecting motor function. Some patients may have mild to moderate limb weakness, and muscle atrophy may occur in the distribution area of ​​sensory lesions. Peripheral neurotoxicity significantly shortens the course of paclitaxel treatment for patients, reduces the exposure time of effective drug concentration in tumor tissue, and reduces the therapeutic effect of paclitaxel drugs. Docetaxel is similar to paclitaxel neurotoxicity, but the incidence is lower. In addition, it is difficult for patients to self-administer medication at home, and paclitaxel injection must be intravenously infused with the help of medical care.

[0006] Therefore, the medical market needs to develop an oral paclitaxel drug that can help patients undergo chemotherapy at home, significantly reduce the risk of infection during the infusion process, improve patient compliance and quality of life, and reduce medical costs, reduce the incidence or severity of neurotoxicity. Consolidate the position of paclitaxel as a first-line treatment drug, significantly increase the compliance and quality of life of tumor patients, and reduce drug costs.

[0007] However, paclitaxel drugs have a high molecular weight, are highly lipophilic and poorly soluble, and are BCS IV drugs that are difficult to dissolve and are almost not absorbed by the stomach and intestines. In addition, paclitaxel is a substrate of P-glycoprotein, which is prone to excretion effects and is easily metabolized by liver metabolic enzymes such as CYP2A8 and CYP3C4. The oral bioavailability of the existing paclitaxel oral preparations under development is very low, the solubility is poor, and the stability is poor, the therapeutic effect is limited, and the preclinical and clinical side effects are large. Summary of the invention

[0008] The present invention aims to solve the defects of the prior art paclitaxel oral preparations, such as low oral bioavailability, poor solubility, poor stability, limited therapeutic effect, and large preclinical and clinical side effects, thereby providing a paclitaxel oral pharmaceutical composition, preparation, and preparation method and application thereof. The paclitaxel oral preparation of the present invention can significantly increase the solubility and stability of paclitaxel drugs, improve oral bioavailability, and has few side effects, good tolerance and safety, as well as superior tumor inhibition and therapeutic effects.

[0009] In order to achieve the above object, the present invention adopts the following technical solutions:

[0010] The present invention provides an oral pharmaceutical composition of paclitaxel drugs, which comprises the following components: paclitaxel drugs, lipid substances, solubilizers and glycoprotein inhibitors; wherein the lipid substances include a polyglycerol oleate mixture, and the HLB value of the polyglycerol oleate mixture is 8-9.

[0011] In some preferred embodiments, the solubilizer is a castor oil-based solubilizer.

[0012] In some preferred embodiments, the polyglycerol oleate mixture includes polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate.

[0013] The paclitaxel oral pharmaceutical composition of the present invention is a self-emulsifying preparation system in liquid form with high viscosity. The polyglycerol oleate mixture (HLB of 8-9) is insoluble in water and has high hydrophobicity. It can be used as an oil phase and emulsifier in the paclitaxel oral pharmaceutical composition to increase the solubility of the paclitaxel and its distribution in the oil phase. When the paclitaxel oral pharmaceutical composition also contains castor oil solubilizer, when encountering aqueous solution and animal body fluid, the oral preparation can form countless stable oil-in-water particles, promote the uniform distribution of the paclitaxel in these particles, and significantly increase the solubility, gastrointestinal absorption surface area and oral bioavailability of the paclitaxel. In addition, the addition of glycoprotein inhibitor can significantly inhibit the excretion effect of glycoprotein on tumor drugs and enhance the tumor treatment effect.

[0014] In the present invention, the paclitaxel drug can be a conventional paclitaxel drug in the art, preferably paclitaxel or docetaxel.

[0015] In the present invention, the content of the paclitaxel drug can be a conventional pharmaceutically acceptable amount, preferably 1.5% to 2.0%, such as 1.6% or 1.8%, where the percentage is the mass percentage relative to the total mass of the paclitaxel drug oral pharmaceutical composition.

[0016] In the present invention, the polyglycerol oleate mixture may be composed of two or more different types of polyglycerol oleates. The polyglycerol oleate refers to an ester formed by esterification of polyglycerol and oleic acid, and different types of polyglycerol oleates are obtained based on the degree of polymerization of polyglycerol and the amount of oleic acid involved in the esterification reaction.

[0017] In the present invention, the HLB value can be measured by the Griffin method.

[0018] In the present invention, the content of the polyglycerol oleate mixture can be 40% to 70%, preferably 49% to 69%, for example, 46.4%, 48.2%, 50%, 51.2%, 51.4%, 53%, 54%, 57.4%, 58%, 62.5%, 65.4% or 68.5%, where the percentage is the mass percentage relative to the total mass of the lipid substance.

[0019] In some preferred embodiments of the present invention, the polyglyceryl oleate mixture includes polyglyceryl-3 oleate (Polyglyceryl-3Oleate) and polyglyceryl-10 mono / dioleate (Polyglyceryl-10Mono / Dioleate). In the present invention, the mixture of "polyglyceryl-3 oleate and polyglyceryl-10 mono / dioleate" is referred to as Caprol MPGO. Among them, the polyglyceryl-10 mono / dioleate is a mixture of polyglyceryl-10 monooleate and polyglyceryl-10 dioleate.

[0020] In the present invention, the paclitaxel oral preparation adopts a specific polyglycerol oleate mixture, which can improve the solubility of paclitaxel to the greatest extent, and is dispersed in the aqueous phase to be clear and transparent, and can further improve the oral bioavailability of paclitaxel.

[0021] In the above embodiment, preferably, the polyglycerol oleate mixture comprises 51%-65% of polyglycerol-3 oleate and 35%-49% of polyglycerol-10 mono- and di-oleate, and the percentages are mass percentages relative to the total mass of the polyglycerol oleate mixture.

[0022] In the above embodiment, optionally, the model of the polyglycerol-3-oleic acid is Caprol 3GO and / or Plurol Oleique CC497; and / or, the model of the polyglycerol-10 mono- and di-oleate is Caprol PGE 860.

