Docetaxel oral self-microemulsion composition and preparation process thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a docetaxel oral self-microemulsion composition and a preparation process thereof. The docetaxel oral self-microemulsion composition is prepared from docetaxel, an oil phase, a surfactant, a cosurfactant, a stabilizer and an antioxidant, the oil phase is caprylic / capric acid mono / diglyceride, medium chain triglyceride, caprylic acid propylene glycol ester or lauric acid propylene glycol ester. The docetaxel oral self-microemulsion composition provided by the invention has relatively high drug loading capacity, good physical and chemical stability and relatively high bioavailability, and is more suitable for clinical medication.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to an oral self - microemulsion composition of docetaxel and a preparation process thereof. Background Art

[0002] Docetaxel is a white crystalline powder with a melting point of 186°C - 192°C. It is insoluble in water and soluble in organic solvents such as ethanol, acetone, ether, and benzene.

[0003] Clinically, docetaxel has been approved for the treatment of various cancers such as breast cancer, gastric cancer, non - small cell cancer, head and neck cancer, prostate cancer, and uterine cancer.

[0004] The only dosage form of docetaxel drug approved for marketing worldwide is an injection. It has a two - bottle packaging structure. Before use, the concentrated Tween 80 solution of docetaxel needs to be diluted with a special solvent (13% ethanol aqueous solution). After checking for clarity, it is diluted again in normal saline or 5% glucose solution and then administered by intravenous drip.

[0005] During clinical use, the operation process of docetaxel injection is very cumbersome. The main reason is that the product has poor stability and needs to be used within a few hours after dilution, otherwise drug crystallization will occur. At the same time, docetaxel injection is also extremely likely to cause bone marrow suppression, neurotoxic reactions, cardiotoxic reactions, joint or muscle pain, and allergic reactions, etc. It is necessary to orally take glucocorticoids (such as dexamethasone) one or two days before use and continue to take them for desensitization treatment to prevent and reduce the occurrence of toxic and side reactions.

[0006] In view of the inconvenience in clinical use and serious toxic and side reactions of docetaxel injection, the development of new dosage forms of docetaxel (taxane drugs) has been a hot research direction in recent years. Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide an oral self - microemulsion composition of docetaxel and a preparation process thereof, and the prepared oral self - microemulsion composition of docetaxel has a high drug loading, stability, and bioavailability.

[0008] To achieve the above object, the present invention provides an oral self - microemulsion composition of docetaxel, comprising:

[0009] Docetaxel, an oil phase, a surfactant, a co - surfactant, a stabilizer, and an antioxidant;

[0010] The oil phase is caprylic / capric mono - and diglycerides, medium - chain triglycerides, propylene glycol caprylate, or propylene glycol laurate.

[0011] In the development of docetaxel self - microemulsion, it was found that due to the presence of five double bonds in the chemical molecular structure of docetaxel, it is extremely unstable and prone to decomposition to produce degradation products and other inherent properties. When preparing the self - microemulsion dosage form, there are problems such as very low drug loading, which cannot meet the clinical needs; poor physical stability, and the drug is extremely easy to precipitate; poor chemical stability, and the degradation products (related substances) increase rapidly. Through a large number of prescription compatibilities, the present invention uses caprylic / capric mono - and diglycerides, medium - chain triglycerides, propylene glycol caprylate and propylene glycol laurate as the oil phase, and preferably propylene glycol laurate or caprylic / capric mono - and diglycerides as the oil phase, and obtains a stable docetaxel oral self - microemulsion composition, which solves the above problems.

[0012] The mass ratio of the oil phase to the docetaxel is preferably 5:1 to 15:1, more preferably 10:1 to 15:1. In some specific embodiments of the present invention, the mass ratio of the oil phase to the docetaxel is 5:1, 10:1, 15:1, or a range value with the above values as the upper or lower limit.

[0013] Preferably, the above - mentioned docetaxel oral self - microemulsion composition, by weight, comprises:

[0014] Docetaxel 0.05 - 0.5 parts, oil phase 1 - 4 parts, surfactant 0.5 - 6 parts, co - surfactant 0.5 - 3 parts, stabilizer 0.1 - 0.5 parts and antioxidant 0.01 - 0.3 parts.

[0015] Preferably, the above - mentioned docetaxel oral self - microemulsion composition, by weight, comprises:

[0016] Docetaxel 0.1 - 0.5 parts, oil phase 1 - 3 parts, surfactant 1 - 5 parts, co - surfactant 1 - 2 parts, stabilizer 0.1 - 0.5 parts and antioxidant 0.01 - 0.1 parts.

[0017] Preferably, the surfactant is one or both of polysorbate 80 and polyoxyethylene 40 hydrogenated castor oil.

[0018] The surfactant is preferably a combination of polysorbate 80 and polyoxyethylene 40 hydrogenated castor oil. The mass ratio of polysorbate 80 to the polyoxyethylene 40 hydrogenated castor oil is preferably 1:1 to 1:4, more preferably 1:1 to 1:3, and most preferably 1:3.

[0019] The above - mentioned surfactant can further form a homogeneous liquid - phase system with water for the mixture of docetaxel and the oil phase, which is conducive to the absorption and utilization of the drug in the body. The present invention selects the mixture of polysorbate 80 and polyoxyethylene 40 hydrogenated castor oil as the surfactant, which can reduce the particle size of the microemulsion droplets after emulsification, increase the physical stability of the emulsified sample, and the stability time can be increased from 4 hours to 8 hours.

[0020] The co-surfactant includes one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, ethanol, anhydrous ethanol, propylene glycol, diethylene glycol monoethyl ether, etc.;

[0021] Preferably, the co-surfactant comprises anhydrous ethanol and polyethylene glycol, and the polyethylene glycol is preferably polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600 or polyethylene glycol 800.

[0022] The mass ratio of the anhydrous ethanol to the polyethylene glycol is preferably 1:2 to 1:5, specifically 1:2, 1:3, 1:4, 1:5, or a range value with the above values ​​as the upper or lower limits, and most preferably 1:3.

[0023] The addition of the co-surfactant solves the problem of drug precipitation occurring within 2 hours after emulsification of the self-microemulsion preparation formed by docetaxel, oil phase and surfactant, thereby improving the stability of the drug in the body.

