Oral pharmaceutical composition and formulation of paclitaxel drug, preparation method therefor, and use thereof

Abstract

Disclosed in the present invention are an oral pharmaceutical composition and formulation of a paclitaxel drug, a preparation method therefor, and a use thereof. The oral pharmaceutical composition of the paclitaxel drug comprises a paclitaxel drug, a lipid substance, a solubilizer, and a glycoprotein inhibitor. The lipid substance comprises a polyglycerol oleate mixture having an HLB value of 8-9. The present invention can significantly increase the solubility of the paclitaxel drug and improve oral bioavailability, and exhibits few side effects, good tolerability and safety, and excellent tumor inhibitory and therapeutic effects.

Description

Paclitaxel oral pharmaceutical compositions, formulations, preparation methods and applications

[0001] This application claims priority to Chinese patent application 2024119812692, filed on 2024 / 12 / 31. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to an oral pharmaceutical composition, formulation, preparation method and application of paclitaxel-based drugs. Background Technology

[0003] Paclitaxel is an antimicrotubule drug, belonging to the class of cytotoxic antitumor drugs. It binds to tubulin in cells, stabilizing microtubules by promoting the polymerization of tubulin dimers and preventing their depolymerization. This inhibits the normal dynamic reorganization of microtubules, which is crucial for cell function during interphase and mitosis. Paclitaxel-based drugs arrest the cell cycle at the G2 / M phase, leading to abnormal or stopped mitosis, hindering tumor cell replication, and causing cancer cells to die and die, thus inhibiting cancer cell growth. In addition, paclitaxel also has a radiosensitizing effect, promoting damage to cancer cells caused by ionization. Paclitaxel-based drugs are widely used clinically to treat ovarian cancer, breast cancer, lung cancer, head and neck tumors, esophageal cancer, gastric cancer, and soft tissue sarcomas.

[0004] The primary clinical application is paclitaxel injection. Paclitaxel injection requires the addition of excipients such as high-concentration polyoxyethylated castor oil, Tween 80, anhydrous ethanol, and micellar polymers to aid solubilization. Polyoxyethylated castor oil (Cremophor EL or Kolliphor EL) can cause varying degrees of allergic reactions after entering the systemic circulation following injection. High concentrations of polyoxyethylated castor oil form micelles, affecting the diffusion of drug molecules into tissues and impacting the antitumor effect. Furthermore, during intravenous infusion, polyoxyethylated castor oil can dissolve diethylene ethyl phthalate in PVC infusion sets, causing serious adverse reactions. To prevent allergic reactions to paclitaxel injection, complex medical pretreatment is required before paclitaxel treatment, including oral administration of dexamethasone 20mg approximately 12 hours and 6 hours before treatment, intramuscular injection of diphenhydramine 50mg 30–60 minutes before treatment, and intravenous injection of cimetidine 300mg or ranitidine 50mg.

[0005] Docetaxel (also known as docetaxel) 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, and advanced gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) in patients who have not previously received chemotherapy. Similar to paclitaxel, docetaxel has low water solubility and requires the addition of high concentrations of polysorbate 80 and anhydrous ethanol for solubilization; both can increase the incidence of adverse reactions. Ethanol can inhibit the central nervous system and cross the red blood cell membrane, causing red blood cell degeneration or hemolysis. Polysorbate 80 is a nonionic surfactant that can cause allergic reactions and hemolytic reactions. To reduce the occurrence and severity of fluid retention after docetaxel injection and to mitigate the severity of allergic reactions, all patients must take pre-administered glucocorticoids before receiving docetaxel treatment. Dexamethasone is usually taken one day before docetaxel administration, at 8 mg twice daily for 3 days.

[0006] New intravenous formulations of paclitaxel, such as albumin-bound paclitaxel, micellar paclitaxel, and liposomal paclitaxel, can only reduce side effects; they cannot change the route of administration or completely overcome the inherent drawbacks of intravenous formulations. Injectable paclitaxel commonly causes side effects such as phlebitis and peripheral neurotoxicity. Symptoms of peripheral neurotoxicity include glove-and-stocking-like numbness in the extremities, symptoms and signs of sensory nerve involvement including paresthesia, hypoesthesia, hyperesthesia, and pain; burning sensation, decreased vibration sensation, loss of tendon reflexes, and even impaired motor function. Some patients may experience 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, reduces the effective drug concentration exposure time in tumor tissue, and decreases the therapeutic effect of paclitaxel-like drugs. Docetaxel has similar neurotoxicity to paclitaxel, but the incidence is lower. Furthermore, patients often cannot administer the medication at home and must receive intravenous infusion of paclitaxel injections with the assistance of a healthcare professional.

[0007] Therefore, the medical market needs to develop an oral paclitaxel drug that allows patients to undergo chemotherapy at home, significantly reducing the risk of infection during infusion, improving patient adherence and quality of life, and lowering medical costs, as well as reducing the incidence or severity of neurotoxicity. This would solidify paclitaxel's position as a first-line treatment, achieving the goals of significantly increasing patient adherence and quality of life in cancer patients, and reducing medication costs.

[0008] However, paclitaxel drugs have a high molecular weight, are highly lipophilic and poorly soluble, and are classified as BCS IV drugs, meaning they are difficult to dissolve and almost not absorbed by the gastrointestinal tract. Furthermore, paclitaxel is a substrate of P-glycoproteins, which readily leads to excretion, and it is easily metabolized by hepatic enzymes such as CYP2A8 and CYP3C4. Existing oral formulations of paclitaxel drugs under development have very low oral bioavailability, poor solubility, and poor stability, resulting in limited therapeutic efficacy and significant preclinical and clinical side effects. Summary of the Invention

[0009] This invention addresses the shortcomings of existing oral paclitaxel formulations, such as low oral bioavailability, poor solubility, poor stability, limited therapeutic efficacy, and significant preclinical and clinical side effects. It provides an oral paclitaxel drug composition, formulation, preparation method, and application. The oral paclitaxel formulation of this invention significantly increases the solubility and stability of paclitaxel, improves oral bioavailability, has fewer side effects, good tolerability and safety, and superior tumor suppression and therapeutic effects.