[0023] In some optional embodiments of the present invention, the lipid substance also includes: one or more of medium chain triglycerides, tricaprylin, monocaprylin, mono- and di-caprylin capric acid glycerides, propylene glycol monocaprylate, propylene glycol dilaurate, propylene glycol monolaurate, caprylic capric acid polyethylene glycol glyceride, lauric acid polyethylene glycol glyceride, stearic acid polyethylene glycol glyceride, polyethylene glycol (15)-hydroxystearate, lauroyl polyoxyethylene (32) glyceride and stearoyl polyoxyethylene (32) glyceride.

[0024] The medium chain triglyceride is preferably medium chain caprylic capric triglyceride; the mass ratio of caprylic acid to capric acid in the medium chain caprylic capric triglyceride is preferably (60-70):(30-40); the model of the medium chain caprylic capric triglyceride is preferably CAPTEX 300EP / NF and / or CAPTEX 355EP / NF). CAPTEX 300EP / NF means that the mass ratio of caprylic acid to capric acid is 70:30, and CAPTEX 355EP / NF means that the mass ratio of caprylic acid to capric acid is 60:40.

[0025] The model of the tricaprylin is preferably CAPTEX 8000.

[0026] The monocaprylic glycerol is preferably of the type CAPMUL 808G, One or more of GMO-50 and CAPMUL MCM C8.

[0027] The mono- and di-caprylic-capric glycerides preferably include one or more of monoacylglycerols, diacylglycerols and triacylglycerols.

[0028] In some preferred embodiments, the mono- and di-caprylic-capric glyceride includes monoglyceride, diglyceride and triglyceride; wherein the content of the monoglyceride is preferably 60%-65%, the content of the diglyceride is preferably 30%-35%, and the content of the triglyceride is preferably 4%-5%, and the percentages are mass percentages relative to the total mass of the mono- and di-caprylic-capric glyceride.

[0029] The model of the mono- and di-caprylic glycerides is preferably CAPMUL MCM EP / NF.

[0030] In some preferred embodiments, the propylene glycol monocaprylate includes monoglyceride and diglyceride; wherein the content of the monoglyceride is 55%-80%, and the content of the diglyceride is 20%-45%;

[0031] Alternatively, the content of the monoglyceride is greater than 90%, and the content of the diglyceride is less than 10%; the percentage is the mass percentage relative to the total mass of the propylene glycol monocaprylate. Wherein, the model of the propylene glycol monocaprylate is preferably CAPMUL PG-8NF (Propylene Glycol Monocaprylate Type II) and / or CAPMUL PG-8-70NF (Propylene Glycol Monocaprylate Type I). Wherein, CAPMUL PG-8NF means that the content of monoglyceride is greater than 90% and the content of diglyceride is less than 10%. Wherein, CAPMUL PG-8-70NF means that the content of monoglyceride is 55%-80% and the content of diglyceride is 20%-45%, and the percentage is the mass percentage relative to the total mass of the propylene glycol monocaprylate.

[0032] Wherein, the model of the propylene glycol dilaurate is preferably CAPMUL PG-2L EP / NF.

[0033] Wherein, the model of the propylene glycol monolaurate is preferably CAPMUL PG-12EP / NF.

[0034] The caprylocaproyl macrogolglycerides are preferably of Acconon MC8-2.

[0035] The model of the lauroyl macrogolglycerides is preferably Acconon C-44.

[0036] The preferred model of the stearic acid macrogol glyceride is Acconon C-50.

[0037] Wherein, the model of the polyethylene glycol (15)-hydroxystearate is preferably Solutol HS15.

[0038] The model of the lauroyl polyoxyl-32glycerides / lauroyl macrogol-32glycerides is preferably Gelucire 44 / 14.

[0039] The model of the Stearoyl polyoxyl-32glycerides / Stearoyl macrogol-32glycerides is preferably Gelucire 55 / 13.

[0040] In the present invention, the content of the lipid substance may be 40%-97%, preferably 40%-70%, more preferably 45%-65%, for example 48.2%, 50%, 51%, 53%, 54%, 56.4%, 57.4%, 58%, 62.5%, 63.4%, 65.4%, 68.5%, 93%, 96%, 96.2% or 96.4%; the percentage is the mass percentage relative to the total mass of the paclitaxel pharmaceutical composition.

[0041] In the present invention, the castor oil solubilizer is preferably one or more of polyoxyethylene ether 35 castor oil (Kolliphor EL or Cremophor EL), polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH40 or Cremophor RH40) and polyoxyethylene 60 hydrogenated castor oil (Kolliphor RH60 or Cremophor RH60).

[0042] In the present invention, the content of the castor oil solubilizer is preferably 22% to 45%, more preferably 25% to 35%, for example 28%, 30%, 31%, 32% or 33%; the percentage is the mass percentage relative to the total mass of the paclitaxel oral pharmaceutical composition.

[0043] In the present invention, the glycoprotein inhibitor can be a conventional glycoprotein inhibitor in the art, and its function is as follows: paclitaxel drugs are substrates of glycoprotein (P-glycoprotein, Pgp), which are easily excreted by tumor tissues and cancer cells, inhibiting the tumor treatment effect of paclitaxel. Adding glycoprotein inhibitors can significantly inhibit the excretion effect of glycoprotein on tumor drugs and enhance the tumor treatment effect.

[0044] Preferably, the glycoprotein inhibitor is D-α-tocopherylpolyethylene glycol succinate (TPGS), such as D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS1000) or D-α-tocopheryl polyethylene glycol 400 succinate (TPGS 400).

[0045] Preferably, the content of the glycoprotein inhibitor is 1% to 8%, more preferably 2% to 5%, for example 3% or 4%; the percentage is the mass percentage relative to the total mass of the paclitaxel oral pharmaceutical composition.

[0046] In some preferred embodiments, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% to 2.0% of paclitaxel drugs, 40% to 70% of lipid substances, 22% to 45% of castor oil solubilizers and 1% to 8% of glycoprotein inhibitors, and the percentages are the mass percentages of each component relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs; wherein the lipid substances include a polyglycerol oleate mixture, and the polyglycerol oleate mixture includes polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate.