[0024] The polarity of the co-surfactant has a crucial influence on the physical stability of the docetaxel oral self-microemulsification composition after emulsification. When diethylene glycol monoethyl ether, ethanol or anhydrous ethanol is used as a co-surfactant, due to the strong binding ability of the above components with water, when purified water is used for emulsification, the above three components are quickly separated from the self-microemulsion droplets, causing leakage of docetaxel.

[0025] The present invention preferably uses anhydrous ethanol and the polyethylene glycol combination as a co-surfactant, and the microemulsion droplets formed after emulsification have high stability and good solubility for docetaxel.

[0026] The stabilizer includes one or more of povidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose and urea.

[0027] Preferably, the stabilizer is povidone.

[0028] The povidone is preferably povidone K25 or povidone K30.

[0029] The antioxidant includes one or more of butylated hydroxytoluene, butylated hydroxyanisole, diethylaminetetraacetic acid, citric acid, citric acid, tartaric acid, succinic acid, gallic acid, sodium sulfite, sodium bisulfite, vitamin E, etc.

[0030] Preferably, the antioxidant includes one or both of citric acid and vitamin E, more preferably citric acid.

[0031] In the present invention, the docetaxel oral self-microemulsification composition may further include a pharmacokinetic enhancer.

[0032] The pharmacokinetic enhancer may be one or more of clarithromycin salt, telithromycin, cyclosporine, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir sulfate, nelfinavir mesylate, saquinavir, etc.;

[0033] The pharmacokinetic enhancer preferably includes one or two of cyclosporin A and ritonavir; more preferably ritonavir.

[0034] The mass ratio of the pharmacokinetic enhancer to the docetaxel is preferably 4-5:0.5-2, further preferably 4-5:1-2, and still further preferably 4-5:2.

[0035] The present invention provides a self-microemulsion for docetaxel and ritonavir. Through experiments, it is found that when the weight ratio of ritonavir to docetaxel is 4-5:0.5-2, a therapeutic effect comparable to that of intravenous injection can be obtained, and a series of adverse reactions such as allergic reactions caused by the injection dosage form are greatly reduced.

[0036] Preferably, the particle size of the emulsified docetaxel oral self-microemulsion composition is 54-77 nm.

[0037] The present invention also provides a preparation method of the above-mentioned docetaxel oral self-microemulsion composition, which includes the following steps:

[0038] Mix the oil phase and the surfactant to obtain a first solution, disperse the stabilizer evenly with a co-surfactant other than absolute ethanol to obtain a second solution, and mix the first solution and the second solution to obtain a premix 1;

[0039] Mix the antioxidant, absolute ethanol, and docetaxel to obtain a premix 2;

[0040] Mix the above-mentioned premix 1 and the above-mentioned premix 2 to obtain a docetaxel oral self-microemulsion composition.

[0041] The pharmacokinetic enhancer can be added during the preparation of the premix 2.

[0042] Preferably, the preparation process includes the following steps:

[0043] Pre-disperse the stabilizer in a co-surfactant other than absolute ethanol, add the oil phase and the surfactant to obtain a premix 1; add the antioxidant, the pharmacokinetic enhancer, and docetaxel to absolute ethanol to obtain a premix 2; mix the premix 1 and the premix 2 to obtain a homogeneous oily liquid.

[0044] In some specific embodiments of the present invention, the preparation process includes the following steps:

[0045] Step (1): Take an oil phase and a surfactant, mix them to dissolve completely to obtain a first solution; take a stabilizer, disperse it evenly with a co-surfactant other than absolute ethanol, and then add it to the above first solution, mix until clear and transparent to obtain a premix 1.

[0046] Step (2): Dissolve an antioxidant in absolute ethanol, add a pharmacokinetic enhancer, after dissolution, add the active ingredient docetaxel, mix to dissolve completely to obtain a premix 2.

[0047] Step (3): Transfer the above premix 2 to the above premix 1, mix evenly to obtain a docetaxel self-microemulsion composition.

[0048] The present invention has no special limitation on the above mixing method, and it can be a mixing method well-known to those skilled in the art, including but not limited to vortex, ultrasound or stirring, or the combination of any two or three methods.

[0049] The docetaxel self-microemulsion composition provided by the present invention can be further prepared into various dosage forms, including but not limited to oral solution, tablets, capsules, etc. The capsules can be soft capsules or hard capsules. Specifically:

[0050] 1. According to the clinical dosage, it is dispensed into glass bottles to make an oral solution.

[0051] 2. Solid powder excipients such as povidone and / or lactose and / or colloidal silicon dioxide can be added to prepare a solid self-microemulsion, and then prepared into tablets, capsules and other preparations.

[0052] 3. It can be pressed into a soft capsule shell to prepare a soft capsule.

[0053] 4. It is filled into a hard capsule to make a liquid-filled hard capsule.

[0054] 5. Or filled into other liquid dosage forms suitable for oral administration.

[0055] The hard capsules can be made of gelatin, hypromellose or enteric-coated hard capsules, etc.

[0056] The present invention confirms through intragastric administration animal experiments on rats that the above docetaxel oral self-microemulsion composition has a very high absolute bioavailability; through pharmacodynamic animal experiments on mice, it is confirmed that it has a high inhibitory effect on breast cancer tumors and a high effective rate; and the onset concentration of this composition is low, the blood drug concentration lasts for a long time, and the toxic and side effects are small, and there is no need to use glucocorticoids for desensitization treatment.

[0057] Based on this, the present invention provides the application of the above docetaxel oral self-microemulsion composition in the preparation of anti-tumor drugs.

[0058] Preferably, the above-mentioned tumors are breast cancer, gastric cancer, non-small cell carcinoma, head and neck cancer, prostate cancer, uterine cancer, etc., and more preferably breast cancer.

[0059] Compared with the prior art, the present invention provides a docetaxel oral self-microemulsion composition, comprising: docetaxel, an oil phase, a surfactant, a co-surfactant, a stabilizer and an antioxidant; the oil phase is composed of monocaprylate / dicaprylate glycerol, medium-chain triglycerides, propylene glycol caprylate and propylene glycol laurate as the oil phase, and preferably propylene glycol laurate or monocaprylate / dicaprylate glycerol. The docetaxel oral self-microemulsion composition provided by the present invention has a high drug loading capacity, good physical and chemical stability, and high bioavailability, and is more suitable for clinical use. Detailed implementation manners

[0060] To further illustrate the present invention, the following will be described in detail with reference to examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention.