[0010] To achieve the above objectives, the present invention adopts the following technical solution:

[0011] This invention provides an oral pharmaceutical composition for paclitaxel drugs, comprising the following components: paclitaxel drugs, lipids, solubilizers, and glycoprotein inhibitors; wherein the lipids comprise a mixture of polyglycerol oleate esters, the HLB value of which is 8-9.

[0012] In some preferred embodiments, the solubilizer is a castor oil-based solubilizer.

[0013] In some preferred embodiments, the polyglycerol oleate mixture comprises polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate.

[0014] The paclitaxel oral pharmaceutical composition of this invention is a self-emulsifying liquid formulation system with high viscosity. The polyglycerol oleate mixture (HLB 8-9) is insoluble in water and exhibits high hydrophobicity. It acts as the oil phase and emulsifier in the paclitaxel oral pharmaceutical composition, increasing the solubility and distribution of the paclitaxel in the oil phase. When the paclitaxel oral pharmaceutical composition also contains castor oil as a solubilizer, upon contact with aqueous solutions and animal body fluids, the oral formulation can form numerous stable oil-in-water particles, promoting the uniform distribution of the paclitaxel in these particles and significantly increasing the solubility, gastrointestinal absorption surface area, and oral bioavailability of the paclitaxel. Furthermore, the addition of a glycoprotein inhibitor can significantly inhibit the excretion effect of glycoproteins on tumor drugs, enhancing the therapeutic effect on tumors.

[0015] In this invention, the paclitaxel drug can be a conventional paclitaxel drug in the art, preferably paclitaxel or docetaxel.

[0016] In this invention, the content of the paclitaxel drug can be a pharmaceutically acceptable conventional dosage, preferably 1.5% to 2.0%, for example 1.6% or 1.8%, and the percentage is a mass percentage relative to the total mass of the oral paclitaxel drug composition.

[0017] In this invention, the polyglycerol oleate mixture may be composed of two or more different types of polyglycerol oleate. The polyglycerol oleate refers to an ester formed by the esterification reaction of polyglycerol and oleic acid, and different types of polyglycerol oleate are obtained based on the degree of polymerization of polyglycerol and the amount of oleic acid participating in the esterification reaction.

[0018] In this invention, the HLB value can be measured using the Griffin method.

[0019] In this 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 a mass percentage relative to the total mass of the lipid substances.

[0020] In some preferred embodiments of the present invention, the polyglycerol oleate mixture comprises polyglyceryl-3 oleate and polyglyceryl-10 mono / dioleate. In this invention, the mixture of "polyglyceryl-3 oleate and polyglyceryl-10 mono / dioleate" is abbreviated as Caprol MPGO. Specifically, the polyglyceryl-10 mono / dioleate is a mixture of polyglyceryl-10 monooleate and polyglyceryl-10 dioleate.

[0021] In this invention, the oral formulation of paclitaxel drugs utilizes a specific mixture of polyglycerol oleate, which maximizes the solubility of paclitaxel and ensures a clear and transparent dispersion in the aqueous phase, further enhancing the oral bioavailability of paclitaxel.

[0022] In the above embodiments, preferably, the polyglycerol oleate mixture comprises 51%-65% polyglycerol-3 oleate and 35%-49% polyglycerol-10 mono- and di-oleate, the percentages being mass percentages relative to the total mass of the polyglycerol oleate mixture.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] The type of the tricaprylic acid glyceride is preferably CAPTEX 8000.

[0027] Preferably, the type of the glyceryl monocaprylate is CAPMUL 808G. One or more of GMO-50 and CAPMUL MCM C8.

[0028] The mono- and di-caprylic / caprylic glycerides preferably include one or more of monoacylglycerols, diacylglycerols, and triacylglycerols.

[0029] 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.

[0030] The type of the mono- and dicaprylic / capric glycerides is preferably CAPMUL MCM EP / NF.

[0031] In some preferred embodiments, the propylene glycol monooctanoate comprises monoglyceride and diglyceride; wherein the content of monoglyceride is 55%-80%, and the content of diglyceride is 20%-45%.

[0032] Alternatively, the content of the monoglyceride is greater than 90%, and the content of the diglyceride is less than 10%; the percentage is a mass percentage relative to the total mass of the propylene glycol monocaprylate. Preferably, the propylene glycol monocaprylate is CAPMUL PG-8NF (Propylene Glycol Monocaprylate Type II) and / or CAPMUL PG-8-70NF (Propylene Glycol Monocaprylate Type I). CAPMUL PG-8NF refers to a content of greater than 90% of monoglycerides and less than 10% of diglycerides. CAPMUL PG-8-70NF refers to a content of 55%-80% of monoglycerides and 20%-45% of diglycerides, with the percentage being a mass percentage relative to the total mass of the propylene glycol monocaprylate.

[0033] The propylene glycol dilaurate is preferably CAPMUL PG-2L EP / NF.

[0034] The propylene glycol monolaurate is preferably CAPMUL PG-12EP / NF.

[0035] The preferred type of the caprylocaproyl macrogolglycerides is Acconon MC8-2.

[0036] The type of the lauryl glycol glycerides is preferably Acconon C-44.

[0037] The type of the stearic acid polyethylene glycol glyceride (Stearoyl Macrogolglycerides) is preferably Acconon C-50.

[0038] The polyethylene glycol (15)-hydroxystearate is preferably Solutol HS 15.

[0039] The lauroyl polyoxyethylene (32) glycerides are preferably Gelucire 44 / 14.

[0040] The preferred type of the stearoyl polyoxyethylene (32) glycerides is Gelucire 55 / 13.

[0041] In this invention, the content of the lipid substances can 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 a mass percentage relative to the total mass of the paclitaxel pharmaceutical composition.

[0042] In this 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).

[0043] In some preferred embodiments, the castor oil solubilizer is polyoxyethylene ether 35 castor oil.

[0044] In this 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 a mass percentage relative to the total mass of the oral paclitaxel drug composition.

[0045] In this invention, the glycoprotein inhibitor can be a conventional glycoprotein inhibitor in the art, and its function is as follows: Paclitaxel drugs are substrates of glycoproteins (P-glycoprotein, Pgp), which are 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 glycoproteins on tumor drugs and improve the tumor treatment effect.

[0046] 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).