[0047] In the present invention, optionally, the oral pharmaceutical composition of the paclitaxel drug further comprises a co-surfactant. The co-surfactant can promote the distribution of the paclitaxel drug in the aqueous phase and promote oral absorption. The co-surfactant can be selected from one or more of ethylene glycol monoethyl ether (Transcutol), propylene glycol, glycerol glycerol and polyethylene glycol (PEG). Wherein, the polyethylene glycol can be PEG200, PEG300 or PEG400.

[0048] When the paclitaxel oral pharmaceutical composition further includes ethylene glycol monoethyl ether, the content of ethylene glycol monoethyl ether may be 0% to 13%, preferably 0% to 12%, more preferably 5% to 10%, for example 6%, 8% or 9%; the percentage is the mass percentage relative to the total mass of the paclitaxel oral pharmaceutical composition.

[0049] When the paclitaxel oral pharmaceutical composition further comprises propylene glycol, the content of propylene glycol is preferably 0% to 10%, more preferably 5% to 8%; the percentage is the mass percentage relative to the total mass of the paclitaxel oral pharmaceutical composition.

[0050] In some preferred embodiments of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% to 2.0% of paclitaxel drugs, 40% to 70% of polyglycerol oleate and polyglycerol mono- and di-oleate, 1% to 8% of vitamin E polyethylene glycol succinate, 22% to 45% of castor oil solubilizer, 0% to 12% of ethylene glycol monoethyl ether and 0% to 10% of propylene glycol; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0051] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 2.0% paclitaxel, 58% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate, 32% polyoxyethylene ether 35 castor oil and 6.0% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0052] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.6% paclitaxel, 57.4% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate, 31% polyoxyethylene ether 35 castor oil and 8.0% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0053] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.6% paclitaxel, 65.4% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 31% polyoxyethylene ether 35 castor oil; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0054] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 2.0% paclitaxel, 54% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate, 32% polyoxyethylene ether 35 castor oil and 10% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0055] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 2.0% paclitaxel, 54% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 3.0% vitamin E polyethylene glycol succinate, 32% polyoxyethylene ether 35 castor oil and 9.0% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0056] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% paclitaxel, 62.5% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 3.0% vitamin E polyethylene glycol 1000 succinate and 33% polyoxyethylene ether 35 castor oil; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0057] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% paclitaxel, 68.5% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 28% polyoxyethylene ether 35 castor oil; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0058] In some preferred embodiments of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% to 2.0% paclitaxel, 40% to 70% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 22% to 45% polyoxyethylene ether 35 castor oil, 1% to 8% vitamin E polyethylene glycol 1000 succinate and 0 to 10% propylene glycol; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0059] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.6% paclitaxel, 57.4% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate, 31% polyoxyethylene ether 35 castor oil and 8.0% propylene glycol; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0060] In some preferred embodiments of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% to 2.0% paclitaxel, 40% to 70% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 22% to 45% polyoxyethylene ether 35 castor oil, 1% to 8% vitamin E polyethylene glycol 1000 succinate and 0% to 10% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0061] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 2.5% paclitaxel, 50% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 7.5% vitamin E polyethylene glycol 1000 succinate, 30% polyoxyethylene ether 35 castor oil and 10% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0062] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 2.0% paclitaxel, 50% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 8.0% vitamin E polyethylene glycol 1000 succinate, 30% polyoxyethylene ether 35 castor oil and 10% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0063] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 2.0% paclitaxel, 50% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 4.0% vitamin E polyethylene glycol 1000 succinate, 32% polyoxyethylene ether 35 castor oil and 12% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0064] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 3.0% paclitaxel, 49% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 3.0% vitamin E polyethylene glycol 1000 succinate, 32% polyoxyethylene ether 35 castor oil and 13% ethylene glycol monoethyl ether; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0065] In some preferred embodiments of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% to 2.0% of paclitaxel drugs, 40% to 70% of polyglycerol oleate and polyglycerol mono- and di-oleate, 1% to 8% of vitamin E polyethylene glycol succinate and 40% to 70% of lauric acid polyethylene glycol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0066] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.6% paclitaxel, 51.4% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 45% lauric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0067] In some preferred embodiments of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% to 2.0% of paclitaxel drugs, 40% to 70% of polyglycerol oleate and polyglycerol mono- and di-oleate, 1% to 8% of vitamin E polyethylene glycol succinate and 40% to 70% of stearic acid polyethylene glycol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0068] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.6% paclitaxel, 51.4% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 45% stearic acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0069] In some preferred embodiments of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.5% to 2.0% of paclitaxel drugs, 40% to 70% of polyglycerol oleate and polyglycerol mono- and di-oleate, 1% to 8% of vitamin E polyethylene glycol succinate and 40% to 70% of caprylic capric acid polyethylene glycol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0070] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.6% paclitaxel, 51.4% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 45% caprylic capric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0071] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 2.0% paclitaxel, 51% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 45% caprylic capric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0072] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.8% paclitaxel, 48.2% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 48% caprylic capric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0073] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.6% paclitaxel, 46.4% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 50% caprylic capric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0074] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 2.0% paclitaxel, 53% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 5.0% vitamin E polyethylene glycol 1000 succinate and 40% caprylic capric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0075] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.6% paclitaxel, 51.4% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 45% caprylic capric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0076] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.8% paclitaxel, 51.2% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 45% caprylic capric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0077] In a specific embodiment of the present invention, the oral pharmaceutical composition of paclitaxel drugs comprises the following components: 1.8% paclitaxel, 48.2% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 2.0% vitamin E polyethylene glycol 1000 succinate and 48% caprylic capric acid macrogol glyceride; the percentages are mass percentages relative to the total mass of the oral pharmaceutical composition of paclitaxel drugs.

[0078] The present invention also provides a method for preparing the paclitaxel-based oral pharmaceutical composition, which comprises heating and mixing the components.

[0079] The heating temperature may be 35°C to 60°C, preferably 35°C to 55°C, such as 45°C or 50°C.