[0061] For all raw materials of the present invention, there is no special limitation on their sources, and they can be purchased on the market or prepared according to the conventional methods well-known to those skilled in the art.

[0062] For the convenience of description, the names of the various raw and auxiliary materials mentioned in the examples are expressed by the abbreviations in Table 1.

[0063] Table 1: Abbreviations of each raw and auxiliary material

[0064] Material Name Material Abbreviation Docetaxel DCT Ritonavir RTN Propylene glycol monocaprylate (also known as monocaprylic acid propylene glycol ester) PGMC Propylene glycol monolaurate (also known as propylene glycol monododecanoate) PGML (also known as Lauroglycol 90) Caprylic / capric mono- and diglycerides GMDC (also known as Labrafac MC60) Medium-chain triglycerides MCT Polyoxyethylene (40) hydrogenated castor oil RH40 Polyoxyethylene (35) castor oil EL35 Polysorbate 80 Tween 80 Polyethylene glycol 600 PEG600 Polyvinylpyrrolidone K30 PVP K30 Diethylene glycol monoethyl ether DGME Citric acid CA

[0065] Example 1: Preliminary screening of different oil phases

[0066] 1. Select the oily excipients as follows: propylene glycol caprylate, propylene glycol caprylate / caprate, propylene glycol laurate, monocaprylate / dicaprylate glycerol, isopropyl myristate, isopropyl palmitate, glycerol mono-γ-linolenate, glycerol monooleate, medium-chain triglycerides, soybean oil, olive oil, sesame oil, peanut oil, corn oil.

[0067] 2. Preparation process: Disperse docetaxel in the above-mentioned oily excipients respectively.

[0068] 3. Solubility determination: Shake at a frequency of 180 rpm in a constant temperature oscillator at 25°C for 24 hours, centrifuge, take the supernatant, and determine the content of docetaxel. The specific content determination method is as follows:

[0069] Preparation of test samples: Take an appropriate amount of each test sample, place it in a 25 ml volumetric flask, dissolve it with a suitable solvent, and then dilute it to the mark with the mobile phase, and shake well;

[0070] Preparation of reference substance: Take an appropriate amount of docetaxel reference substance and prepare a solution with a concentration of 0.2 mg / ml using a diluent.

[0071] Chromatographic conditions: Use octadecylsilane-bonded silica gel as the filler (Waters C18, 150×4.6 mm, 3.5 μm or a chromatographic column with equivalent efficiency); use water-acetonitrile (50:50) as the mobile phase; the flow rate is 1.2 ml / min; the detection wavelength is 232 nm; the column temperature is 45 °C; the injection tray temperature is 4 °C.

[0072] Detection method: Precisely measure 20 μl of the test solution and the reference solution respectively, inject them into the liquid chromatograph, and record the chromatogram. Calculate the content by the external standard method based on the peak area.

[0073] 4. The results are shown in Table 2:

[0074] Table 2: Screening of oily excipients

[0075] Name Solubility of docetaxel (mg / ml) Caprylic / capric mono- and diglycerides 88.41 Medium-chain triglycerides 45.795 Propylene glycol monocaprylate 45.239 Propylene glycol monolaurate 40.120 Propylene glycol dicaprylate / dicaprate (propylene glycol dioctanoate / dicaprate) 26.467 Isopropyl myristate 7.007 Monoolein 6.371 Isopropyl palmitate 5.146 Monoolein 3.921 Soybean oil (for injection) 1.886 Olive oil 1.056 Sesame oil 0.734 Peanut oil 2.043 Corn oil 4.286

[0076] The results in Table 2 show that when the oily excipients are caprylic / capric mono- and diglycerides, medium-chain triglycerides, propylene glycol caprylate, and propylene glycol laurate, the solubility of docetaxel is relatively good (higher than 40 mg / ml).

[0077] Conclusion: Caprylic / capric mono- and diglycerides, medium-chain triglycerides, propylene glycol caprylate, and propylene glycol laurate can be selected as the oil phase among the four oily excipients.

[0078] Example 2: Investigation of adding different surfactants

[0079] (I). Mix docetaxel and surfactants

[0080] 1. Selection of surfactants: Select polyglyceryl caprylate / caprate, Tween 80, polyoxyethylene 40 hydrogenated castor oil, and polyoxyethylene 35 castor oil as surfactants respectively.

[0081] 2. Preparation method: Disperse docetaxel in surfactants respectively.

[0082] 3. Solubility detection: The same as in Example 1.

[0083] 4. The results are shown in Table 3:

[0084] Table 3: Screening of surfactants

[0085] Name Docetaxel solubility (mg / ml) Caprylic / capric polyethylene glycol glycerides 67.917 Tween 80 4.397 Polyoxyethylene 40 hydrogenated castor oil 3.024 Polyoxyethylene 35 castor oil 2.421

[0086] The results in Table 3 show that compared with other surfactants, polyglyceryl caprylate / caprate has a better solubility ability for docetaxel.

[0087] (II), Compound of Docetaxel with Oil Phase and Surfactant

[0088] 1. To further investigate the effect of the surfactant, the above surfactant was compounded with docetaxel and the oil phase screened in Example 1, and its stability (whether it layers) was observed.

[0089] 2. It was found that:

[0090] Caprylic / Capric PEG Glycerides has limited emulsifying ability. After being mixed with the oil phase, it quickly layers (the higher the proportion of the oily component, the more obvious the layering phenomenon), and it is difficult to form a homogeneous system;

[0091] After mixing Tween 80, Polyoxyethylene 40 Hydrogenated Castor Oil or Polyoxyethylene 35 Castor Oil with the oil phase, no layering phenomenon occurred after long-term placement.

[0092] 3. Conclusion: Compounding Tween 80, Polyoxyethylene 40 Hydrogenated Castor Oil or Polyoxyethylene 35 Castor Oil with the oil phase has a better effect.