[0047] Preferably, the content of the glycoprotein inhibitor is 1% to 8%, more preferably 2% to 5%, for example 3% or 4%; the percentage is a mass percentage relative to the total mass of the oral paclitaxel pharmaceutical composition.

[0048] In some preferred embodiments, the oral paclitaxel composition comprises the following components: 1.5%–2.0% paclitaxel, 40%–70% lipids, 22%–45% castor oil solubilizer, and 1%–8% glycoprotein inhibitor, the percentages being the mass percentage of each component relative to the total mass of the oral paclitaxel composition; wherein the lipids include a mixture of polyglycerol oleate esters, the polyglycerol oleate ester mixture comprising polyglycerol-3 oleate and polyglycerol-10 mono- and di-oleate esters.

[0049] In some preferred embodiments, the oral paclitaxel composition comprises the following components: 1.5%–2.0% paclitaxel, 40%–70% lipids, 22%–45% castor oil solubilizer, and 1%–8% glycoprotein inhibitor, the percentages being the mass percentage of each component relative to the total mass of the oral paclitaxel composition; the castor oil solubilizer is polyoxyethylene ether 35 castor oil; the lipids comprise a polyglycerol oleate mixture comprising 51%–65% polyglycerol-3 oleate and 35%–49% polyglycerol-10 mono- and di-oleate, the percentages being the mass percentage relative to the total mass of the polyglycerol oleate mixture.

[0050] In some preferred embodiments, the oral paclitaxel composition comprises the following components: 1.5%–2.0% paclitaxel, 40%–70% lipids, 22%–45% castor oil solubilizer, and 1%–8% glycoprotein inhibitor, the percentages being the mass percentage of each component relative to the total mass of the oral paclitaxel composition; the castor oil solubilizer is polyoxyethylene ether 35 castor oil; the lipids comprise a polyglycerol oleate mixture comprising 51%–65% polyglycerol-3 oleate and 35%–49% polyglycerol-10 mono- and di-oleate, the percentages being the mass percentage relative to the total mass of the polyglycerol oleate mixture; and the glycoprotein inhibitor is vitamin E polyethylene glycol succinate.

[0051] Optionally, in this invention, the oral paclitaxel drug composition further includes a co-surfactant. The co-surfactant promotes the distribution of the paclitaxel drug in the aqueous phase and enhances oral absorption. The co-surfactant may be selected from one or more of ethylene glycol monoethyl ether (Transcutol), propylene glycol, glycerol glycerol, and polyethylene glycol (PEG). The polyethylene glycol may be PEG200, PEG300, or PEG400.

[0052] When the oral paclitaxel composition further includes ethylene glycol monoethyl ether, the content of the 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 a mass percentage relative to the total mass of the oral paclitaxel composition.

[0053] When the oral paclitaxel composition further includes propylene glycol, the propylene glycol content is preferably 0% to 10%, more preferably 5% to 8%; the percentage is a mass percentage relative to the total mass of the oral paclitaxel composition.

[0054] In some preferred embodiments of the present invention, the oral paclitaxel composition comprises the following components: 1.5% to 2.0% paclitaxel, 40% to 70% polyglycerol oleate and polyglycerol mono- and di-oleate, 1% to 8% vitamin E polyethylene glycol succinate, 22% to 45% castor oil solubilizer, 0% to 12% ethylene glycol monoethyl ether, and 0% to 10% propylene glycol; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0055] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 58%, vitamin E polyethylene glycol 1000 succinate 2.0%, polyoxyethylene ether 35 castor oil 32%, and ethylene glycol monoethyl ether 6.0%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0056] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.6%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 57.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, polyoxyethylene ether 35 castor oil 31%, and ethylene glycol monoethyl ether 8.0%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0057] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.6%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 65.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, and polyoxyethylene ether 35 castor oil 31%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0058] In a specific embodiment of the present invention, the oral paclitaxel drug composition comprises the following components: paclitaxel 2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 54%, vitamin E polyethylene glycol 1000 succinate 2.0%, polyoxyethylene ether 35 castor oil 32%, and ethylene glycol monoethyl ether 10%; the percentages are mass percentages relative to the total mass of the oral paclitaxel drug composition.

[0059] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 54%, vitamin E polyethylene glycol succinate 3.0%, polyoxyethylene ether 35 castor oil 32%, and ethylene glycol monoethyl ether 9.0%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0060] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.5%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 62.5%, vitamin E polyethylene glycol 1000 succinate 3.0%, and polyoxyethylene ether 35 castor oil 33%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0061] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.5%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 68.5%, vitamin E polyethylene glycol 1000 succinate 2.0%, and polyoxyethylene ether 35 castor oil 28%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0062] In some preferred embodiments of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.5%–2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 40%–70%, polyoxyethylene ether 35 castor oil 22%–45%, vitamin E polyethylene glycol 1000 succinate 1%–8%, and propylene glycol 0–10%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0063] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.6%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 57.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, polyoxyethylene ether 35 castor oil 31%, and propylene glycol 8.0%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0064] In some preferred embodiments of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.5%–2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 40%–70%, polyoxyethylene ether 35 castor oil 22%–45%, vitamin E polyethylene glycol 1000 succinate 1%–8%, and ethylene glycol monoethyl ether 0–10%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0065] In a specific embodiment of the present invention, the oral paclitaxel drug composition comprises the following components: paclitaxel 2.5%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 50%, vitamin E polyethylene glycol 1000 succinate 7.5%, polyoxyethylene ether 35 castor oil 30%, and ethylene glycol monoethyl ether 10%; the percentages are mass percentages relative to the total mass of the oral paclitaxel drug composition.

[0066] In a specific embodiment of the present invention, the oral paclitaxel drug composition comprises the following components: paclitaxel 2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 50%, vitamin E polyethylene glycol 1000 succinate 8.0%, polyoxyethylene ether 35 castor oil 30%, and ethylene glycol monoethyl ether 10%; the percentages are mass percentages relative to the total mass of the oral paclitaxel drug composition.

[0067] In a specific embodiment of the present invention, the oral paclitaxel drug composition comprises the following components: paclitaxel 2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 50%, vitamin E polyethylene glycol 1000 succinate 4.0%, polyoxyethylene ether 35 castor oil 32%, and ethylene glycol monoethyl ether 12%; the percentages are mass percentages relative to the total mass of the oral paclitaxel drug composition.

