Paclitaxel oral pharmaceutical compositions, formulations, methods of making and use thereof

Abstract

The application discloses a paclitaxel oral drug composition, a preparation and a preparation method and application thereof. The paclitaxel oral drug 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 polyglycerol oleate mixture has an HLB value of 8-9. The paclitaxel oral drug composition disclosed by the application can significantly increase the solubility of the paclitaxel drug, improve the oral bioavailability, has small side effects, good tolerance and safety, and superior tumor inhibition and treatment effects.

Description

TECHNICAL FIELD

[0001] The present application relates to a paclitaxel drug oral pharmaceutical composition, preparation and its preparation method and application. BACKGROUND

[0002] Paclitaxel is an anti-microtubule drug, belonging to the cytotoxic antitumor drug, which can bind to tubulin protein, promote the assembly of tubulin dimers and prevent its depolymerization to achieve the effect of stabilizing microtubules, thereby inhibiting the normal dynamic reorganization of microtubules which is essential for the function of interphase and mitotic phase cells. Paclitaxel drugs block the cell cycle at the G2 / M phase, leading to abnormal or stopping of mitosis, hindering tumor cell replication, making cancer cells unable to continue to divide and die, thereby inhibiting the growth of cancer cells. In addition, paclitaxel also has a radiosensitizing effect, which can promote cell damage caused by ionizing radiation. Paclitaxel drugs are widely used in the treatment of ovarian cancer, breast cancer, lung cancer, head and neck tumors, esophageal cancer, gastric cancer and soft tissue sarcoma, etc.

[0003] The main clinical application is paclitaxel injection. Paclitaxel injection must be added with excipients such as high content polyoxyethyl castor oil, Tween 80, anhydrous ethanol and micellar polymer to aid dissolution. Polyoxyethyl castor oil (Cremophor EL or Kolliphor EL) can cause varying degrees of allergic reactions after entering the systemic circulation after injection, and high-concentration polyoxyethyl castor oil forms micelles to affect the diffusion of drug molecules to the interstitium, affecting the antitumor effect. In addition, polyoxyethyl castor oil can dissolve divinyl ethyl phthalate in PVC infusion devices during intravenous infusion, causing serious adverse reactions. In order to prevent the occurrence of allergic reactions of paclitaxel injection, complex medical pretreatment is required before paclitaxel treatment, including 20 mg of dexamethasone orally given at 12 hours and 6 hours, 50 mg of benadryl intramuscular injection given 30-60 minutes before treatment, 300 mg of cimetidine or 50 mg of ranitidine intravenous injection.

[0004] Docetaxel (also known as Taxotere) is indicated 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 cancer of the gastroesophageal junction) who have not received prior chemotherapy, etc. Similar to paclitaxel, docetaxel has low water solubility and requires high concentrations of polysorbate 80 and anhydrous ethanol to aid solubilization, both of which can increase the incidence of adverse reactions. Ethanol can inhibit the central nervous system and cause red blood cell degeneration or hemolysis by passing through the human red blood cell membrane. Polysorbate 80 is a non-ionic surfactant that can cause allergic reactions and also cause hemolytic reactions. To reduce the incidence and severity of fluid retention of docetaxel injection and reduce the severity of allergic reactions, all patients must take prednisone before receiving docetaxel treatment. Usually, dexamethasone is taken one day before docetaxel administration, twice a day, 8 mg each time, for 3 days.

[0005] New dosage forms of paclitaxel intravenous injection such as albumin paclitaxel, micellar paclitaxel and liposomal paclitaxel can only reduce side effects, but cannot change the administration route and completely overcome the inherent disadvantages of intravenous injection preparations. Injection of paclitaxel drugs commonly causes side effects such as phlebitis and peripheral neurotoxicity. Peripheral neurotoxicity symptoms include numbness at the end of the limbs similar to wearing gloves and socks, symptoms and signs of sensory nerve involvement, including paresthesia, dysesthesia, hypoaesthesia, hyperalgesia and pain; burning sensation, decreased vibration sensation, tendon reflex loss, and even motor function can be affected. Some patients can have mild to moderate limb weakness, and muscle atrophy can occur in the distribution area of sensory lesions. Peripheral neurotoxicity significantly shortens the course of paclitaxel treatment in patients, reduces the effective drug concentration exposure time of tumor tissue, and reduces the therapeutic effect of paclitaxel drugs. Docetaxel has similar neurotoxicity to paclitaxel, but the incidence is lower. In addition, patients have difficulty in self-administration at home, and must receive intravenous infusion of paclitaxel injection with the help of medical staff.

[0006] Therefore, there is a need in the medical market to develop an oral paclitaxel drug that helps patients to receive chemotherapy at home, significantly reduces the risk of infection during the infusion process of patients, improves the compliance and quality of life of patients, and reduces the cost of medical treatment, reduces 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 the cost of medication.

[0007] However, paclitaxel drugs have high molecular weight, high lipophilicity and poor solubility, are BCS IV drugs, are difficult to dissolve and are hardly absorbed in the gastrointestinal tract. In addition, paclitaxel is a substrate of P-glycoprotein, is prone to efflux effect, and is prone to be metabolized by metabolic enzymes such as CYP2A8 and CYP3C4 in the liver. The existing paclitaxel drug oral preparations under development have low oral bioavailability, poor solubility and poor stability, limited therapeutic effect, and large preclinical and clinical side effects. SUMMARY

[0008] In order to solve the defects of low oral bioavailability, poor solubility and poor stability, limited therapeutic effect, and large preclinical and clinical side effects of the paclitaxel drug oral preparations in the prior art, the present application provides a paclitaxel drug oral pharmaceutical composition, a preparation and a preparation method and application thereof. The paclitaxel drug oral preparation described in the present application can significantly increase the solubility and stability of paclitaxel drugs, improve the oral bioavailability, has small side effects, good tolerability and safety, and superior tumor inhibition and treatment effect.