[0093] Example 3: Investigation of Adding Different Co-surfactants

[0094] 1. Co-surfactants: Diethylene Glycol Monoethyl Ether, Ethanol, Absolute Ethanol, Polyethylene Glycol 200, Polyethylene Glycol 400, Polyethylene Glycol 600, Propylene Glycol.

[0095] 2. Preparation method: Docetaxel was separately dispersed in the co-surfactants.

[0096] 3. Solubility detection: The same as in Example 1.

[0097] 4. Results: See Table 4

[0098] Table 4: Screening of Co-surfactants

[0099] Name Docetaxel solubility (mg / ml) Diethylene glycol monoethyl ether 201.341 Ethanol 138.523 Absolute ethanol 117.106 Polyethylene glycol 200 44.524 Polyethylene glycol 400 35.042 Polyethylene glycol 600 21.43 Propylene glycol 5.834

[0100] The results in Table 4 show that Diethylene Glycol Monoethyl Ether, Ethanol and Absolute Ethanol have a strong solubilizing effect on docetaxel.

[0101] Example 4: Docetaxel Self-microemulsion Composition Containing Different Oil Phases and Dosages

[0102] 1. Composition: See Table 5;

[0103] Table 5: Examples of Different Oil Phases and Dosages and Particle Sizes after Emulsification

[0104]

[0105] 2. Preparation method:

[0106] Step (1): Take the oil phase and surfactants (Tween 80 and RH40), vortex or stir for 15 min to completely dissolve them; add the stabilizer (Povidone K30) dispersed uniformly with the co-surfactant (PEG600), vortex or stir for 30 min until it becomes clear and transparent to obtain Solution 1.

[0107] Step (2): Dissolve citric acid in absolute ethanol, add the pharmacokinetics enhancer (ritonavir), vortex and / or ultrasonicate, or stir for 15 min to dissolve it; add docetaxel, and completely dissolve it by vortexing and / or ultrasonication, or stirring for 30 min to obtain Solution 2.

[0108] Step (3): Transfer Solution 2 to Solution 1, stir for 30 min to make it uniform to obtain the self-microemulsion composition.

[0109] Experimental Example 1: Appearance and self-microemulsion particle size detection

[0110] 1. Sample: The sample provided in Example 4.

[0111] 2. Observation indicators:

[0112] 2.1 Physical stability

[0113] Add 5 ml (50-fold amount) of pH 1.2 medium, pH 6.8 medium, and purified water to each formulated sample, emulsify uniformly and then let it stand for 4 h, and observe the properties 4 h after emulsification.

[0114] 2.2 Detection index - particle size detection:

[0115] Detect the particle size with a Malvern dynamic light scattering particle size analyzer (model Zetasizes Advance), and the parameters are as follows: the sample cell temperature is set at 25 °C, the sample classification is set as Polytyrene, the dilution solvent is purified water, the equilibration time is 60 S, and the number of measurements is 3 times.

[0116] Take an appropriate amount of the self-microemulsion composition, emulsify it uniformly with purified water, pour it into a plastic colorimetric cell for detection, and place it in the sample cell of the instrument for determination.

[0117] 3. Results and analysis:

[0118] 3.1 Investigation of the oil phase

[0119] 3.1.1 Results of physical stability: For Formulations 1-1 to 1-4, clear yellowish oily liquids can be obtained. Among them, Formulation 1-4 is more viscous and has slightly poorer fluidity.

[0120] After emulsification with purified water, no drug precipitation is observed within 4 h. For Formulations 1-1 to 1-3, clear and transparent liquids can be formed, while the solution formed by Formulation 1-4 is white.

[0121] 3.1.2 Particle size detection results: see Table 5

[0122] The particle sizes of Formulation 1-1 to Formulation 1-4 are 44 nm, 70 nm, 62 nm, and 108 nm respectively.

[0123] 3.1.3 Result analysis:

[0124] For the screening of the particle size of self-microemulsion, it can spontaneously form a particle size less than 100 nm under slight agitation at room temperature. Therefore, during the experiment, a particle size less than 100 nm was selected as the selection criterion for excipients.

[0125] The particle size of medium-chain triglyceride is 108 nm, and the particle sizes of caprylic / capric monoglyceride, propylene glycol caprylate, and propylene glycol laurate are 70 nm, 44 nm, and 62 nm respectively.

[0126] The formulation containing propylene glycol caprylate has a relatively small particle size (44 nm) after emulsification with purified water, indicating that it has a large specific surface area and is beneficial to the penetration and absorption of drugs. However, the dosage of propylene glycol caprylate in FDA-approved oral drugs is 24 mg / day, and its dosage in this formulation greatly exceeds this amount, which may bring unnecessary risks.

[0127] The dosages of propylene glycol laurate and caprylic / capric monoglyceride in approved oral drugs are 2115 mg / day and 13770 mg / d respectively, which can fully meet the requirements of clinical drug use, and the obtained particle sizes are also relatively small. Therefore, propylene glycol laurate or caprylic / capric monoglyceride is preferably selected as the oil phase.

[0128] 3.2 Investigation on the dosage of propylene glycol laurate as the oil phase

[0129] 3.2.1 Physical stability:

[0130] When the dosage of propylene glycol laurate is 1.0 g to 4.0 g, a clear and transparent liquid can be formed.

[0131] After emulsification with purified water, when the dosage of propylene glycol laurate is 1.0 g to 3.0 g, a stable clear and transparent microemulsion can be formed. When the dosage is increased to 4.0 g, adding purified water will form a small amount of unemulsified oil droplets.

[0132] 3.2.2 Particle size: see Table 5. The particle sizes after emulsification of Formulation 1-2, 1-4, 1-5, and 1-6 are 62 nm, 60 nm, 65 nm, and 77 nm respectively.

[0133] 3.2.3 Result analysis: When the dosage range of propylene glycol laurate to docetaxel is 1.0 - 3.0:0.2 (converted to 5 - 15:1), the particle size meets the requirements (≤100 nm), and no oil droplets will appear.

[0134] Example 5: Docetaxel self - microemulsion composition with different surfactants and dosages

[0135] When using Tween 80, RH40, and EL35 separately as surfactants, according to the formulation in Table 6, a self - microemulsion composition with stable quality cannot be obtained. Among them, when using Tween 80 alone, strip - shaped gel micelles are easily formed during emulsification with purified water, seriously affecting the size of the microemulsion particles; while when using RH40 and EL35 alone, no gel micelles are formed, but the color of the solution turns white after emulsification and the particle size is relatively large.