[0080] The mixing can be performed in a conventional manner in the art, such as stirring. The mixing time is based on the time required to make the mixture become a uniform and clear liquid, that is, the paclitaxel drug is completely dissolved without containing solid particles visible to the naked eye. Generally, the mixing time can be 60 to 180 minutes.

[0081] The present invention provides an oral preparation of paclitaxel drugs, which comprises the above-mentioned oral pharmaceutical composition of paclitaxel drugs.

[0082] Wherein, the dosage form of the paclitaxel oral preparation can be a liquid preparation or a capsule preparation.

[0083] In the present invention, the dosage form of the paclitaxel oral preparation is preferably a liquid-filled capsule.

[0084] When the dosage form of the paclitaxel oral preparation is a liquid-filled capsule, the preparation method of the paclitaxel oral preparation preferably comprises the following steps: heating and mixing the components, cooling the mixture, and filling the mixture into a medicinal capsule.

[0085] The present invention also provides a use of the paclitaxel-based oral pharmaceutical composition or the paclitaxel-based oral preparation in preparing a drug for treating cancer.

[0086] In the present invention, the cancer may be breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, lung cancer, head and neck tumors, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer or soft tissue sarcoma.

[0087] Preferably, the breast cancer is locally advanced or metastatic breast cancer. Preferably, the prostate cancer is hormone-refractory metastatic prostate cancer. Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer. Preferably, the gastric cancer is advanced gastric adenocarcinoma that has not received chemotherapy before; and preferably, the gastric adenocarcinoma includes gastroesophageal junction adenocarcinoma.

[0088] The present invention also provides a method for preventing and / or treating cancer, which comprises administering a therapeutically effective amount of the aforementioned paclitaxel-type oral pharmaceutical composition or the aforementioned paclitaxel-type oral preparation to a patient.

[0089] The present invention also provides a paclitaxel-based oral pharmaceutical composition or the paclitaxel-based oral preparation as described above, which is used for preventing and / or treating cancer.

[0090] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0091] The reagents and raw materials used in the present invention are commercially available.

[0092] The positive and progressive effects of the present invention are:

[0093] The paclitaxel oral preparation obtained by the paclitaxel oral pharmaceutical composition developed by the present invention can overcome the inherent disadvantages of injectable drugs, provide better clinical treatment solutions for tumor patients, improve patients' medication compliance and quality of life, and significantly reduce the medication cost and medical care cost of cancer patients.

[0094] Specifically, the paclitaxel oral preparation has the following advantages:

[0095] ① It can significantly increase the solubility of paclitaxel drugs and improve oral bioavailability;

[0096] ②It has excellent tumor inhibition and therapeutic effects;

[0097] ③Has good storage stability;

[0098] ④ Low toxicity and side effects, good tolerance and safety;

[0099] ⑤The preparation process is simple and safe, and no organic solvents with potential safety hazards are used. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] Figure 1 This is a graph showing the change in average tumor volume over the number of days after treatment when different preparations in Example 2 of the present invention were used to treat a nude mouse subcutaneous transplanted tumor model of human breast cancer cells MDA-MB-231.

[0101] Figure 2 This is a graph showing the change in relative tumor proliferation rate over the number of days after treatment when different preparations in Example 2 of the present invention were used to treat a nude mouse subcutaneous transplanted tumor model of human breast cancer cells MDA-MB-231.

[0102] Figure 3This is a graph showing the change in average tumor volume over the number of days after treatment when different preparations in Example 2 of the present invention were used to treat a subcutaneous transplanted tumor model of human ovarian cancer cells SK-OV-3 in nude mice.

[0103] Figure 4 This is a graph showing the change in relative tumor proliferation rate over the number of days after treatment when different preparations in Example 2 of the present invention were used to treat a subcutaneous transplanted tumor model of human ovarian cancer cells SK-OV-3 in nude mice.

[0104] Figure 5 This is a graph showing the change in average tumor volume over the number of days after treatment when different preparations in Example 2 of the present invention were used to treat the subcutaneous transplanted tumor model of human non-small cell lung cancer cells NCI-H358 in nude mice.

[0105] Figure 6 This is a graph showing the change in relative tumor proliferation rate over the number of days after treatment when different preparations in Example 2 of the present invention were used to treat a subcutaneous transplanted tumor model of human non-small cell lung cancer cells NCI-H358 in nude mice.

[0106] Figure 7 This is a graph showing the change in average tumor volume over the number of days after treatment when different preparations in Example 2 of the present invention were used to treat the subcutaneous transplanted tumor model of human gastric cancer cells NCI-N87 in nude mice.

[0107] Figure 8 This is a graph showing the change in relative tumor proliferation rate over the number of days after treatment when different preparations in Example 2 of the present invention were used to treat the subcutaneous transplanted tumor model of human gastric cancer cells NCI-N87 in nude mice.

[0108] Fig. 9 This is a graph showing the change in paclitaxel content over storage time when the paclitaxel oral preparation is stored at 5°C in Example 3 of the present invention.

[0109] Fig.10 This is a graph showing the change in paclitaxel content over storage time when the paclitaxel oral preparation is stored at 25°C in Example 3 of the present invention. DETAILED DESCRIPTION

[0110] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0111] Examples 1-12 and Comparative Examples 1-17

[0112] In the following examples and comparative examples:

[0113] Taxol drugs: Taxol was purchased from Fujian Nanfang Pharmaceutical Co., Ltd.

[0114] Caprol MPGO: polyglycerol oleate and polyglycerol mono- and di-oleate, purchased from Abitec Corporation;

[0115] TPGS1000: Vitamin E polyethylene glycol 1000 succinate, purchased from BASF SE;

[0116] Kolliphor EL / Cremophor EL: polyoxyethylene ether 35 castor oil, purchased from BASF SE;

[0117] Acconon MC8-2: caprylic acid capric acid macrogol glycerides, purchased from Abitec Corporation;

[0118] Acconon C-44: laurate macrogol glycerides, purchased from Abitec Corporation;

[0119] Acconon C-50: stearic acid macrogol glycerides, purchased from Abitec Corporation;

[0120] Transcutol: ethylene glycol monoethyl ether, purchased from Gattefosse SAS;

[0121] CAPTEX 300EP / NF: medium chain triglycerides, purchased from Abitec Corporation;

[0122] Caprol PGE 860: polyglyceryl-10 mono- and di-oleate, available from Abitec Corporation;

[0123] Caprol 3GO: polyglycerol-3-oleoic acid, purchased from Abitec Corporation.