[0009] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0010] The present application provides a paclitaxel drug oral pharmaceutical composition, which comprises the following components: a paclitaxel drug, a lipid substance, a solubilizer and a glycoprotein inhibitor; wherein the lipid substance comprises a polyglyceryl oleate mixture, and the polyglyceryl oleate mixture has an HLB value of 8-9.

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

[0012] In some preferred embodiments, the polyglyceryl oleate mixture comprises polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate.

[0013] The paclitaxel drug oral pharmaceutical composition described in the present application is a liquid form of a self-emulsifying preparation system with high viscosity. The polyglyceryl oleate mixture (HLB 8-9) is insoluble in water and has high hydrophobicity, and serves as an oil phase and an emulsifier in the paclitaxel drug oral pharmaceutical composition, which can increase the solubility of paclitaxel drugs and the distribution of paclitaxel drugs in the oil phase. When the paclitaxel drug oral pharmaceutical composition further contains a castor oil solubilizer, the oral preparation can form countless stable oil-in-water particles when encountering aqueous solutions and animal body fluids, which promotes the uniform distribution of paclitaxel drugs in these particles, significantly increases the solubility, gastrointestinal absorption surface area and oral bioavailability of paclitaxel drugs. In addition, the addition of a glycoprotein inhibitor can significantly inhibit the efflux effect of glycoprotein on tumor drugs and improve the tumor treatment effect.

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

[0015] In the present application, the content of the paclitaxel drug can be a conventional pharmaceutically acceptable amount, preferably 1.5% to 2.0%, for example 1.6% or 1.8%, the percentage being a mass percentage relative to the total mass of the paclitaxel oral drug composition.

[0016] In the present application, the polyglyceryl oleate mixture can be composed of two or more different types of polyglyceryl oleate. Among them, the polyglyceryl oleate refers to an ester formed by esterification of polyglycerol and oleic acid, and different types of polyglyceryl oleate are obtained based on the degree of polymerization of polyglycerol and the amount of oleic acid participating in the esterification reaction.

[0017] In the present application, the measurement method of the HLB value can be the Griffin method.

[0018] In the present application, the content of the polyglyceryl 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%, the percentage being a mass percentage relative to the total mass of the lipid material.

[0019] In some preferred embodiments of the present application, the polyglyceryl oleate mixture includes polyglyceryl-3 oleate and polyglyceryl-10 mono / dioleate. In the present application, 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 application, in the paclitaxel oral preparation, by using a specific polyglyceryl oleate mixture, the solubility of paclitaxel can be maximized, and it is clear and transparent when dispersed in the aqueous phase, and the oral bioavailability of paclitaxel can be further improved.

[0021] In the above embodiments, preferably, the polyglyceryl oleate mixture includes 51% to 65% of polyglyceryl-3 oleate and 35% to 49% of polyglyceryl-10 mono / dioleate, the percentage being a mass percentage relative to the total mass of the polyglyceryl oleate mixture.

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

[0023] In some optional embodiments of the present invention, the lipid substance further includes one or more of the following: medium-chain triglycerides, tricaprylic acid glycerides, monocaprylic acid glycerides, monocaprylic / dicaprylic / capric acid glycerides, monocaprylic acid propylene glycol ester, propylene glycol dilaurate, propylene glycol monolaurate, caprylic / capric acid propylene glycol glycerides, lauric acid propylene glycol glycerides, stearic acid propylene glycol glycerides, polyethylene glycol (15)-hydroxystearate, lauroyl polyoxyethylene (32) glycerides, and stearoyl polyoxyethylene (32) glycerides.

[0024] Preferably, the medium-chain triglyceride is a 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 type of the medium-chain caprylic / capric triglyceride is preferably CAPTEX 300EP / NF and / or CAPTEX 355EP / NF. CAPTEX 300EP / NF refers to a mass ratio of caprylic acid to capric acid of 70:30, and CAPTEX 355EP / NF refers to a mass ratio of caprylic acid to capric acid of 60:40.

[0025] The type of the tricaprylic acid glyceride is preferably CAPTEX 8000.

[0026] The preferred type of the glyceryl monocaprylate is CAPMUL 808G. One or more of GMO-50 and CAPMUL MCM C8.

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

[0028] In some preferred embodiments, the mono- and dicaprylic / caprylic glycerides comprise monoglycerides, diglycerides, and triglycerides; wherein the content of monoglycerides is preferably 60%-65%, the content of diglycerides is preferably 30%-35%, and the content of triglycerides is preferably 4%-5%, the percentages being mass percentages relative to the total mass of the mono- and dicaprylic / caprylic glycerides.

[0029] Preferably, the type of the single-dicaprylyl caprylyl glyceride is CAPMUL MCM EP / NF.

[0030] In some preferred embodiments, the single-propylene glycol monocaprylate comprises glycerol monoesters and glycerol diesters; wherein the content of the glycerol monoesters is 55%-80%, and the content of the glycerol diesters is 20%-45%.

[0031] Alternatively, the content of the glycerol monoesters is greater than 90%, and the content of the glycerol diesters is less than 10%; the percentages are mass percentages relative to the total mass of the single-propylene glycol monocaprylate. Preferably, the type of the single-propylene glycol monocaprylate is CAPMUL PG-8 NF (Propylene Glycol Monocaprylate Type II) and / or CAPMUL PG-8-70 NF (Propylene Glycol Monocaprylate Type I). CAPMUL PG-8 NF refers to a content of glycerol monoesters greater than 90% and a content of glycerol diesters less than 10%. CAPMUL PG-8-70 NF refers to a content of glycerol monoesters of 55%-80% and a content of glycerol diesters of 20%-45%, the percentages being mass percentages relative to the total mass of the single-propylene glycol monocaprylate.