[0136] Therefore, considering the combination of surfactants.

[0137] 1. Prescription and composition: See Table 6

[0138] Table 6: Examples of surfactant compounding and dosages and particle size results after emulsification

[0139]

[0140] (Note: Prescription 2 - 1 is the same as Prescription 1 - 2)

[0141] 2. Preparation method: The same as Example 4.

[0142] Experimental Example 2: Appearance and self - microemulsion particle size detection

[0143] 1. Sample: The sample provided in Example 5.

[0144] 2. Detection method and index: The particle size detection is the same as in Example 4.

[0145] Physical stability: In hours, visually observe the properties of the microemulsion and whether there is sediment deposition. If sedimentation occurs before 4 h, it is considered that the system is not stable enough; if sedimentation occurs after 4 h, it is considered that the system has good stability.

[0146] 3. Results:

[0147] 3.1 Surfactant compounding investigation

[0148] 3.1.1 Physical stability results: Prescriptions 2 - 1, 2 - 2, and 2 - 3 can all obtain a clear yellowish - brown oily liquid. Among them, Prescription 2 - 3 is relatively viscous and has slightly poor fluidity.

[0149] After emulsification with purified water, from Prescription 2 - 1 to Prescription 2 - 3, clear and transparent liquids can be formed, and no drug precipitation is observed within 8 hours.

[0150] 3.1.2 Particle size detection results are shown in Table 6. The particle sizes of Prescription 2-1 to Prescription 2-3 are 44 nm, 54 nm, and 118 nm respectively.

[0151] 3.1.3 Result analysis: From the test results, it can be seen that the combined effects of polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil with Tween 80 are comparable.

[0152] After querying the FDA IID database, it is known that the maximum daily exposure of polyoxyl 35 castor oil is 1170 mg, while the maximum daily exposure of polyoxyl 40 hydrogenated castor oil is 3319 mg. It has a larger dosage space and a smaller safety risk. Therefore, polyoxyl 40 hydrogenated castor oil and Tween 80 are selected for further investigation in combination.

[0153] 3.2 Mass ratio of Tween 80 and RH40

[0154] 3.2.2 Physical stability results: When the mass ratio of Tween 80 and RH40 is in the range of 1:0.5 to 4, a clear and transparent self-microemulsion composition system can be formed.

[0155] Using a mixed surfactant can reduce the particle size of the microemulsion droplets after emulsification and increase the physical stability of the emulsified sample (from 4 hours of stability in Example 4 to 8 hours of stability).

[0156] 3.2.2 Particle size detection results: See Table 6.

[0157] The particle sizes of Prescription 2-4 to Prescription 2-7 are 76, 68, 72, and 63 nm respectively.

[0158] 3.2.3 Results show that using a mixed surfactant can improve the physical stability of the drug. When compounded, when the ratio of the dosages of Tween 80 and RH40 is greater than 1:1 (Prescription 2-4), the particle size after emulsification tends to increase. Therefore, finally, a surfactant ratio of 1:1 - 4 has a good effect.

[0159] Example 6: Docetaxel self-microemulsion composition with different co-surfactants

[0160] 1. Composition: See Tables 7-1 and 7-2.

[0161] Table 7-1: Docetaxel self-microemulsion composition with different co-surfactants and ratios

[0162]

[0163]

[0164] Table 7-2: Docetaxel self-microemulsion composition with different co-surfactants and ratios

[0165]

[0166] (Note: Prescriptions 3 - 8 are the same as Prescriptions 1 - 2)

[0167] 2. Preparation method: The same as Example 4.

[0168] Experimental Example 3: Appearance and particle size detection of self - microemulsion

[0169] 1. Sample: The sample provided in Example 6.

[0170] 2. Detection methods and indicators:

[0171] 2.1 Particle size detection is the same as Experimental Example 1.

[0172] 2.2 Physical stability:

[0173] Emulsify with 50 - fold volume of self - microemulsion composition in pH 1.2, pH 6.8 or purified water respectively, and observe the color and emulsion droplets to see if it is a clear and transparent liquid.

[0174] Meanwhile, observe the properties of the microemulsion with the naked eye in hours to see if there is sediment deposition. If sedimentation occurs before 4 hours, it is considered that the system is not stable enough; if sedimentation occurs after 4 hours, it is considered that the system has good stability.

[0175] 3. Results

[0176] 3.1 Using co - surfactant alone

[0177] 3.1.1 Results of physical stability: For Prescriptions 3 - 1 to 3 - 3, clear and oily liquids with light yellow color can be obtained, and they have good fluidity. However, the dissolution ability of Docetaxel in Prescription 3 - 4 is limited and a clear liquid cannot be formed.

[0178] After emulsifying with pH 1.2, pH 6.8 and purified water respectively, clear and transparent liquids can be formed, but the physical stabilities of Prescriptions 3 - 1 to 3 - 3 are all poor, and precipitates appear in 2 hours. So the particle size was not detected.

[0179] 3.1.2 Conclusion: Using co - surfactant alone has poor stability.

[0180] 3.2 Compound formulation

[0181] 3.2.1 Physical stability results: For Formulations 3-5 to 3-8, clear yellowish oily liquids with good fluidity were obtained. After emulsification with pH 1.2, pH 6.8, and purified water respectively, except for Formulation 3-7 which showed precipitation around 3 hours, Formulations 3-5, 3-6, and 3-8 could obtain microemulsion solutions that were stable for 4 hours. It indicates that when the mass ratio of absolute ethanol to PEG600 is 1:2 - 5 (i.e., 0.3 - 0.75:1.5 in Table 7-1), self-microemulsions with good physical stability can be obtained.

[0182] Formulations 3-9 and 3-10 could both form clear and transparent liquids, and no drug precipitation occurred after 4 hours of emulsification. It indicates that when the mass ratio of absolute ethanol to PEG600 is 1:2 - 5 (i.e., 0.5:1.0 - 2.5 in Table 7-2), self-microemulsions with good physical stability can be obtained.

[0183] 3.2.2 Particle size detection results: See Table 7-1 and Table 7-2

[0184] The particle sizes of Formulations 3-5, 3-6, and 3-8 were 50 nm, 49 nm, and 62 nm respectively.