[0124] According to the formula in Table 1, each component is weighed, added to a container, heated and stirred for mixing, the heating temperature is as shown in Table 1, the mixing time is 60-180 minutes, until the mixture becomes a uniform clear liquid, paclitaxel can be completely dissolved, and no solid particles visible to the naked eye are contained. After the obtained clear liquid is cooled, it is filled into a medicinal capsule to obtain a paclitaxel oral preparation in the form of a liquid-filled capsule, referred to as paclitaxel soft capsule.

[0125] Table 1

[0126]

[0127]

[0128] Note: “ / ” in Table 1 means that the condition parameter is not involved in the specific experiment.

[0129] Effect Example 1 Dissolution and Dispersion Effect and Bioavailability

[0130] Test method for oral bioavailability in rats:

[0131] Different preparations were administered to SD rats by intravenous injection or oral gavage, and blood samples were collected at different time points. The concentrations of each test substance in the plasma of SD rats after administration of the test substance were determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated. Specifically, the pharmacokinetic parameters (AUC (0-t) , T 1 / 2 , C max , Tmax and oral bioavailability). Among them, oral bioavailability is calculated using the following formula:

[0132] F = AUC (0-t),PO ×C IV / (AUC (0-t),IV ×C PO )×100

[0133] Among them, AUC (0-t),PO Refers to the AUC of paclitaxel soft capsule preparations taken orally by oral gavage (0-t) (area under the curve); C IV Refers to the intravenous administration of paclitaxel; AUC (0-t),IV Refers to the intravenous administration of paclitaxel drug AUC (0-t) (area under the curve); C PO It refers to the dosage of paclitaxel soft capsules administered orally by oral gavage.

[0134] In Examples 1-12, paclitaxel can be completely dissolved in the preparation to form a clear, transparent and uniform solution, and the solution preparation can maintain stability when stored at room temperature for a long time (more than four months), without the formation of particles, stratification and precipitation, and the preparation remains clear, transparent and uniform.

[0135] In Example 4, the preparation can completely dissolve paclitaxel to obtain a completely clear, transparent and uniform solution. After the preparation is stored at room temperature for more than four months, it still maintains a clear, transparent and uniform solution. The oral bioavailability in rats is 11%.

[0136] In Example 9, paclitaxel can be completely dissolved to obtain a completely clear, transparent and uniform solution. After the preparation is stored at room temperature for more than three months, it still remains a clear, transparent and uniform solution.

[0137] In Example 11, paclitaxel can be completely dissolved to obtain a completely clear, transparent and uniform solution. After the preparation is stored at room temperature for more than three months, it still remains a clear, transparent and uniform solution.

[0138] However, if only polyglyceryl-3 oleate is used instead of a polyglyceryl oleate mixture (Caprol MPGO), although paclitaxel can be dissolved, precipitation will occur to form a semi-solid when stored at room temperature or at a low temperature of 5°C ± 3°C.

[0139] However, if only polyglycerol-10 mono- and di-oleate (Caprol PGE 860) is used instead of polyglycerol oleate mixture (Caprol MPGO), although paclitaxel can be dissolved, the liquid preparation has a high viscosity and will produce precipitation when stored at room temperature for a long time. The oral bioavailability in rats is only 4%, which is relatively low.

[0140] Comparative Example 1 does not use the oil phase Caprol MPGO and the castor oil solubilizer Kolliphor EL, but only uses TPGS1000. Although paclitaxel can be completely dissolved, the dispersion effect in the aqueous solution is poor, resulting in a milky white opaque solution.

[0141] Comparative Example 2 does not use the oil phase Caprol MPGO and TPGS1000, but only uses Kolliphor EL, which cannot completely dissolve paclitaxel, and obtains a slightly milky white preparation, the solution viscosity is relatively large, the dispersibility in the aqueous solution is poor, the solution is milky white and opaque, and a clear and transparent solution cannot be obtained. After being stored at room temperature for one month, the preparation becomes slightly milky white and opaque, and there is precipitation and stratification.

[0142] Comparative Example 3 does not use Caprol MPGO as the oil phase, but only uses Caprol PGE-860 (Polyglyceryl-10 Mono / Dioleate), Kolliphor EL and TPGS 1000. The obtained paclitaxel preparation has poor dispersibility in the aqueous phase, and the oral bioavailability of the paclitaxel preparation in rats is not high, only 4%.

[0143] Comparative Example 4 uses Caprol MPGO and TPGS1000 as the oil phase, but does not use Kolliphor EL, which cannot fully dissolve paclitaxel, and the resulting paclitaxel preparation has poor dispersibility in the aqueous phase. The oral bioavailability in rats is relatively low, only 1.4%.

[0144] Comparative Example 5 did not use the oil phase Caprol MPGO and TPGS1000, but only used Kolliphor EL, which could not fully dissolve paclitaxel and obtained a milky white uneven liquid preparation.

[0145] Comparative Example 6 did not use the oil phase Caprol MPGO and Kolliphor EL, but only used TPGS1000, which could not fully dissolve paclitaxel.

[0146] Comparative Example 7 used only Polyglyceryl-3 Oleate and Kolliphor EL When paclitaxel preparations were prepared with TPGS1000, paclitaxel could not be completely dissolved. When the prepared paclitaxel preparations were stored at room temperature, stratification was easily generated.

[0147] In Comparative Example 9, the preparation can completely dissolve paclitaxel to obtain a completely clear, transparent and uniform solution. After the preparation is stored at room temperature for more than four months, it still remains a clear, transparent and uniform solution. The oral bioavailability in rats is 5.9%.

[0148] In Comparative Example 10, paclitaxel can be completely dissolved to obtain a completely clear, transparent and uniform preparation. After four months, the preparation still remains clear, transparent and uniform, with no particle formation, stratification and precipitation. The oral bioavailability of paclitaxel in rats reaches 9%.