[0032] Preferably, the type of the propylene glycol laurate is CAPMUL PG-12 EP / NF.

[0033] Preferably, the type of the propylene glycol laurate is CAPMUL PG-12 EP / NF.

[0034] Preferably, the type of the caprylocaproyl macrogolglycerides is Acconon MC8-2.

[0035] Preferably, the type of the lauroyl macrogolglycerides is Acconon C-44.

[0036] Preferably, the type of the stearoyl macrogolglycerides is Acconon C-50.

[0037] Preferably, the type of the polyethylene glycol (15)-hydroxystearate is Solutol HS15.

[0038] Preferably, the lauroyl polyoxyl-32 glycerides (Lauroyl Macrogol-32 glycerides) are Gelucire 44 / 14.

[0039] Preferably, the stearoyl polyoxyl-32 glycerides (Stearoyl Macrogol-32 glycerides) are Gelucire 55 / 13.

[0040] In the present application, the content of the lipid substance can be 40% to 97%, preferably 40% to 70%, more preferably 45% to 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 application, the castor oil-based solubilizer is preferably one or more of polyoxyl 35 castor oil (Kolliphor EL or Cremophor EL), polyoxyl 40 hydrogenated castor oil (Kolliphor RH40 or Cremophor RH40), and polyoxyl 60 hydrogenated castor oil (Kolliphor RH60 or Cremophor RH60).

[0042] In the present application, the content of the castor oil-based 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 application, the glycoprotein inhibitor can be a conventional glycoprotein inhibitor in the art, which functions as follows: paclitaxel is a substrate of glycoprotein (P-glycoprotein, Pgp) and is easily excreted by tumor tissues and cancer cells, inhibiting the tumor treatment effect of paclitaxel; adding a glycoprotein inhibitor can significantly inhibit the excretion effect of glycoprotein on tumor drugs, thereby improving the tumor treatment effect.

[0044] Preferably, the glycoprotein inhibitor is vitamin E polyethylene glycol succinate (TPGS), such as vitamin E polyethylene glycol 1000 succinate (TPGS 1000) or vitamin E polyethylene glycol 400 succinate (TPGS 400).

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

[0046] In some preferred embodiments, the paclitaxel drug oral pharmaceutical composition comprises the following components: paclitaxel drug 1.5% to 2.0%, lipid material 40% to 70%, castor oil-based solubilizer 22% to 45%, and glycoprotein inhibitor 1% to 8%; the percentage is the mass percentage of each component relative to the total mass of the paclitaxel drug oral pharmaceutical composition; wherein the lipid material comprises a polyglyceryl oleate mixture, and the polyglyceryl oleate mixture comprises polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate.

[0047] In the present application, the paclitaxel drug oral pharmaceutical composition can optionally further comprise 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). Among them, the polyethylene glycol can be PEG200, PEG300 or PEG400.

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

[0049] When the paclitaxel drug oral pharmaceutical composition further comprises propylene glycol, the content of the 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 drug oral pharmaceutical composition.

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

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

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

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

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

[0055] In a particular embodiment of the application, the paclitaxel oral pharmaceutical composition comprises the following components: paclitaxel 2.0%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 54%, vitamin E polyethylene glycol succinate 3.0%, polyoxyl 35 castor oil 32% and ethylene glycol monoethyl ether 9.0%; the percentages being mass percentages with respect to the total mass of the paclitaxel oral pharmaceutical composition.

[0056] In a particular embodiment of the application, the paclitaxel oral pharmaceutical composition comprises the following components: paclitaxel 1.5%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 62.5%, vitamin E polyethylene glycol 1000 succinate 3.0% and polyoxyl 35 castor oil 33%; the percentages being mass percentages with respect to the total mass of the paclitaxel oral pharmaceutical composition.

[0057] In a particular embodiment of the application, the paclitaxel oral pharmaceutical composition comprises the following components: paclitaxel 1.5%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 68.5%, vitamin E polyethylene glycol 1000 succinate 2.0% and polyoxyl 35 castor oil 28%; the percentages being mass percentages with respect to the total mass of the paclitaxel oral pharmaceutical composition.

[0058] In some preferred embodiments of the application, the paclitaxel oral pharmaceutical composition comprises the following components: paclitaxel 1.5% to 2.0%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 40% to 70%, polyoxyl 35 castor oil 22% to 45%, vitamin E polyethylene glycol 1000 succinate 1% to 8% and propylene glycol 0 to 10%; the percentages being mass percentages with respect to the total mass of the paclitaxel oral pharmaceutical composition.

[0059] In a particular embodiment of the application, the paclitaxel oral pharmaceutical composition comprises the following components: paclitaxel 1.6%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 57.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, polyoxyl 35 castor oil 31% and propylene glycol 8.0%; the percentages being mass percentages with respect to the total mass of the paclitaxel oral pharmaceutical composition.

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

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

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

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

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

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

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

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

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

[0069] In some preferred embodiments of the present application, the paclitaxel-based oral pharmaceutical composition comprises the following components: paclitaxel-based drug 1.5% to 2.0%, polyglyceryl oleate and polyglyceryl mono-dioleate 40% to 70%, vitamin E polyethylene glycol succinate 1% to 8%, and lauric acid polyethylene glycol glyceride 40% to 70%; the percentages are mass percentages relative to the total mass of the paclitaxel-based oral pharmaceutical composition.