[0068] In a specific embodiment of the present invention, the oral paclitaxel drug composition comprises the following components: paclitaxel 3.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 49%, vitamin E polyethylene glycol 1000 succinate 3.0%, polyoxyethylene ether 35 castor oil 32%, and ethylene glycol monoethyl ether 13%; the percentages are mass percentages relative to the total mass of the oral paclitaxel drug composition.

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

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

[0071] In some preferred embodiments of the present invention, the oral paclitaxel composition comprises the following components: 1.5% to 2.0% paclitaxel, 40% to 70% polyglycerol oleate and polyglycerol mono- and di-oleate, 1% to 8% vitamin E polyethylene glycol succinate, and 40% to 70% polyethylene glycol stearate; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0072] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.6%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 51.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, and polyethylene glycol stearate 45%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0073] In some preferred embodiments of the present invention, the oral paclitaxel composition comprises the following components: 1.5% to 2.0% paclitaxel, 40% to 70% polyglycerol oleate and polyglycerol mono- and dioleate, 1% to 8% vitamin E polyethylene glycol succinate, and 40% to 70% caprylic / capric glyceride polyethylene glycol glyceride; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0074] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.6%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 51.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, and caprylic / capric glyceride polyethylene glycol glyceride 45%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0075] In a specific embodiment of the present invention, the oral paclitaxel drug composition comprises the following components: paclitaxel 2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 51%, vitamin E polyethylene glycol 1000 succinate 2.0%, and caprylic / capric glyceride polyethylene glycol glyceride 45%; the percentages are mass percentages relative to the total mass of the oral paclitaxel drug composition.

[0076] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.8%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 48.2%, vitamin E polyethylene glycol 1000 succinate 2.0%, and caprylic / capric glyceride polyethylene glycol glyceride 48%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0077] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.6%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 46.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, and caprylic / capric glyceride polyethylene glycol glyceride 50%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0078] In a specific embodiment of the present invention, the oral paclitaxel drug composition comprises the following components: paclitaxel 2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 53%, vitamin E polyethylene glycol 1000 succinate 5.0%, and caprylic / capric glyceride polyethylene glycol glyceride 40%; the percentages are mass percentages relative to the total mass of the oral paclitaxel drug composition.

[0079] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.6%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 51.4%, vitamin E polyethylene glycol 1000 succinate 2.0%, and caprylic / capric glyceride polyethylene glycol glyceride 45%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0080] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.8%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 51.2%, vitamin E polyethylene glycol 1000 succinate 2.0%, and caprylic / capric glyceride polyethylene glycol glyceride 45%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0081] In a specific embodiment of the present invention, the oral paclitaxel composition comprises the following components: paclitaxel 1.8%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 48.2%, vitamin E polyethylene glycol 1000 succinate 2.0%, and caprylic / capric glyceride polyethylene glycol glyceride 48%; the percentages are mass percentages relative to the total mass of the oral paclitaxel composition.

[0082] The present invention also provides a method for preparing the oral pharmaceutical composition of the paclitaxel class of drugs, which includes heating and mixing the components.

[0083] The heating temperature can be 35℃ to 60℃, preferably 35℃ to 55℃, for example 45℃ or 50℃.

[0084] The mixing can be carried out using conventional methods in the art, such as stirring. The mixing time is determined by ensuring that the mixture becomes a homogeneous and clear liquid, i.e., the paclitaxel drug is completely dissolved and contains no visible solid particles. Generally, the mixing time can be 60–180 minutes.

[0085] The present invention provides an oral formulation of a paclitaxel drug, comprising the oral paclitaxel drug composition as described above.

[0086] The dosage form of the oral paclitaxel drug can be a liquid formulation or a capsule formulation.

[0087] In this invention, the dosage form of the oral paclitaxel drug is preferably a liquid-filled capsule.

[0088] When the dosage form of the oral paclitaxel drug is a liquid-filled capsule, the preparation method of the oral paclitaxel drug preferably includes the following steps: heating and mixing the components, then cooling the mixture and filling it into a pharmaceutical capsule.

[0089] The present invention also provides the use of the oral pharmaceutical composition of the paclitaxel class of drugs or the oral formulation of the paclitaxel class of drugs in the preparation of a drug for treating cancer.

[0090] In this 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, liver cancer, pancreatic cancer, rectal cancer, or soft tissue sarcoma.

[0091] 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 previously received chemotherapy; wherein, the gastric adenocarcinoma preferably includes adenocarcinoma of the gastroesophageal junction.

[0092] The present invention also provides a method for preventing and / or treating cancer, comprising administering to a patient a therapeutically effective amount of the oral paclitaxel drug composition or the oral paclitaxel drug formulation described above.

[0093] The present invention also provides an oral pharmaceutical composition of paclitaxel or an oral formulation of paclitaxel as described above, for the prevention and / or treatment of cancer.

[0094] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0095] The reagents and raw materials used in this invention are all commercially available.

[0096] The positive and progressive effects of this invention are as follows:

[0097] The oral paclitaxel formulation developed in this invention overcomes the inherent drawbacks of injectable drugs, provides better clinical treatment solutions for cancer patients, improves patient medication adherence and quality of life, and significantly reduces medication and healthcare costs for cancer patients.

[0098] Specifically, this oral formulation of paclitaxel has the following advantages:

[0099] ① It can significantly increase the solubility of paclitaxel drugs and improve their oral bioavailability;

[0100] ② It has superior tumor suppression and therapeutic effects;

[0101] ③ It has good storage stability;

[0102] ④ It has low toxicity and side effects, and good tolerability and safety;

[0103] ⑤ The preparation process is simple and safe, and does not use organic solvents that pose safety hazards. Attached Figure Description

[0104] Figure 1 shows the change in average tumor volume over the number of days after treatment when different formulations were used to treat a human breast cancer cell MDA-MB-231 subcutaneous xenograft model in nude mice.

[0105] Figure 2 shows the change in relative tumor proliferation rate with the number of days after treatment when different formulations were used to treat the human breast cancer cell MDA-MB-231 subcutaneous xenograft model in nude mice.

[0106] Figure 3 shows the change in average tumor volume over the number of days after treatment when different formulations were used to treat the human ovarian cancer cell SK-OV-3 subcutaneous xenograft model in nude mice.