[0149] In Comparative Example 15, the oral bioavailability of paclitaxel in rats reached 7%.

[0150] In Comparative Example 17, paclitaxel can be completely dissolved to obtain a completely clear, transparent and uniform preparation solution. After the preparation is stored at room temperature for more than four months, it still remains a clear, transparent and uniform solution. The oral bioavailability in rats reaches 12%.

[0151] Compared with Example 4, the oral preparation of paclitaxel drugs obtained in Comparative Example 17 does not contain castor oil solubilizer, although the bioavailability and stability are comparable. This may be because in fact, 10% ethylene glycol monoethyl ether (Transcutol) is also used in Example 4. Although the large amount of Transcutol can reduce the viscosity of the preparation and is conducive to filling capsules, ethylene glycol monoethyl ether cannot significantly improve the oral bioavailability of paclitaxel, but may reduce the oral bioavailability of rats. When ethylene glycol monoethyl ether is not used in Comparative Example 17, the oral bioavailability and stability of paclitaxel in rats can be comparable to those in Example 4, indicating that the castor oil solubilizer Kolliphor EL has a better effect on the oral bioavailability of paclitaxel drugs in rats, and can ensure good bioavailability and stability when 10% ethylene glycol monoethyl ether is used.

[0152] Effect Example 2 Evaluation of in vivo antitumor effect based on nude mouse subcutaneous transplanted tumor model

[0153] In the present invention, the paclitaxel liquid preparation prepared for filling capsules is defined as a paclitaxel soft capsule intermediate. Two types of paclitaxel injection preparations, namely Taxol and Abraxane, are used as references to prepare the paclitaxel soft capsules prepared in Example 3. Intermediates in four mouse and human cancer cells Xenograft tumor model: human breast cancer cells (MDA-MB -231), human ovarian cancer cells (SK-OV-3), human non-small cell lung cancer cells NSCLC (NCI-H358), and human gastric cancer cells (NCI-N87).

[0154] 1. Evaluation of the in vivo anti-tumor effect on the nude mouse subcutaneous transplanted tumor model of human breast cancer cells MDA-MB-231

[0155] Female nude mice were subcutaneously inoculated with MDA-MB-231 tumor cells to establish the MDA-MB-231 nude mouse xenograft tumor model. 3 When the animals were randomly divided into groups according to the tumor volume, the difference in tumor volume between groups was less than 10% of the mean. The animals were divided into 6 groups according to the tumor volume using the random block method, with 8 animals in each group.

[0156] (1) Experimental group 1: Taxane oral preparations were administered orally by gavage at a dose of 10 mg / kg, once every 3 days for 3 weeks, for a total of 7 doses;

[0157] (2) Experimental group 2: Taxane oral preparations were administered orally by gavage at a dose of 30 mg / kg, once every 3 days for 3 weeks, for a total of 7 doses;

[0158] (3) Experimental group 3: Taxane oral preparations were administered orally by gavage at a dose of 100 mg / kg, once every 3 days for 3 weeks, for a total of 7 times;

[0159] (4) Positive control group 1: Taxol injection 15 mg / kg dose group, single tail vein (IV) administration, once every 3 days, 3 weeks, a total of 7 doses;

[0160] (5) Positive control group 2: 30 mg / kg nab-paclitaxel injection group, administered by tail vein (IV) alone, once a week for 3 weeks, for a total of 3 times;

[0161] (6) Negative control group: A vehicle negative control group was set up at the same time, and the drug was administered orally or by gavage once every 3 days for 3 weeks, for a total of 7 times.

[0162] After 21 days of administration, the average tumor volume of the negative control group was 747.36±52.74mm3 The experimental results are as follows Figure 1 and Figure 2 As shown: Compared with the negative control group, the paclitaxel soft capsule intermediate was administered orally at different doses of 10 mg / kg, 30 mg / kg and 100 mg / kg. The relative tumor proliferation rate T / C on Day 21 was 75.42% (TGI = 24.45 P < 0.05), 37.02% (TGI = 62.21% P < 0.001) and 17.79% (TGI = 81.61% P < 0.001). The positive control group 1 Taxol paclitaxel injection and the positive control group 2 albumin paclitaxel injection were administered by tail vein at doses of 15 mg / kg and 30 mg / kg, respectively. The relative tumor proliferation rate at Day 21 was T / C were 26.28% (TGI = 71.51%, P < 0.001) and 18.51% (TGI = 80.04%, P < 0.001). The experimental results showed that the new oral paclitaxel drug had significantly better inhibitory and therapeutic effects on human breast cancer cells than Taxol and was comparable to that of albumin paclitaxel.

[0163] 2. Evaluation of the anti-tumor effect in vivo on the subcutaneous transplantation tumor model of human ovarian cancer cells SK-OV-3 in nude mice

[0164] SK-OV-3 tumor cells were subcutaneously inoculated into female nude mice to establish a SK-OV-3 nude mouse xenograft tumor model. 3 When the tumor volume was about 20 μg / cm2, the animals were randomly divided into 6 groups according to the tumor volume, so that the difference of tumor volume in each group was less than 10% of the mean. The animals were randomly divided into 6 groups according to the tumor volume, with 8 animals in each group.

[0165] (1) Experimental group 1: Taxane oral preparations were administered orally by gavage at a dose of 10 mg / kg, once every 3 days for 3 weeks, for a total of 7 doses;

[0166] (2) Experimental group 2: Taxane oral preparations were administered orally by gavage at a dose of 30 mg / kg, once every 3 days for 3 weeks, for a total of 7 doses;

[0167] (3) Experimental group 3: Taxane oral preparations were administered orally by gavage at a dose of 100 mg / kg, once every 3 days for 3 weeks, for a total of 7 times;

[0168] (4) Positive control group 1: Taxol injection 15 mg / kg dose group, single tail vein (IV) administration, once every 3 days, 3 weeks, a total of 7 doses;

[0169] (5) Positive control group 2: 30 mg / kg nab-paclitaxel injection group, administered by tail vein (IV) alone, once a week for 3 weeks, for a total of 3 times;

[0170] (6) Negative control group: A vehicle negative control group was set up at the same time, and the drug was administered orally or by gavage once every 3 days for 3 weeks, for a total of 7 times.