[0070] In a specific embodiment of the present application, the paclitaxel-based oral pharmaceutical composition comprises the following components: paclitaxel 1.6%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 51.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, and lauric acid polyethylene glycol glyceride 45%; the percentages are mass percentages relative to the total mass of the paclitaxel-based oral pharmaceutical composition.

[0071] In a particular embodiment of the application, the paclitaxel-based oral pharmaceutical composition comprises the following components: paclitaxel 2.0%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 51%, vitamin E polyethylene glycol 1000 succinate 2.0% and caprylocaproyl macrogolglycerides 45%; the percentages being mass percentages with respect to the total mass of the paclitaxel-based oral pharmaceutical composition.

[0072] In a particular embodiment of the application, the paclitaxel-based oral pharmaceutical composition comprises the following components: paclitaxel 1.8%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 48.2%, vitamin E polyethylene glycol 1000 succinate 2.0% and caprylocaproyl macrogolglycerides 48%; the percentages being mass percentages with respect to the total mass of the paclitaxel-based oral pharmaceutical composition.

[0073] In a particular embodiment of the application, the paclitaxel-based oral pharmaceutical composition comprises the following components: paclitaxel 1.6%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 46.4%, vitamin E polyethylene glycol 1000 succinate 2.0% and caprylocaproyl macrogolglycerides 50%; the percentages being mass percentages with respect to the total mass of the paclitaxel-based oral pharmaceutical composition.

[0074] In a particular embodiment of the application, the paclitaxel-based oral pharmaceutical composition comprises the following components: paclitaxel 2.0%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 53%, vitamin E polyethylene glycol 1000 succinate 5.0% and caprylocaproyl macrogolglycerides 40%; the percentages being mass percentages with respect to the total mass of the paclitaxel-based oral pharmaceutical composition.

[0075] In a particular embodiment of the application, the paclitaxel-based oral pharmaceutical composition comprises the following components: paclitaxel 1.6%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 51.4%, vitamin E polyethylene glycol 1000 succinate 2.0% and caprylocaproyl macrogolglycerides 45%; the percentages being mass percentages with respect to the total mass of the paclitaxel-based oral pharmaceutical composition.

[0076] In a particular embodiment of the application, the paclitaxel-based oral pharmaceutical composition comprises the following components: paclitaxel 1.8%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 51.2%, vitamin E polyethylene glycol 1000 succinate 2.0% and caprylocaproyl macrogolglycerides 45%; the percentages being mass percentages with respect to the total mass of the paclitaxel-based oral pharmaceutical composition.

[0077] In a specific embodiment of the present application, the paclitaxel oral pharmaceutical composition comprises the following components: paclitaxel 1.8%, polyglyceryl-3 oleate and polyglyceryl-10 mono-dioleate 48.2%, vitamin E polyethylene glycol 1000 succinate 2.0%, and caprylocaproyl macrogolglycerides 48%; the percentages are mass percentages relative to the total mass of the paclitaxel oral pharmaceutical composition.

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

[0079] The temperature of the heating can be 35-60°C, preferably 35-55°C, for example 45°C or 50°C.

[0080] The mixing can be performed in a conventional manner in the art, for example by stirring. The mixing time can be 60-180 minutes, until the mixture becomes a homogeneous and clear liquid, i.e. the paclitaxel is completely dissolved and does not contain visible solid particles.

[0081] The present application provides a paclitaxel oral preparation, which comprises the paclitaxel oral pharmaceutical composition as described above.

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

[0083] In the present application, 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 method for preparing the paclitaxel oral preparation preferably comprises the following steps: heating and mixing the components, then cooling the mixture and filling it into a medicinal capsule.

[0085] The present application also provides the use of the paclitaxel oral pharmaceutical composition or the paclitaxel oral preparation in the preparation of a medicament for treating cancer.

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

[0087] The breast cancer is preferably locally advanced or metastatic breast cancer. The prostate cancer is preferably hormone-refractory metastatic prostate cancer. The non-small cell lung cancer is preferably locally advanced or metastatic non-small cell lung cancer. The gastric cancer is preferably advanced gastric adenocarcinoma that has not been previously treated with chemotherapy; the gastric adenocarcinoma preferably includes gastroesophageal junction adenocarcinoma.

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

[0089] The present application also provides a paclitaxel oral pharmaceutical composition or a paclitaxel oral preparation as described above for use in preventing and / or treating cancer.

[0090] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining various preferred examples of the present application.

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

[0092] The positive progress effect of the present application is that:

[0093] The paclitaxel oral pharmaceutical composition developed in the present application can overcome the inherent shortcomings of injection drugs, provide better clinical treatment solutions for tumor patients, improve the medication compliance and quality of life of patients, and significantly reduce the medication cost and medical cost of cancer patients.

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

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

[0096] ②It has superior tumor inhibition and treatment effects;

[0097] ③It has good storage stability;

[0098] ④It has low toxicity and side effects, good tolerance and safety;

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

[0100] Figure 1 Figure 1 is a graph showing the change in average tumor volume over time after treatment when different preparations in Effect Example 2 were used to treat a human breast cancer cell MDA-MB-231 subcutaneous xenograft model in nude mice.

[0101] Figure 2 Figure 2 is a graph showing the change in relative tumor proliferation rate over time after treatment when different preparations in Effect Example 2 were used to treat a human breast cancer cell MDA-MB-231 subcutaneous xenograft model in nude mice.

[0102] Figure 3Figure 2 is a graph showing the change of average tumor volume with post-treatment days when the different formulations in the effect example 2 of the present application were used to treat the human ovarian cancer cell SK-OV-3 subcutaneously transplanted tumor model of nude mice.