[0107] Figure 4 shows the change in relative tumor proliferation rate with the number of days after treatment when different formulations were used to treat the human ovarian cancer cell SK-OV-3 nude mouse subcutaneous xenograft tumor model.

[0108] Figure 5 shows the change in average tumor volume over the number of days after treatment when different formulations were used to treat a human non-small cell lung cancer cell NCI-H358 subcutaneous xenograft tumor model in nude mice.

[0109] Figure 6 shows the change in relative tumor proliferation rate with the number of days after treatment when different formulations were used to treat the NCI-H358 human non-small cell lung cancer cell subcutaneous xenograft model in nude mice in Example 2 of the present invention.

[0110] Figure 7 shows the change in average tumor volume with the number of days after treatment when different formulations were used to treat the NCI-N87 human gastric cancer cell subcutaneous transplantation tumor model in nude mice in Example 2 of the present invention.

[0111] Figure 8 shows the change in relative tumor proliferation rate with the number of days after treatment when different formulations were used to treat the NCI-N87 human gastric cancer cell subcutaneous transplantation tumor model in nude mice in Example 2 of the present invention.

[0112] Figure 9 shows the change in paclitaxel content over storage time when the oral formulation of paclitaxel drugs in Example 3 of the present invention is stored at 5°C.

[0113] Figure 10 shows the change in paclitaxel content over storage time when the oral formulation of paclitaxel drugs in Example 3 of the present invention is stored at 25°C. Detailed Implementation

[0114] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0115] Examples 1-12 and Comparative Examples 1-17

[0116] In the following examples and comparative examples:

[0117] Paclitaxel-based drugs: Paclitaxel was used and purchased from Fujian Nanfang Pharmaceutical Co., Ltd.

[0118] Caprol MPGO: polyglycerol oleate and polyglycerol mono- and di-oleate, purchased from Abitec Corporation;

[0119] TPGS 1000: Vitamin E polyethylene glycol 1000 succinate, purchased from BASF SE;

[0120] Kolliphor EL / Cremophor EL: Polyoxyethylene ether 35 castor oil, purchased from BASF SE;

[0121] Acconon MC8-2: Polyethylene glycol glyceryl caprylate-capric acid, purchased from Abitec Corporation;

[0122] Acconon C-44: Polyethylene glycol glyceryl laurate, purchased from Abitec Corporation;

[0123] Acconon C-50: Polyethylene glycol glyceryl stearate, purchased from Abitec Corporation;

[0124] Transcutol: Ethylene glycol monoethyl ether, purchased from Gattefosse SAS;

[0125] CAPTEX 300EP / NF: Medium-chain triglyceride, purchased from Abitec Corporation;

[0126] Caprol PGE 860: Polyglycerol-10 mono- and dioleate, purchased from Abitec Corporation;

[0127] Caprol 3GO: Polyglycerol-3-oleic acid, purchased from Abitec Corporation.

[0128] Weigh each component according to the formula in Table 1, add them to a container, and heat and stir to mix. The heating temperature is shown in Table 1, and the mixing time is 60-180 minutes, until the mixture becomes a homogeneous and clear liquid, in which paclitaxel can be completely dissolved and there are no visible solid particles. After cooling the resulting clear liquid, fill it into pharmaceutical capsules to obtain an oral preparation of paclitaxel drugs in liquid-filled capsule form, abbreviated as paclitaxel soft capsules.

[0129] Table 1

[0130] Note: In Table 1, " / " indicates that the condition parameter is not involved in the specific experiment.

[0131] Example 1: Dissolution and Dispersion Effects and Bioavailability

[0132] Methods for testing oral bioavailability in rats:

[0133] SD rats were administered different formulations via intravenous injection or oral gavage. Blood samples were collected at different time points, and the concentrations of each test substance in the plasma of SD rats after administration were determined by LC-MS / MS, and relevant pharmacokinetic parameters were calculated. Specifically, pharmacokinetic parameters (AUC) were calculated using the blood drug concentration data at different time points using Phoenix WinNonlin 7.0 (Pharsight, USA). (0-t) T 1 / 2 C max T max (and oral bioavailability). Oral bioavailability is calculated using the following formula: F = AUC (0-t) ,PO×CIV / (AUC (0-t) (IV×CPO)×100

[0134] Among them, AUC (0-t) PO refers to the AUC of paclitaxel soft capsules administered orally via gavage. (0-t) (Area under the curve); CIV refers to the intravenous dose of paclitaxel; AUC (0-t) IV refers to the AUC of paclitaxel administered intravenously. (0-t) (Area under the curve); CPO refers to the dosage of paclitaxel soft capsules administered orally via gavage.

[0135] In Examples 1-12, paclitaxel was able to completely dissolve in the formulation to form a clear, transparent, and homogeneous solution. The solution formulation was able to maintain stability when stored at room temperature for an extended period (more than four months), without the formation of particulate matter, separation, or precipitation. The formulation remained clear, transparent, and homogeneous.

[0136] In Example 4, the formulation completely dissolved paclitaxel, yielding a completely clear, transparent, and homogeneous solution. The formulation remained a clear, transparent, and homogeneous solution after being stored at room temperature for more than four months. The oral bioavailability in rats was 11%.

[0137] In Example 9, paclitaxel was completely dissolved, yielding a completely clear, transparent, and homogeneous solution. The formulation remained a clear, transparent, and homogeneous solution even after being stored at room temperature for more than three months.

[0138] In Example 11, paclitaxel was completely dissolved, yielding a completely clear, transparent, and homogeneous solution. The formulation remained a clear, transparent, and homogeneous solution even after being stored at room temperature for more than three months.

[0139] However, if only polyglyceryl-3 oleate is used instead of a mixture of polyglyceryl oleate (Caprol MPGO), although paclitaxel can be dissolved, a precipitate will form a semi-solid when stored at room temperature or at a low temperature of 5℃±3℃.

[0140] However, if only polyglycerol-10 mono- and dioleate esters (Caprol PGE 860) are used instead of a mixture of polyglycerol oleates (Caprol MPGO), although paclitaxel can be dissolved, the liquid formulation has a higher viscosity and will precipitate after long-term storage at room temperature. The oral bioavailability in rats is also only 4%, which is relatively low.