[0171] After 21 days of administration, the average tumor volume of the negative control group was 1062.42±107.11mm 3 The experimental results are as follows Figure 3 and Figure 4 As shown: Compared with the negative control group, the relative tumor proliferation rates T / C on Day 21 of the paclitaxel soft capsule intermediate at different doses of 10 mg / kg, 30 mg / kg and 100 mg / kg were 62.46% (TGI = 36.21%, P < 0.05), 24.91% (TGI = 75.48%, P < 0.001) and 8.42% (TGI = 91.52, P < 0.001), respectively. Positive control group 2: albumin paclitaxel injection at a dose of 15 mg / kg and 30 mg / kg, respectively, intravenously The drug was administered intravenously once a week for 3 weeks, a total of 3 times. The relative tumor proliferation rates T / C at Day 21 were 39.48% (TGI=60.36, P<0.001) and 15.02% (TGI=84.38, P<0.001), respectively.

[0172] The experimental results show that the inhibitory and therapeutic effects of this new oral paclitaxel-type drug on human ovarian cancer cells are significantly better than those of taxol-paclitaxel; the effects are comparable to those of albumin-paclitaxel and slightly better than those of albumin-paclitaxel.

[0173] 3. Evaluation of the in vivo anti-tumor effect on the subcutaneous transplanted tumor model of human non-small cell carcinoma cell NCI-H358 in nude mice

[0174] NCI-H358 tumor cells were subcutaneously inoculated into female nude mice to establish the NCI-H358 nude mouse xenograft tumor model. When the average tumor volume reached 145.65 mm 3 When the animals were randomly divided into groups according to the tumor volume, the difference in tumor volume between groups was less than 10% of the mean. The animals were divided into 6 groups according to the tumor volume using the random block method, with 8 animals in each group.

[0175] (1) Experimental group 1: Taxane oral preparations were administered orally by gavage at a dose of 10 mg / kg, once every 3 days for 3 weeks, for a total of 7 doses;

[0176] (2) Experimental group 2: Taxane oral preparations were administered orally by gavage at a dose of 30 mg / kg, once every 3 days for 3 weeks, for a total of 7 doses;

[0177] (3) Experimental group 3: Taxane oral preparations were administered orally by gavage at a dose of 100 mg / kg, once every 3 days for 3 weeks, for a total of 7 times;

[0178] (4) Positive control group 1: Taxol injection 15 mg / kg dose group, single tail vein (IV) administration, once every 3 days, 3 weeks, a total of 7 doses;

[0179] (5) Positive control group 2: 30 mg / kg nab-paclitaxel injection group, administered by tail vein (IV) alone, once a week for 3 weeks, for a total of 3 times;

[0180] (6) Negative control group: A vehicle negative control group was set up at the same time, and the drug was administered orally or by gavage once every 3 days for 3 weeks, for a total of 7 times.

[0181] After 21 days of administration, the average tumor volume of the negative control group was 2022.26±173.01mm 3 The experimental results are as follows Figure 5 and Figure 6 Compared with the negative control group, the relative tumor size at Day 21 was observed after oral administration of paclitaxel soft capsule intermediate at different doses of 10 mg / kg, 30 mg / kg and 100 mg / kg. The proliferation rate T / C was 33.93% (TGI = 65.69%, P < 0.001), 27.14% (TGI=72.67%, P<0.001) and 6.50% (TGI=93.85%, P<0.001). Positive control group 1 Taxol paclitaxel injection and positive control group 2 albumin paclitaxel injection were administered via tail vein at doses of 15 mg / kg and 30 mg / kg, respectively, once a week for 3 weeks, and a total of 3 doses. The relative tumor proliferation rates T / C on Day 21 were 30.50% (TGI=69.49%, P<0.001) and 21.36% (TGI=78.22%, P<0.001), respectively.

[0182] The experimental results show that the new oral paclitaxel drug has significantly better inhibitory and therapeutic effects on human non-small cell cancer cells than paclitaxel and albumin paclitaxel.

[0183] 4. Evaluation of the in vivo anti-tumor effect on the subcutaneous transplanted tumor model of human gastric cancer cells NCI-N87 in nude mice

[0184] NCI-N87 tumor cells were subcutaneously inoculated into female nude mice to establish the NCI-N87 nude mouse xenograft tumor model.3 When the tumor volume was about 10%, the animals were randomly divided into 6 groups according to the tumor volume, with 8 animals in each group.

[0185] (1) Experimental group 1: Taxane oral preparations were administered orally by gavage at a dose of 10 mg / kg, once every 3 days for 3 weeks, for a total of 7 doses;

[0186] (2) Experimental group 2: Taxane oral preparations were administered orally by gavage at a dose of 30 mg / kg, once every 3 days for 3 weeks, for a total of 7 doses;

[0187] (3) Experimental group 3: Taxane oral preparations were administered orally by gavage at a dose of 100 mg / kg, once every 3 days for 3 weeks, for a total of 7 times;

[0188] (4) Positive control group 1: Taxol injection 15 mg / kg dose group, single tail vein (IV) administration, once every 3 days, 3 weeks, a total of 7 doses;

[0189] (5) Positive control group 2: 30 mg / kg nab-paclitaxel injection group, administered by tail vein (IV) alone, once a week for 3 weeks, for a total of 3 times;

[0190] (6) Negative control group: A vehicle negative control group was set up at the same time, and the drug was administered orally or by gavage once every 3 days for 3 weeks, for a total of 7 times.