[0103] Figure 4 Figure 3 is a graph showing the change of relative tumor proliferation rate with post-treatment days when the different formulations in the effect example 2 of the present application were used to treat the human ovarian cancer cell SK-OV-3 subcutaneously transplanted tumor model of nude mice.

[0104] Figure 5 Figure 4 is a graph showing the change of average tumor volume with post-treatment days when the different formulations in the effect example 2 of the present application were used to treat the human non-small cell lung cancer cell NCI-H358 subcutaneously transplanted tumor model of nude mice.

[0105] Figure 6 Figure 5 is a graph showing the change of relative tumor proliferation rate with post-treatment days when the different formulations in the effect example 2 of the present application were used to treat the human non-small cell lung cancer cell NCI-H358 subcutaneously transplanted tumor model of nude mice.

[0106] Figure 7 Figure 6 is a graph showing the change of average tumor volume with post-treatment days when the different formulations in the effect example 2 of the present application were used to treat the human gastric cancer cell NCI-N87 subcutaneously transplanted tumor model of nude mice.

[0107] Figure 8 Figure 7 is a graph showing the change of relative tumor proliferation rate with post-treatment days when the different formulations in the effect example 2 of the present application were used to treat the human gastric cancer cell NCI-N87 subcutaneously transplanted tumor model of nude mice.

[0108] Figure 9 Figure 8 is a graph showing the change of paclitaxel content with storage time when the paclitaxel oral formulation in the effect example 3 of the present application was stored at 5°C.

[0109] Figure 10 Figure 9 is a graph showing the change of paclitaxel content with storage time when the paclitaxel oral formulation in the effect example 3 of the present application was stored at 25°C. DETAILED DESCRIPTION

[0110] The present application will be further described in the following by way of examples without thereby limiting the present application to the described examples. The experimental methods in the following examples, for which no specific conditions are mentioned, are selected according to the conventional methods and conditions, or according to the commercial instructions.

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

[0112] In the following examples and comparative examples:

[0113] Paclitaxel: paclitaxel was purchased from Fujian South Pharmaceutical Co., Ltd.;

[0114] Caprol MPGO: polyglyceryl oleate and polyglyceryl mono / dioleate, available from Abitec Corporation;

[0115] TPGS 1000: Vitamin E polyethylene glycol 1000 succinate, available from BASF SE;

[0116] Kolliphor EL / Cremophor EL: polyoxyl 35 castor oil, available from BASF SE;

[0117] Acconon MC8-2: caprylocaproyl macrogolglycerides, available from Abitec Corporation;

[0118] Acconon C-44: lauryl macrogolglycerides, available from Abitec Corporation;

[0119] Acconon C-50: stearoyl macrogolglycerides, available from Abitec Corporation;

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

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

[0122] Caprol PGE 860: polyglyceryl-10 mono / dioleate, available from Abitec Corporation;

[0123] Caprol 3GO: polyglyceryl-3-oleate, available from Abitec Corporation.

[0124] Each component was weighed according to the formulation in Table 1, and was added into a container for mixing under heating and stirring. The temperature of heating was shown in Table 1, and the mixing time was 60-180 min, until the mixture became a homogeneous and clear liquid, and paclitaxel was completely dissolved without visible solid particles. The obtained clear liquid was cooled and filled into pharmaceutical capsules, to obtain a paclitaxel pharmaceutical oral preparation in the form of liquid-filled capsules, which was referred to as paclitaxel soft capsules.

[0125] Table 1

[0126]

[0127]

[0128] Note: " / " in Table 1 represents that the condition parameter is not involved in the specific experiment.

[0129] Dissolution and dispersion effect and bioavailability of effect example 1

[0130] Method for testing bioavailability of rats by oral administration:

[0131] SD rats were administered with different preparations by intravenous injection or oral gavage, respectively, 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 product were determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated. Specifically, by using the blood concentration data at different time points, the pharmacokinetic parameters (AUC (0-t) , T 1 / 2 , C max , Tmax and oral bioavailability) were calculated by Phoenix WinNonlin 7.0 (Pharsight, USA). Among them, the oral bioavailability was calculated by the following formula:

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

[0133] Among them, AUC (0-t),PO refers to the AUC (0-t) (area under the curve) of paclitaxel soft capsule preparation by oral gavage administration; C IV refers to the administration dose of paclitaxel drug by intravenous injection; AUC (0-t),IV refers to the AUC (0-t) (area under the curve) of paclitaxel drug by intravenous injection; C PO refers to the administration dose of paclitaxel soft capsule by oral gavage administration.

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

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

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

[0137] In Example 11, paclitaxel was completely dissolved to obtain a completely clear and transparent homogeneous solution. The formulation remained a clear and transparent homogeneous solution after being stored at room temperature for more than three months.

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

[0139] However, if only polyglyceryl-10 mono / dioleate (Caprol PGE 860) is used instead of the polyglyceryl oleate mixture (Caprol MPGO), although paclitaxel can be dissolved, the liquid formulation has a large viscosity, and will precipitate 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 solubilizer Kolliphor EL, but only uses TPGS 1000. Although paclitaxel can be completely dissolved, it does not disperse well in an aqueous solution, resulting in a milky white opaque solution.

[0141] Comparative Example 2 does not use the oil phase Caprol MPGO and TPGS 1000, but only uses Kolliphor EL. Paclitaxel cannot be completely dissolved, resulting in a slightly milky white formulation. The solution has a large viscosity, and does not disperse well in an aqueous solution. 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 formulation becomes slightly milky white and opaque, and has precipitation and stratification.

[0142] Comparative Example 3 does not use the oil phase Caprol MPGO, but only uses Caprol PGE-860 (polyglyceryl-10 mono / dioleate), Kolliphor EL, and TPGS 1000. The obtained paclitaxel formulation does not disperse well in an aqueous phase. The oral bioavailability of the paclitaxel formulation in rats is only 4%, which is not high.