[0141] Comparative Example 1 did not use the oil phase Caprol MPGO and the castor oil solubilizer Kolliphor EL, but only TPGS 1000. Although paclitaxel could be completely dissolved, the dispersion effect in aqueous solution was poor, resulting in a milky white opaque solution.

[0142] Comparative Example 2, without using the oil phase Caprol MPGO and TPGS 1000, only used Kolliphor EL. Paclitaxel could not be completely dissolved, resulting in a slightly milky white formulation with high viscosity and poor dispersibility in aqueous solution. The solution was milky white and opaque, and a clear, transparent solution could not be obtained. After one month of storage at room temperature, the formulation became slightly milky white and opaque, with precipitation and layering.

[0143] Comparative Example 3 did not use the oil phase Caprol MPGO, but only Caprol PGE-860 (polyglyceryl-10 mono / dioleate alone), Kolliphor EL, and TPGS 1000. The resulting paclitaxel formulation had poor dispersibility in the aqueous phase, and the oral bioavailability of the paclitaxel formulation in rats was low, only 4%.

[0144] Comparative Example 4 used Caprol MPGO and TPGS 1000 in the oil phase, but did not use Kolliphor EL, which failed to adequately dissolve paclitaxel, resulting in poor dispersion of the paclitaxel formulation in the aqueous phase. The oral bioavailability in rats was relatively low, only 1.4%.

[0145] Comparative Example 5 did not use the oil phase Caprol MPGO and TPGS 1000, but only Kolliphor EL. Paclitaxel could not be fully dissolved, resulting in a milky white, non-uniform liquid formulation.

[0146] Comparative Example 6 did not use the oil phase Caprol MPGO and Kolliphor EL, but only TPGS 1000, which could not fully dissolve paclitaxel.

[0147] Comparative Example 7, which used polyglyceryl-3 oleate and Kolliphor EL and TPGS 1000 to prepare paclitaxel formulations, could not completely dissolve paclitaxel. The prepared paclitaxel formulations readily separated into layers when stored at room temperature.

[0148] In Comparative Example 9, the formulation completely dissolved paclitaxel, yielding a completely clear, transparent, and homogeneous solution. After being stored at room temperature for more than four months, the formulation remained a clear, transparent, and homogeneous solution. The oral bioavailability in rats was 5.9%.

[0149] In Comparative Example 10, paclitaxel was completely dissolved, yielding a completely clear, transparent, and homogeneous formulation. Four months later, the formulation remained clear, transparent, and homogeneous, with no particle formation, layering, or precipitation. The oral bioavailability of paclitaxel in rats reached 9%.

[0150] In Comparative Example 15, the oral bioavailability of paclitaxel in rats reached 7%.

[0151] In Comparative Example 17, paclitaxel was completely dissolved, yielding a completely clear, transparent, and homogeneous formulation solution. The formulation remained a clear, transparent, and homogeneous solution after being stored at room temperature for more than four months. The oral bioavailability in rats reached 12%.

[0152] Compared to Example 4, the oral formulation of paclitaxel obtained in Comparative Example 17 did not contain castor oil as a solubilizer, although the bioavailability and stability were comparable. This may be because 10% ethylene glycol monoethyl ether (Transcutol) was also used in Example 4. Although the use of large amounts of Transcutol can reduce the viscosity of the formulation, which is beneficial for capsule filling, ethylene glycol monoethyl ether does not significantly improve the oral bioavailability of paclitaxel; on the contrary, it may reduce the oral bioavailability in rats. When ethylene glycol monoethyl ether was not used in Comparative Example 17, the oral bioavailability and stability of paclitaxel in rats were comparable to those in Example 4, indicating that the castor oil solubilizer Kolliphor EL is effective in improving the oral bioavailability of paclitaxel formulations in rats, thus ensuring good bioavailability and stability even when using 10% ethylene glycol monoethyl ether.

[0153] Example 2: Evaluation of in vivo antitumor effect based on a nude mouse subcutaneous tumor transplantation model

[0154] In this invention, the prepared paclitaxel liquid formulation for filling capsules is defined as a paclitaxel soft capsule intermediate. Two types of paclitaxel injection formulations, namely Taxol and Abraxane, are used as references to study the tumor therapeutic effects of the paclitaxel drug soft capsule intermediate prepared in Example 3 in four mouse xenograft tumor models of human cancer cells: 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).

[0155] 1. Evaluation of the in vivo antitumor effect of human breast cancer cells MDA-MB-231 subcutaneously transplanted into a nude mouse tumor model.

[0156] MDA-MB-231 tumor cells were subcutaneously inoculated into female nude mice to establish an MDA-MB-231 xenograft model in nude mice. The tumors reached an average volume of 180 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, animals were randomly divided into 6 groups of 8 animals each.

[0157] (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;

[0158] (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;

[0159] (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;

[0160] (4) Positive control group 1: Taxol injection 15mg / kg dose group, administered via tail vein (IV) alone, once a week for 3 weeks, for a total of 3 administrations;

[0161] (5) Positive control group 2: Albumin-bound paclitaxel injection preparation 30mg / kg dose group, administered via tail vein (IV) alone, once a week for 3 weeks, for a total of 3 administrations;

[0162] (6) Negative control group: A negative control group was set up at the same time. The solvent was administered orally by gavage once every 3 days for 3 weeks, for a total of 7 times.

[0163] Twenty-one days after drug administration, the mean tumor volume in the negative control group was 747.36 ± 52.74 mm. 3 The experimental results are shown in Figures 1 and 2: 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 (paclitaxel injection) and positive control group 2 (albumin-bound paclitaxel injection) were administered via tail vein at doses of 15 mg / kg and 30 mg / kg, respectively, once weekly for 3 weeks (3 doses in total). After these administrations, the relative tumor proliferation rates (T / C) at Day 21 were 26.28% (TGI = 71.51%, P < 0.001) and 18.51% (TGI = 80.04%, P < 0.001), respectively. The results indicate that this novel oral paclitaxel formulation is significantly more effective than paclitaxel in inhibiting and treating human breast cancer cells; its efficacy is comparable to that of albumin-bound paclitaxel.