[0185] Precipitates appeared after emulsification of Formulation 3-7, and particle size detection was not carried out anymore.

[0186] The particle sizes of Formulations 3-9 and 3-10 were 63 nm and 66 nm respectively.

[0187] 3.2.3 Conclusion: Selecting the combination of absolute ethanol and polyethylene glycol 600 (with a dosage ratio of 1:2 - 5) can not only meet the drug loading requirements but also meet the physical stability requirements of the self-microemulsion composition after emulsification, and good effects can be obtained.

[0188] Example 7: Docetaxel self-microemulsion composition with different stabilizers

[0189] 1. Composition: See Table 8

[0190] Table 8: Docetaxel self-microemulsion compositions with different stabilizers

[0191]

[0192]

[0193] (Note: Formulation 4-4 is the same as Formulation 1-2)

[0194] 2. Preparation method: The same as Example 4.

[0195] Experimental Example 4: Appearance and self-microemulsion particle size detection

[0196] 1. Samples: Samples provided in Example 7.

[0197] 2. Detection methods and indicators:

[0198] The particle size and stability were investigated in the same way as in Experimental Example 2.

[0199] 3. Results:

[0200] 3.1 Stability results: For Formulations 4-1 to 4-4, clear light yellow oily liquids with good fluidity were obtained. However, Formulation 4-5 could not form a clear solution, presumably due to the ineffective dissolution of PVP K90. The emulsions of Formulations 4-1 to 4-4 with purified water could all form clear and transparent liquids, but only Formulations 4-3 and 4-4 were stable within 4 hours.

[0201] 3.2 Particle size detection results: See Table 8. The particle sizes were 60 and 62 nm.

[0202] 4. Conclusion: The selection of polyvinylpyrrolidone K25 and polyvinylpyrrolidone K30 as stabilizers can both achieve good results.

[0203] Example 8: Docetaxel self-microemulsion compositions with different antioxidants

[0204] 1. Composition: See Table 9.

[0205] Table 9: Docetaxel self-microemulsion compositions with different antioxidants

[0206]

[0207]

[0208] (Note: Formulation 5-1 is the same as Formulation 1-2)

[0209] 2. Preparation method: The same as in Example 4.

[0210] Experimental Example 5: Appearance and self-microemulsion particle size detection

[0211] 1. Samples: The samples provided in Example 8.

[0212] 2. Detection methods and indicators:

[0213] 2.1 Stability investigation: The same as in Example 4.

[0214] 2.2 Particle size, the same as in Example 4.

[0215] 2.3 Investigation of related substances at 60 °C:

[0216] Four groups of self-microemulsion composition samples were stored at 60 °C, and the increase in related substances was measured to confirm the protective ability of different antioxidants on docetaxel.

[0217] 3. Results:

[0218] 3.1 Results of stability investigation: For Formulations 5-1 to 5-4, clear light yellow oily liquids with good fluidity were obtained. After emulsification with purified water, clear and transparent liquids were formed and were stable within 4 hours.

[0219] 3.2 Results of particle size detection: See Table 9. The particle size was 58 - 64 nm.

[0220] 3.3 Conclusion: From the results of related substances at 60 °C, all four antioxidants can provide good protection for docetaxel.

[0221] Butylated hydroxytoluene and butylated hydroxyanisole have large absorption peaks under the chromatographic conditions of related substances, which will interfere with the determination of related substances in the product; vitamin E is an oil solution with high viscosity and requires a large amount to achieve the antioxidant effect; while citric acid does not interfere with the product determination and can achieve the ideal antioxidant effect with a small amount. Considering the industrial transformation, citric acid is preferably used as the antioxidant.

[0222] Example 9: Docetaxel self-microemulsion composition with different drug loadings

[0223] 1. Composition: See Table 10.

[0224] Table 10: Docetaxel self-microemulsion composition with different drug loadings

[0225]

[0226]

[0227] (Note: Formulation 6-5 is the same as Formulation 1-2)

[0228] 2. Preparation method: The same as that in Example 4.

[0229] Example 10: Preparation

[0230] The self-microemulsion compositions described in Examples 4 to 9 can be prepared into the following preparations:

[0231] 1. According to the clinical dosage, it is dispensed into glass bottles to make an oral solution.

[0232] 2. Solid powder excipients such as povidone and / or lactose and / or colloidal silicon dioxide can be added to prepare a solid self-microemulsion, and tablets, capsules and other preparations can be prepared.

[0233] 3. It can be pressed into soft capsule shells to prepare soft capsules.

[0234] 4. It is filled into hard capsules to make liquid-filled hard capsules.

[0235] The hard capsules described above can be made of gelatin, hypromellose, or enteric-coated hard capsules;

[0236] 5. Or filled in other liquid dosage forms suitable for the oral route.

[0237] Experimental Example 6: Particle size detection of self-microemulsions

[0238] 1. Samples: The samples provided in Example 9; at the same time, self-emulsifying samples were prepared according to the prescription 5 of the patent of Kunming Jida Pharmaceutical (application number 201811463623.7, publication number CN109589305A).

[0239] 2. Detection method and indicators: The particle size detection was the same as in Example 4.

[0240] 3. Particle size detection results: See Table 10.

[0241] After emulsification with purified water, drugs will precipitate from Prescription 6-3, and particle size detection will no longer be carried out.

[0242] Except for Prescription 6-3, the particle sizes formed after emulsification of Prescriptions 6-1 to 6-9 with purified water are all small (54 - 77 nm); while the particle size of the prescription in the patent of Kunming Jida is 124 nm.

[0243] 4. Conclusion: For the saturated drug loading of docetaxel, it can reach 110 mg / ml, but drug precipitation will occur after emulsification. When the drug loading of docetaxel is reduced to 50 mg / ml, a stable self-microemulsion sample can be prepared after emulsification.

[0244] The particle sizes of the prescriptions shown in Table 10 (except Prescription 6-3) are all smaller (54 - 77 nm) compared with the particle size (124 nm) of the prescription included in the patent of Kunming Jida Pharmaceutical, indicating that there may be a better absorption effect.