[0143] Comparative Example 4 uses the oil phase Caprol MPGO and TPGS 1000, but does not use Kolliphor EL. Paclitaxel cannot be completely dissolved, and the obtained paclitaxel formulation does not disperse well in an aqueous phase. The oral bioavailability in rats is relatively low, only 1.4%.

[0144] Comparative Example 5 did not use oil phase Caprol MPGO and TPGS 1000, only Kolliphor EL, and could not sufficiently dissolve paclitaxel, resulting in a milky white, non-uniform liquid preparation.

[0145] Comparative Example 6 did not use oil phase Caprol MPGO and Kolliphor EL, only TPGS 1000, and could not sufficiently dissolve paclitaxel.

[0146] Comparative Example 7 only used Polyglyceryl-3 Oleate and Kolliphor EL Paclitaxel could not be completely dissolved in the preparation of paclitaxel with Caprol MPGO and TPGS 1000. The prepared paclitaxel preparation was prone to delamination when stored at room temperature.

[0147] In Comparative Example 9, the preparation could completely dissolve paclitaxel, resulting in a completely clear, transparent, and uniform solution. The preparation remained clear, transparent, and uniform after being stored at room temperature for more than four months. The rat oral bioavailability was 5.9%.

[0148] In Comparative Example 10, paclitaxel could be completely dissolved, resulting in a completely clear, transparent, and uniform preparation. After four months, the preparation remained clear, transparent, and uniform, without the formation of particles, delamination, or precipitation. The rat oral bioavailability of paclitaxel reached 9%.

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

[0150] In Comparative Example 17, paclitaxel could be completely dissolved, resulting in a completely clear, transparent, and uniform preparation solution. The preparation remained clear, transparent, and uniform after being stored at room temperature for more than four months. The rat oral bioavailability reached 12%.

[0151] Compared with Example 4, there was no castor oil solubilizer in the paclitaxel drug oral preparation obtained in Comparative Example 17, although the bioavailability and stability were comparable. This may be because, in fact, 10% ethylene glycol monoethyl ether (Transcutol) was also used in Example 4. Although the use of a large amount of Transcutol can reduce the viscosity of the preparation to facilitate capsule filling, ethylene glycol monoethyl ether cannot significantly improve the oral bioavailability of paclitaxel, and may even reduce the rat oral bioavailability. When ethylene glycol monoethyl ether was not used in Comparative Example 17, the rat oral bioavailability and stability of paclitaxel were comparable to those of Example 4, indicating that the castor oil solubilizer Kolliphor EL has a better effect on the rat oral bioavailability of paclitaxel drug oral preparations, which can ensure better bioavailability and stability when 10% ethylene glycol monoethyl ether is used.

[0152] Effect Example 2 Evaluation of in vivo anti-tumor effect based on a subcutaneous tumor transplantation model in nude mice

[0153] In the present application, the prepared paclitaxel liquid preparation for filling capsules is defined as paclitaxel soft capsule intermediate, and the paclitaxel soft capsule prepared in Example 3 is compared with two types of paclitaxel injection preparations, Taxol and Abraxane, respectively, as references. Intermediate in four mouse human cancer cell Allograft 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) were studied.

[0154] 1. In vivo anti-tumor effect evaluation on human breast cancer cell MDA-MB-231 subcutaneously transplanted tumor model in nude mice

[0155] Female nude mice were subcutaneously inoculated with MDA-MB-231 tumor cells to establish a MDA-MB-231 nude mouse transplanted tumor model. When the average tumor volume reached 180 mm 3 to the left and right, the animals were randomly grouped according to tumor volume, with a difference of less than 10% of the mean value. According to the size of the tumor volume, the animals were randomly divided into 6 groups, 8 in each group. Among them:

[0156] (1) Experimental group 1: Paclitaxel oral preparation was administered at a dose of 10 mg / kg by oral gavage, once every 3 days, for 3 weeks, a total of 7 times;

[0157] (2) Experimental group 2: Paclitaxel oral preparation was administered at a dose of 30 mg / kg by oral gavage, once every 3 days, for 3 weeks, a total of 7 times;

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

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

[0160] (5) Positive control group 2: Abraxane injection 30 mg / kg dose group, tail vein (IV) administration alone, once a week, for 3 weeks, a total of 3 times;

[0161] (6) Negative control group: A solvent negative control group was also set up, which was administered by oral gavage, once every 3 days, for 3 weeks, a total of 7 times.

[0162] After 21 days of administration, the average tumor volume of the negative control group was 747.36 ± 52.74 mm3 The experimental results are as follows: Figure 1 and Figure 2 As shown: Compared with the negative control group, the relative tumor proliferation rates (T / C) at Day 21 after oral gavage administration of paclitaxel soft capsule intermediates at different doses of 10 mg / kg, 30 mg / kg, and 100 mg / kg were 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), respectively. Positive control group 1 received paclitaxel injection at doses of 15 mg / kg and 30 mg / kg, respectively, via tail vein administration. Drug, once a week, for 3 weeks, a total of 3 times, the relative tumor proliferation rate on Day 21 The T / C ratios were 26.28% (TGI = 71.51%, P < 0.001) and 18.51% (TGI = 80.04%, P < 0.001), respectively. The experimental results indicate that this novel oral formulation of paclitaxel showed significantly better inhibitory and therapeutic effects on human breast cancer cells than paclitaxel; and comparable to albumin-bound paclitaxel.

[0163] 2. Evaluation of the in vivo antitumor effect of SK-OV-3 human ovarian cancer cells subcutaneously transplanted into a nude mouse tumor model.