[0164] 2. Evaluation of the in vivo antitumor effect of SK-OV-3 human ovarian cancer cells subcutaneously transplanted into a nude mouse tumor model.

[0165] 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.

[0166] (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;

[0167] (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;

[0168] (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;

[0169] (4) Positive control group 1: Taxol injection 15mg / kg dose group, administered via tail vein (IV) alone, once a week for 3 weeks, for a total of 3 administrations;

[0170] (5) Positive control group 2: Albumin-bound paclitaxel injection preparation 30mg / kg dose group, administered via tail vein (IV) alone, once a week for 3 weeks, for a total of 3 administrations;

[0171] (6) Negative control group: A negative control group was set up at the same time. The solvent was administered orally by gavage once every 3 days for 3 weeks, for a total of 7 times.

[0172] After 21 days of drug administration, the mean tumor volume in the negative control group was 1062.42 ± 107.11 mm. 3 The experimental results are shown in Figures 3 and 4: 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 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 1 (Taxotaxel injection) and positive control group 2 (Albumin-bound Taxotaxel injection) were administered via tail vein at doses of 15 mg / kg and 30 mg / kg, respectively, once a week for 3 weeks, for a total of 3 administrations. After these administrations, 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.

[0173] The experimental results show that the oral formulation of this novel paclitaxel drug has significantly better inhibitory and therapeutic effects on human ovarian cancer cells than paclitaxel; its effects are comparable to, and slightly better than, albumin-bound paclitaxel.

[0174] 3. Evaluation of the in vivo antitumor effect on a human non-small cell carcinoma NCI-H358 tumor model subcutaneously transplanted into nude mice.

[0175] Female nude mice were subcutaneously inoculated with NCI-H358 tumor cells to establish an NCI-H358 xenograft model in nude mice. The tumor volume reached an average of 145.65 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, animals were divided into 6 groups of 8 animals each using a randomized block design.

[0176] (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;

[0177] (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;

[0178] (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;

[0179] (4) Positive control group 1: Taxol injection 15mg / kg dose group, administered via tail vein (IV) alone, once a week for 3 weeks, for a total of 3 administrations;

[0180] (5) Positive control group 2: Albumin-bound paclitaxel injection preparation 30mg / kg dose group, administered via tail vein (IV) alone, once a week for 3 weeks, for a total of 3 administrations;

[0181] (6) Negative control group: A negative control group was set up at the same time. The solvent was administered orally by gavage once every 3 days for 3 weeks, for a total of 7 times.

[0182] Twenty-one days after administration, the mean tumor volume in the negative control group was 2022.26 ± 173.01 mm. 3The experimental results are shown in Figures 5 and 6: 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 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), respectively. Positive control group 1 (Taxotaxel injection) and positive control group 2 (Albumin-bound Taxotaxel injection) were administered via tail vein at doses of 15 mg / kg and 30 mg / kg, respectively, once a week for 3 weeks, for a total of 3 administrations. After these administrations, the relative tumor proliferation rates (T / C) at Day 21 were 30.50% (TGI = 69.49%, P < 0.001) and 21.36% (TGI = 78.22%, P < 0.001), respectively.

[0183] The experimental results show that the novel oral formulation of paclitaxel has significantly better inhibitory and therapeutic effects on human non-small cell cancer cells than paclitaxel and albumin-bound paclitaxel.

[0184] 4. Evaluation of the in vivo antitumor effect on the NCI-N87 human gastric cancer cell subcutaneous transplantation tumor model in nude mice.

[0185] Female nude mice were subcutaneously inoculated with NCI-N87 tumor cells to establish an NCI-N87 xenograft model. The tumor volume reached an average of 145.65 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, animals were randomly divided into 6 groups of 8 animals each.

[0186] (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;

[0187] (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;

[0188] (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;

[0189] (4) Positive control group 1: Taxol injection 15mg / kg dose group, administered via tail vein (IV) alone, once a week for 3 weeks, for a total of 3 administrations;

[0190] (5) Positive control group 2: Albumin-bound paclitaxel injection preparation 30mg / kg dose group, administered via tail vein (IV) alone, once a week for 3 weeks, for a total of 3 administrations;

[0191] (6) Negative control group: A negative control group was set up at the same time. The solvent was administered orally by gavage once every 3 days for 3 weeks, for a total of 7 times.

[0192] After 21 days of drug administration, the mean tumor volume in the negative control group was 1184.28 ± 48.32 mm. 3 The experimental results are shown in Figures 7 and 8: 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 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. Positive control group 1 (paclitaxel injection) and positive control group 2 (albumin-bound paclitaxel injection) were administered via tail vein at doses of 15 mg / kg and 30 mg / kg, respectively, once weekly for 3 weeks. After three administrations, the relative tumor proliferation rates (T / C) on Day 21 were 26.52% (TGI = 73.08%, P < 0.001) and 13.48% (TGI = 86.31%, P < 0.001), respectively. Oral paclitaxel significantly inhibited the growth of human gastric cancer cell NCI-N87 xenograft tumors in nude mice, superior to paclitaxel and albumin-bound paclitaxel.

[0193] Effect Example 3: Long-term storage stability study

[0194] The long-term stability of the paclitaxel oral formulation prepared in Example 3 of this invention was studied under room temperature (25℃±3℃) and 2-8℃ conditions. Figures 9 and 10 show the changes in paclitaxel content in the oral formulation over storage time. The results of the long-term storage study indicate that the stability of the paclitaxel oral formulation prepared by this invention exceeds one year, and its stability at room temperature exceeds five months. Specifically, when the paclitaxel content in the oral formulation is above 90%, the formulation is considered stable.

[0195] Example 4: Pharmacokinetic Study Based on Beagle Dogs

[0196] The pharmacokinetic study of paclitaxel soft capsules administered orally in beagle dogs after a single oral gavage is as follows:

[0197] Paclitaxel soft capsules were administered to beagle dogs via a single oral gavage. Beagle dogs (average weight 7.8 kg) were given paclitaxel soft capsules (16 mg / capsule) via oral gavage. Plasma samples were collected at different time points after the administration. The concentration of the test substance in the plasma of the beagle dogs after paclitaxel administration was determined by LC-MS / MS, and relevant pharmacokinetic parameters (T0) 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.