[0245] Adding an appropriate amount of the pharmacokinetic enhancer ritonavir to the docetaxel self-microemulsion has little effect on the particle size of the product.

[0246] Experimental Example 7: Stability of docetaxel self-microemulsion composition after emulsification

[0247] 1. Samples: Example 9.

[0248] 2. Detection method:

[0249] Take three portions of 100 mg each of the docetaxel self-microemulsion prepared from the samples and place them in 10 ml centrifuge tubes respectively.

[0250] Add 5 ml (50-fold amount) of pH 1.2 medium, pH 6.8 medium, and purified water to each prescription sample, emulsify evenly, let stand for 4 h, observe the properties after 4 h of emulsification, and determine the content before and 4 h after emulsification of the samples.

[0251] Preparation of test sample: Take about 250 mg of this product, weigh accurately, place it in a 25-ml volumetric flask, dissolve it with solvent and dilute to the mark, and shake well.

[0252] Preparation of reference substance: Take an appropriate amount of docetaxel reference substance, and prepare a solution with a concentration of 0.2 mg / ml with a diluent.

[0253] Chromatographic conditions: Use octadecylsilane-bonded silica gel as the filler (Waters C18, 150×4.6 mm, 3.5 μm or a chromatographic column with equivalent efficiency); use water-acetonitrile (50:50) as the mobile phase; the flow rate is 1.2 ml per minute; the detection wavelength is 232 nm; the column temperature is 45 °C; the injection tray temperature is 4 °C.

[0254] Detection method: Accurately measure 20 μl of the test sample solution and the reference substance solution respectively, inject them into the liquid chromatograph, and record the chromatogram. Calculate according to the external standard method with the peak area.

[0255] 3. Experimental results: See Tables 11-1 and 11-2.

[0256] Table 1-1: Characteristics of the self-microemulsion sample after emulsification

[0257]

[0258] Table 11-2: Content results of the self-microemulsion sample after emulsification (%)

[0259]

[0260] It can be obtained from the experimental results that after emulsifying the docetaxel self-microemulsion prepared in Example 9 for 4 h in three different pH media of water, pH 1.2, and pH 6.8, the physical properties are relatively stable, there is no crystal precipitation phenomenon, and the content has no obvious change.

[0261] 4. Conclusion: For the docetaxel self-microemulsion composition provided by the present invention, samples with clear and transparent characteristics and good stability after emulsification can be obtained. On the basis of emulsification in purified water, the emulsification results in pH 1.2 medium and pH 6.8 medium are added, and the results show that the physical properties are stable, fully demonstrating the excellent performance of the self-microemulsion composition.

[0262] Experimental Example 8: Investigation on the chemical stability of docetaxel self-microemulsion composition

[0263] 1. Sample: Example 9.

[0264] 2. Experimental method:

[0265] Take the docetaxel self - microemulsion sample prepared in Example 9 and conduct a 6 - month retention study under the conditions of 25°C ± 2°C (60% RH ± 5%) and 40°C ± 2°C (75% RH ± 5%), and determine the changes in the related substances of the sample.

[0266] 3. Detection method for related substances:

[0267] Test solution Take about 250 mg of this product, weigh accurately, place it in a 25 - ml volumetric flask, dissolve it with the solvent and dilute to the mark, and shake well.

[0268] Chromatographic conditions Use octadecylsilane chemically bonded silica gel as the filler (Waters C 18 , 150×4.6 mm, 3.5 μm or a chromatographic column with equivalent efficiency); use water as mobile phase A and acetonitrile solution as mobile phase B, and perform gradient elution according to Table 12; the flow rate is 1.2 ml per minute; the detection wavelength is 232 nm; the column temperature is 45°C; the injection volume is 20 μl, and the injection tray temperature is 4°C.

[0269] Table 12: Gradient elution table

[0270] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 72 28 9 72 28 25 55 45 40 55 45 60 28 72 65 28 72 65.1 72 28 70 72 28

[0271] Determination method Accurately measure the test solution, inject it into the liquid chromatograph, and record the chromatogram. Among them, the largest unknown single impurity is simply called single impurity, and the sum of all impurities is simply called total impurity.

[0272] 4. Detection results

[0273] 4.1 Results of storage under the conditions of 25°C ± 2°C (60% RH ± 5%): See Table 13 - 1 Table 13 - 1: Chemical stability results of docetaxel self - microemulsion composition (25°C)

[0274]

[0275] Note: Since drug precipitation occurred after emulsification of Prescription 6 - 3, the retention study was not carried out.

[0276] 4.2 Results of storage under the conditions of 40°C ± 2°C (75% RH ± 5%): See Table 13 - 2 Table 13 - 2: Chemical stability results of docetaxel self - microemulsion composition (40°C)

[0277]

[0278]

[0279] Note: Since drug precipitation occurred after emulsification of Prescription 6 - 3, the retention study was not carried out.

[0280] From the above results, it can be seen that the docetaxel self-microemulsion composition prepared in Example 9 was stored at 25 °C and 40 °C for 6 months respectively. Compared with the related substances of the sample on day 0, both the maximum unknown single impurity and the total impurity increased, but the increase was within the controllable range, indicating that the docetaxel self-microemulsion composition had excellent chemical stability.

[0281] 4. Conclusion: For the docetaxel self-microemulsion composition prepared according to Example 9, the growth of its related substances can meet the requirements of room temperature storage.

[0282] Experimental Example 9: Bioavailability Test of Docetaxel Self-Microemulsion Composition

[0283] 1. Samples: Example 9, Taxotere (produced by Sanofi, production date March 2022, batch number 2F218F).

[0284] 2. Experimental method:

[0285] The sample prepared in Example 9 was subjected to a PK experiment on SD rats.

[0286] 2.1 Animal information: SD rats, fasted for 10 - 14 hours before dosing, and fed again 4 hours after dosing.

[0287] 2.2 Dosing regimen and plasma sample collection:

[0288] IV administration (tail vein injection): The dilution solvent in the commercially available docetaxel preparation (Taxotere) was aspirated with a syringe and added to the concentrated solution, and the mixture was manually inverted and mixed repeatedly for 60 s (without shaking). After standing for 5 min, it was observed whether it was uniformly clear. If it was not clear, it was discarded. The dosing dose for each rat was 12.5 mg / kg.