[0164] SK-OV-3 tumor cells were subcutaneously injected into female nude mice to establish an SK-OV-3 xenograft model in nude mice. The tumors reached an average volume of 119 mm². 3 At approximately 10:00 AM, animals were randomly grouped according to tumor volume, ensuring that the difference in tumor volume between groups was less than 10% of the mean. Based on tumor size, the animals were randomly divided into 6 groups of 8 animals each.

[0165] (1) Experimental group 1: Paclitaxel 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 times;

[0166] (2) Experimental group 2: Paclitaxel 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 times;

[0167] (3) Experimental group 3: Paclitaxel 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 15mg / kg dose group, administered via tail vein (IV) alone, once every 3 days, for 3 weeks, for a total of 7 doses;

[0169] (5) Positive control group 2: albumin paclitaxel injection preparation 30 mg / kg dose group, single tail vein (IV) administration, once a week, administration for 3 weeks, a total of 3 times;

[0170] (6) Negative control group: at the same time, a solvent negative control group was set up, oral gavage administration, once every 3 days, administration for 3 weeks, a total of 7 times.

[0171] After 21 days of administration, the average tumor volume of the negative control group was 1062.42 ± 107.11 mm 3 . The experimental results are shown in Figure 3 and Figure 4 : compared with the negative control group, the relative tumor proliferation rate T / C of the paclitaxel soft capsule intermediate was 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) at Day 21, respectively, after oral gavage administration at different doses of 10 mg / kg, 30 mg / kg and 100 mg / kg. The relative tumor proliferation rate T / C of the positive control group 1 taxol paclitaxel injection and Positive control group 2 albumin paclitaxel injection respectively according to 15mg / kg and 30mg / kg dose, tail intravenous administration, once a week, administration for 3 weeks, a total of 3 times, was 39.48% (TGI = 60.36, P < 0.001) and 15.02% (TGI = 84.38, P < 0.001) at Day 21, respectively.

[0172] The test results show that the new paclitaxel oral preparation has a significantly better inhibitory and therapeutic effect on human ovarian cancer cells than taxol paclitaxel; the effect is comparable to that of albumin paclitaxel, and slightly better than that of albumin paclitaxel.

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

[0174] Female nude mice were subcutaneously inoculated with NCI-H358 tumor cells to establish an NCI-H358 nude mouse transplanted tumor model. When the average tumor volume reached 145.65 mm 3 , the animals were randomly divided into groups according to tumor volume, with the difference in tumor volume of each group being less than 10% of the mean value, and the animals were divided into 6 groups according to tumor volume using a random block method, with 8 animals in each group. Among them:

[0175] (1) Experimental group 1: paclitaxel oral preparation was administered at a dose of 10 mg / kg by oral gavage, once every 3 days, for 3 weeks, a total of 7 times;

[0176] (2) Experimental group 2: Paclitaxel oral preparation was orally administered at a dose of 30 mg / kg, once every 3 days, for 3 weeks, for a total of 7 times;

[0177] (3) Experimental group 3: Paclitaxel oral preparation was orally administered 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 (paclitaxel) injection at a dose of 15 mg / kg was administered intravenously (IV) alone, once every 3 days, for 3 weeks, for a total of 7 times;

[0179] (5) Positive control group 2: Albumin paclitaxel injection preparation at a dose of 30 mg / kg was administered intravenously (IV) alone, once a week, for 3 weeks, for a total of 3 times;

[0180] (6) Negative control group: A solvent negative control group was also set up, which was orally administered 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 ± 173.01 mm 3 . The experimental results are shown in Figure 5 and Figure 6 : compared with the negative control group, the relative tumor The proliferation rate T / C is 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). The positive control group 1 (Taxol injection) and the positive control group 2 (albumin paclitaxel injection) were administered intravenously at doses of 15 mg / kg and 30 mg / kg, respectively, once a week, for 3 weeks, for a total of 3 times. The relative tumor proliferation rate T / C at Day 21 was 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 paclitaxel oral preparation has a significantly better inhibitory and therapeutic effect on human non-small cell carcinoma cells than Taxol and albumin paclitaxel.

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

[0184] Female nude mice were subcutaneously inoculated with NCI-N87 tumor cells to establish an NCI-N87 nude mouse transplanted tumor model. When the average tumor volume reached 145.65 mm3 When the animals were randomly grouped according to the tumor volume, the tumor volume difference of each group was less than 10% of the average value. According to the tumor volume size, the animals were randomly grouped into 6 groups, 8 animals in each group. Among them:

[0185] (1) Experimental group 1: paclitaxel oral preparation was orally administered at a dose of 10 mg / kg, once every 3 days, for 3 weeks, a total of 7 times;

[0186] (2) Experimental group 2: paclitaxel oral preparation was orally administered at a dose of 30 mg / kg, once every 3 days, for 3 weeks, a total of 7 times;

[0187] (3) Experimental group 3: paclitaxel oral preparation was orally administered at a dose of 100 mg / kg, once every 3 days, for 3 weeks, 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, for 3 weeks, a total of 7 times;

[0189] (5) Positive control group 2: albumin paclitaxel injection preparation 30 mg / kg dose group, single tail vein (IV) administration, once a week, for 3 weeks, a total of 3 times;