[0198] Among them, T 1 / 2 This refers to the half-life of a drug, T. max For the time to peak drug concentration, C max Peak drug concentration, AUC (0-t) The area under the curve is AUC. (0-∞) The area under the curve is denoted as .

[0199] Table 2

[0200] The results of the in vivo pharmacokinetic study in comparative dogs show that the AUC is relatively large, indicating that after using the paclitaxel soft capsules of the present invention, the exposure of paclitaxel drugs in the body is high and the duration is long.

[0201] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. An oral pharmaceutical composition for paclitaxel, characterized in that, It comprises the following components: paclitaxel, lipids, solubilizers, and glycoprotein inhibitors; wherein the lipids include a mixture of polyglycerol oleate esters, the HLB value of which is 8-9.

2. The oral paclitaxel composition as described in claim 1, characterized in that, It satisfies one or more of the following conditions: a. The polyglycerol oleate mixture comprises polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate; b. The content of the paclitaxel drug is 1.5% to 2.0%, and the percentage is the mass percentage relative to the total mass of the oral paclitaxel drug composition; c. The content of the lipid substances is 40% to 70%, and the percentage is the mass percentage relative to the total mass of the oral paclitaxel drug composition; d. The content of the glycoprotein inhibitor is 1% to 8%, and the percentage is the mass percentage relative to the total mass of the oral paclitaxel drug composition.

3. The oral paclitaxel composition as described in claim 1, characterized in that, The solubilizer is a castor oil-based solubilizer.

4. The oral paclitaxel composition as described in claim 3, 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 paclitaxel composition as described in claim 4, characterized in that, The castor oil solubilizer is polyoxyethylene ether 35 castor oil.

6. The oral paclitaxel composition as described in claim 3, characterized in that, The content of the castor oil solubilizer is 22% to 45%, and the percentage is a mass percentage relative to the total mass of the oral paclitaxel drug composition.

7. The oral paclitaxel composition as described in claim 6, characterized in that, The content of the castor oil solubilizer is 25% to 35%.

8. The oral paclitaxel composition as described in claim 1, characterized in that, It comprises the following components: 1.5%–2.0% paclitaxel, 40%–70% lipids, 22%–45% castor oil solubilizer, and 1%–8% glycoprotein inhibitor, the percentages being the mass percentage of each component relative to the total mass of the oral paclitaxel composition; wherein the castor oil solubilizer is polyoxyethylene ether 35 castor oil; the lipids comprise a mixture of polyglycerol oleate esters, the polyglycerol oleate ester mixture comprising 51%–65% polyglycerol-3 oleate and 35%–49% polyglycerol-10 mono- and di-oleate esters, the percentages being the mass percentage relative to the total mass of the polyglycerol oleate ester mixture; Alternatively, it may comprise the following components: 1.5%–2.0% of a paclitaxel-based drug, 40%–70% of lipids, 22%–45% of a castor oil solubilizer, and 1%–8% of a glycoprotein inhibitor, the percentages being the mass percentage of each component relative to the total mass of the oral paclitaxel-based drug composition; wherein the castor oil solubilizer is polyoxyethylene ether 35 castor oil; the lipids comprise a mixture of polyglycerol oleate esters, the polyglycerol oleate ester mixture comprising 51%–65% polyglycerol-3 oleate and 35%–49% polyglycerol-10 mono- and di-oleate esters, the percentages being the mass percentage relative to the total mass of the polyglycerol oleate ester mixture; and the glycoprotein inhibitor is vitamin E polyethylene glycol succinate.

9. The oral paclitaxel composition as described in claim 1, characterized in that, It satisfies one or more of the following conditions: a. The paclitaxel-based drug is either paclitaxel or docetaxel; b. The lipid substances also include one or more of the following: medium-chain triglycerides, tricaprylic acid glycerides, caprylic acid glycerides, caprylic / dicaprylic acid glycerides, propylene glycol monocaprylic acid glycerides, propylene glycol dilaurate, propylene glycol monolaurate, caprylic / caprylic acid glycerides, laurate, PEG-15-hydroxystearate, lauroyl polyoxyethylene (32) glycerides, and stearoyl polyoxyethylene (32) glycerides; c. The glycoprotein inhibitor is vitamin E polyethylene glycol succinate; d. The oral paclitaxel composition further includes a cosurfactant; e. The polyglycerol oleate mixture comprises 51%-65% polyglycerol-3 oleate and 35%-49% polyglycerol-10 mono- and di-oleate, the percentages being mass percentages relative to the total mass of the polyglycerol oleate mixture; f. 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.

10. The oral paclitaxel composition as described in claim 1, characterized in that, The oral paclitaxel composition comprises the following components: paclitaxel 1.5%–2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 40%–70%, polyoxyethylene ether 35 castor oil 22%–45%, vitamin E polyethylene glycol 1000 succinate 1%–8%, and ethylene glycol monoethyl ether 5%–13%, where the percentages are the mass percentages of each component relative to the total mass of the oral paclitaxel composition. Alternatively, the oral paclitaxel composition comprises the following components: paclitaxel 1.5%–2.0%, polyglycerol-3 oleate and polyglycerol-10 mono- and dioleate 40%–70%, polyoxyethylene ether 35 castor oil 22%–45%, vitamin E polyethylene glycol 1000 succinate 1%–8%, and propylene glycol 5%–10%, where the percentages are the mass percentages of each component relative to the total mass of the oral paclitaxel composition.

11. An oral formulation of a paclitaxel drug, characterized in that, It includes oral pharmaceutical compositions of paclitaxel as described in any one of claims 1-10.

12. The oral formulation of a paclitaxel drug as described in claim 11, characterized in that, The oral formulation of the paclitaxel drug is a liquid-filled capsule.

13. A method for preparing an oral pharmaceutical composition of paclitaxel as described in any one of claims 1-10, characterized in that, It includes heating and mixing the components; the heating temperature is 35°C to 60°C.

14. The use of an oral paclitaxel composition as described in any one of claims 1-10 in the preparation of a medicament for treating cancer.

15. The application as described in claim 14, characterized in that, The cancers mentioned are breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, lung cancer, head and neck tumors, esophageal cancer, liver cancer, stomach cancer, pancreatic cancer, rectal cancer, or soft tissue sarcoma.

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