[0191] After 21 days of administration, the average tumor volume of the negative control group was 1184.28±48.32mm 3 The experimental results are as follows Figure 7 and Figure 8As shown: Compared with the negative control group, the paclitaxel soft capsule intermediate was administered orally at different doses of 10 mg / kg, 30 mg / kg and 100 mg / kg, and the relative tumor proliferation rate T / C on Day 21 was 60.00% (TGI = 39.80%, P < 0.001), 25.61% (TGI = 73.76%, P < 0.001) and 4.70% (TGI = 95.33%, P < 0.001). The positive control group 1 Taxol paclitaxel injection and the positive control group 2 albumin paclitaxel injection were administered at doses of 15 mg / kg and 30 mg / kg, respectively, through the tail vein, once a week, for 3 weeks. After a total of 3 times of administration, the relative tumor proliferation rate T / C on Day 21 was 26.52% (TGI = 73.08%, P < 0.001) and 13.48% (TGI = 86.31%, P < 0.001). Oral paclitaxel can significantly inhibit the growth of human gastric cancer cell NCI-N87 cell xenografts in nude mice, which is better than taxol-paclitaxel and albumin-paclitaxel.

[0192] Effect Example 3 Long-term storage stability study

[0193] The long-term storage stability of the paclitaxel oral preparation prepared in Example 3 of the present invention at room temperature (25°C ± 3°C) and 2-8°C was studied. The change of paclitaxel content in the paclitaxel oral preparation with storage time is shown in the figure below: Fig. 9 and Fig.10 As shown, the long-term storage study results show that the stability of the paclitaxel oral preparation prepared by the present invention exceeds one year, and the stability at room temperature exceeds 5 months. Among them, when the paclitaxel content in the paclitaxel oral preparation is above 90%, the preparation is considered to be stable.

[0194] Effect Example 4 Pharmacokinetic Study Based on Beagle Dogs

[0195] The in vivo pharmacokinetic study of paclitaxel soft capsules administered orally to beagle dogs was as follows:

[0196] The beagle dogs (average weight 7.8 kg) were given paclitaxel soft capsules by oral gavage once. After oral gavage, plasma samples were collected at different time points. The concentration of the test substance in the plasma of the beagle dogs after paclitaxel administration was determined by LC-MS / MS, and the relevant pharmacokinetic parameters (T) were calculated using Phoenix WinNonlin 7.0 (Pharsight, USA). 1 / 2 , T max , C max , AUC (0-t) , AUC (0-∞) ). The results are shown in Table 2.

[0197] Among them, T 1 / 2 refers to the half-life of the drug, T max is the peak time of the drug, C max Peak drug concentration Value, AUC (0-t) for Area under the curve, AUC (0-∞) is the area under the curve.

[0198] Table 2

[0199]

[0200] The results of the in vivo pharmacokinetic study on beagle dogs show that the AUC is relatively large, which indicates that after the paclitaxel soft capsule of the present invention is used, the exposure degree of paclitaxel drugs in the body is relatively high and the duration is relatively long.

[0201] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. An oral pharmaceutical composition of paclitaxel drugs, characterized in that: The invention comprises the following components: 1.5% to 2.0% of paclitaxel drugs, 40% to 70% of lipid substances, 22% to 45% of castor oil solubilizers and 1% to 8% of glycoprotein inhibitors, wherein the percentages are the mass percentages of each component relative to the total mass of the paclitaxel oral pharmaceutical composition; wherein the lipid substances comprise a polyglycerol oleate mixture, and the polyglycerol oleate mixture comprises polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate.

2. The paclitaxel oral pharmaceutical composition according to claim 1, characterized in that: The polyglycerol oleate mixture comprises 51%-65% of polyglycerol-3 oleate and 35%-49% of polyglycerol-10 mono- and di-oleate, and the percentages are mass percentages relative to the total mass of the polyglycerol oleate mixture.

3. The oral pharmaceutical composition of paclitaxel drugs according to claim 1, characterized in that: The content of the polyglycerol oleate mixture is 40% to 70%, and the percentage is the mass percentage relative to the total mass of the paclitaxel oral pharmaceutical composition.

4. The paclitaxel oral pharmaceutical composition according to claim 1, characterized in that: The castor oil solubilizer is one or more of polyoxyethylene ether 35 castor oil, polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 60 hydrogenated castor oil.

5. The oral pharmaceutical composition of paclitaxel drugs according to claim 1, characterized in that: It meets one or more of the following conditions: a. The taxane drug is paclitaxel or docetaxel; b. The lipid substances further include: one or more of medium chain triglycerides, tricaprylin, monocaprylin, mono- and di-caprylin-decanoylglycerides, monocaprylic acid propylene glycol, propylene glycol dilaurate, propylene glycol monolaurate, caprylic acid capric acid polyethylene glycol glyceride, lauric acid polyethylene glycol glyceride, stearic acid polyethylene glycol glyceride, polyethylene glycol (15)-hydroxystearate, lauroyl polyoxyethylene (32) glyceride and stearoyl polyoxyethylene (32) glyceride; c. The glycoprotein inhibitor is vitamin E polyethylene glycol succinate; d. The paclitaxel-based oral pharmaceutical composition further comprises a co-surfactant.

6. The paclitaxel oral pharmaceutical composition according to claim 1, characterized in that: The paclitaxel oral pharmaceutical composition comprises the following components: 1.5% to 2.0% paclitaxel, 40% to 70% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 22% to 45% polyoxyethylene ether 35 castor oil, 1% to 8% vitamin E polyethylene glycol 1000 succinate and 0% to 10% ethylene glycol monoethyl ether; Alternatively, the paclitaxel oral pharmaceutical composition comprises the following components: 1.5% to 2.0% paclitaxel, 40% to 70% polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate, 22% to 45% polyoxyethylene ether 35 castor oil, 1% to 8% vitamin E polyethylene glycol 1000 succinate and 0% to 10% propylene glycol.

7. An oral preparation of paclitaxel drugs, characterized in that: It comprises the paclitaxel oral pharmaceutical composition according to any one of claims 1 to 6.

8. A method for preparing the oral pharmaceutical composition of paclitaxel drugs according to any one of claims 1 to 6, characterized in that: It involves mixing the components with heating.

9. Use of the paclitaxel oral pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a drug for treating cancer.

10. Use of the paclitaxel oral pharmaceutical composition according to claim 9 in the preparation of a drug for treating cancer, characterized in that: The cancer is breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, lung cancer, head and neck tumors, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer or soft tissue sarcoma.

Images