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

[0191] After 21 days of administration, the average tumor volume of the negative control group was 1184.28 ± 48.32 mm 3 . The experimental results are as follows Figure 7 and Figure 8As shown: compared with the negative control group, the relative tumor proliferation rate T / C of paclitaxel soft capsule intermediates at 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) respectively at different doses of 10 mg / kg, 30 mg / kg and 100 mg / kg by oral gavage. The positive control group 1 taxoprexin paclitaxel injection and the positive control group 2 albumin paclitaxel injection were administered by tail vein at a dose of 15 mg / kg and 30 mg / kg respectively, once a week, for 3 weeks. After a total of 3 administrations, the relative tumor proliferation rate T / C at Day 21 was 26.52% (TGI = 73.08%, P < 0.001) and 13.48% (TGI = 86.31%, P < 0.001) respectively. Oral paclitaxel can significantly inhibit the growth of human gastric cancer cell NCI-N87 xenograft tumor in nude mice, which is better than taxoprexin 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 application was studied at room temperature (25℃±3℃) and 2-8℃. The change of paclitaxel content in the paclitaxel oral preparation with storage time is shown in Figure 9 and Figure 10 The results of the long-term storage study showed that the stability of the paclitaxel oral preparation prepared by the present patent was more than one year, and the stability at room temperature was more than 5 months. When the paclitaxel content in the paclitaxel oral preparation was more than 90%, the preparation was 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 by single oral gavage to beagle dogs is as follows:

[0196] By single oral gavage of paclitaxel soft capsules to beagle dogs, plasma samples were collected at different time points after oral gavage of paclitaxel soft capsules (16 mg / capsule) to beagle dogs (average body weight 7.8 kg), and the concentration of the test substance in the plasma of beagle dogs after administration of paclitaxel was determined by LC-MS / MS, and the relevant pharmacokinetic parameters (T 1 / 2 , T max , C max , AUC (0-t) , AUC (0-∞) ) were calculated by Phoenix WinNonlin 7.0 (Pharsight, USA). The results are shown in Table 2. 1 / 2 , T max , C max , AUC (0-t) , AUC (0-∞) ) were calculated by Phoenix WinNonlin 7.0 (Pharsight, USA). The results are shown in Table 2.

[0197] wherein T 1 / 2 is the half-life of the drug, T max is the time to peak of the drug, C max is the peak concentration of the drug Values, AUC (0-t) To Area under the curve, AUC (0-∞) Area under the curve.

[0198] Table 2

[0199]

[0200] From the above results of the in vivo pharmacokinetic study of beagle dogs, it can be seen that the AUC is large, which indicates that after the paclitaxel soft capsules of the present application are used, the exposure degree of paclitaxel drugs in the body is high, and the duration is long.

[0201] Although the specific embodiments of the present application are described above, those skilled in the art should understand that this is only an example, and the protection scope of the present application is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present application, and these changes and modifications all fall within the protection scope of the present application.

Claims

1. A paclitaxel oral pharmaceutical composition, characterized by, It comprises the following components: Paclitaxel 1.5%~2.0%, lipid material 40%~70%, castor oil solubilizer 22%~45% and glycoprotein inhibitor 1%~8%, the percentage is the mass percentage of each component relative to the total mass of the paclitaxel oral pharmaceutical composition; the castor oil solubilizer is polyoxyethylene glycol 35 castor oil; the lipid material comprises a polyglyceryl oleate mixture, the polyglyceryl oleate mixture comprises 51%-65% of polyglyceryl-3 oleate and 35%-49% of polyglyceryl-10 mono-dioleate, the percentage is the mass percentage relative to the total mass of the polyglyceryl oleate mixture; the glycoprotein inhibitor is vitamin E polyethylene glycol succinate.

2. The paclitaxel oral pharmaceutical composition of claim 1, wherein, The content of the polyglyceryl oleate mixture is 40%~70%, the percentage is the mass percentage relative to the total mass of the paclitaxel oral pharmaceutical composition.

3. The paclitaxel oral pharmaceutical composition of claim 1, wherein, The lipid material further comprises one or more of medium-chain triglycerides, glyceryl monocaprylate, capric and caprylic acid glycerol ester, propylene glycol monocaprylate, propylene glycol dilaurate, propylene glycol monolaurate, caprylic and capric acid polyethylene glycol glycerol ester, lauric acid polyethylene glycol glycerol ester, stearic acid polyethylene glycol glycerol ester, polyethylene glycol (15)-hydroxystearate, lauroyl polyoxyl (32) glycerides and stearoyl polyoxyl (32) glycerides.

4. The paclitaxel oral pharmaceutical composition of claim 1, wherein, The lipid material further comprises glyceryl tricaprylate.

5. An oral paclitaxel formulation, characterized in that, It comprises the paclitaxel oral pharmaceutical composition according to any one of claims 1-4.

6. The oral paclitaxel formulation of claim 5, wherein, The dosage form of the paclitaxel oral preparation is a liquid-filled capsule.

7. A process for the preparation of paclitaxel oral pharmaceutical composition as claimed in any one of claims 1 to 4, wherein the process comprises the steps of: It comprises heating and mixing the components.

8. Use of the paclitaxel oral pharmaceutical composition according to any one of claims 1-4 in the preparation of a medicament for treating cancer.

9. The use of paclitaxel oral pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of cancer, characterized in that, The cancer is breast cancer, ovarian cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer or soft tissue sarcoma.

10. The use of paclitaxel oral pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of cancer, characterized in that, The cancer is non-small cell lung cancer.

11. Use of the paclitaxel oral pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment of cancer, wherein The non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer.

12. The use of paclitaxel oral pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of cancer, characterized in that, The cancer meets the following conditions a or b: a. The breast cancer is locally advanced or metastatic breast cancer; b. The gastric cancer is advanced gastric adenocarcinoma that has not received prior chemotherapy.

13. Use of the paclitaxel oral pharmaceutical composition according to claim 12 for the manufacture of a medicament for the treatment of cancer, characterized in that, The gastric adenocarcinoma includes gastroesophageal junction adenocarcinoma. The gastric adenocarcinoma includes gastroesophageal junction adenocarcinoma.

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