[0289] PO administration (gavage): The sample (self-microemulsion prepared in Example 9) was taken, and it was observed whether the drug precipitated (if it precipitated, it was discarded). The dosing dose for each rat was 5 mg / kg.

[0290] 2.3 Blood collection:

[0291] 0.2 ml of whole blood was collected from the jugular vein at different time points after dosing.

[0292] Blood collection time points: For IV administration, the blood collection time points were before dosing and 0.083 h (5 min), 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h after dosing; for PO gavage administration, the blood collection time points were before dosing and 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h after dosing.

[0293] 2.4: Detection method: After collecting all blood samples, transfer them to a commercial tube containing K2-EDTA, centrifuge at 3200×g for 10 minutes at 4°C, aspirate the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower for LC-MS / MS analysis. Calculate the AUC area and bioavailability according to the blood drug concentration curve.

[0294] 3. Experimental results:

[0295] 3.1 During the experiment, no obvious adverse reactions or symptoms were observed in all rats.

[0296] 3.2 See Table 14.

[0297] Table 14: Bioavailability of the samples

[0298]

[0299] As can be seen from Table 14, when the mass ratio of docetaxel to the pharmacokinetic enhancer is 1:1, the bioavailability is low, while when the mass ratio of the two reaches 1:(2 - 5), the bioavailability is high; when the mass ratio exceeds 1:5, no further increase in bioavailability is observed, indicating that its bioavailability reaches a plateau, and increasing the mass ratio of the pharmacokinetic enhancer cannot further improve the bioavailability, and there is a theoretical risk of increasing toxic and side effects.

[0300] Therefore, a good effect can be obtained when the mass ratio of docetaxel to the pharmacokinetic enhancer is 1:(2 - 5).

[0301] Experimental Example 10: In vitro pharmacodynamic study of docetaxel self-microemulsion combination

[0302] 1. Samples: Prescription 6-2, Taxotere (produced by Sanofi, production date March 2022, batch number 2F218F).

[0303] 2. Experimental method:

[0304] Establish a human breast cancer MDA-MB-231 subcutaneous transplanted tumor model, screen 36 qualified tumor-bearing mice, randomly divide them into 6 groups, with 6 mice in each group, and administer different doses of drugs to investigate the effective concentration and tumor inhibitory effect of the drugs.

[0305] 3. Administration method: See Table 15.

[0306] Table 15: Grouping and TGI data of in vitro pharmacodynamics of docetaxel self-microemulsion combination

[0307] Group number Group DCT concentration DCT dose TGI value A Solvent group 0 0 / B Positive drug group (Taxotere) 10mg / ml 20mg / kg 88％ C Low-dose group 20mg / ml 2mg / kg 81％ D Medium-dose group 20mg / ml 10mg / kg 93％ E High-dose group 20mg / ml 50mg / kg 95％ F Ultra-high-dose group 20mg / ml 100mg / kg 95％

[0308] For groups A - F, the drug was administered once every 7 days for a total of 6 times. Except for group B which was administered intravenously, the remaining groups were administered by gavage. The days of drug administration were the 1st, 8th, 15th, 22nd, 29th, and 36th days.

[0309] 4. Detection indicators:

[0310] The experimental animals were euthanized on the 38th day.

[0311] The tumor nodules were dissected, weighed, and the differences in tumor weights among groups were compared. The tumor growth inhibition rate (TGI value) was calculated using the following formula:

[0312] TGI (%) = (1 - W 治疗组 / W 溶媒组 ) × 100%

[0313] 5. Experimental results: The TGI results of each treatment group are shown in Table 15.

[0314] The results showed that a good tumor growth inhibition rate could be obtained by continuously administering the drug at a low concentration of 2 mg / kg for 6 cycles. However, with the increase in drug dose, obvious toxic and side effects (toxic death / liver toxicity / fluid retention) occurred, which were particularly obvious in the 100 mg / kg treatment group.

[0315] Therefore, choosing a lower drug dose can significantly reduce the incidence of adverse reactions while achieving a good tumor suppression effect, increasing patient compliance.

[0316] The description of the above embodiments is only used to help understand the method of the present invention and its core idea. It should be noted that for those of ordinary skill in the art of this technology, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A docetaxel oral self-microemulsification composition comprising: Docetaxel, oil phase, surfactant, co-surfactant, stabilizer and antioxidant; The oil phase is caprylic acid capric acid mono- and di-glyceride, medium chain triglyceride, caprylic acid propylene glycol ester or lauric acid propylene glycol ester.

2. The docetaxel oral self-microemulsification composition according to claim 1, characterized in that: In parts by weight, it includes: 0.05-0.5 parts of docetaxel, 1-4 parts of oil phase, 0.5-6 parts of surfactant, 0.5-3 parts of co-surfactant, 0.1-0.5 parts of stabilizer and 0.01-0.3 parts of antioxidant.

3. The docetaxel oral self-microemulsification composition according to claim 2, characterized in that: In parts by weight, it includes: 0.1-0.5 parts of docetaxel, 1-3 parts of oil phase, 1-5 parts of surfactant, 1-2 parts of co-surfactant, 0.1-0.5 parts of stabilizer and 0.01-0.1 parts of antioxidant.

4. The docetaxel oral self-microemulsification composition according to claim 1, characterized in that: The surfactant includes polysorbate 80 and polyoxyethylene 40 hydrogenated castor oil; The mass ratio of the polysorbate 80 to the polyoxyethylene 40 hydrogenated castor oil is 1:1 to 1:

4.

5. The docetaxel oral self-microemulsification composition according to claim 1, characterized in that: The co-surfactant includes anhydrous ethanol and polyethylene glycol; The mass ratio of the anhydrous ethanol to the polyethylene glycol 600 is 1:2 to 1:

5.

6. The docetaxel oral self-microemulsification composition according to claim 1, characterized in that: The stabilizer includes povidone.

7. The docetaxel oral self-microemulsification composition according to claim 1, characterized in that: The antioxidant includes one or both of citric acid and vitamin E.

8. The docetaxel oral self-microemulsification composition according to claim 1, characterized in that: The docetaxel oral self-microemulsifying composition further comprises a pharmacokinetic enhancer; The pharmacokinetic enhancer includes one or two of cyclosporine A and ritonavir; The mass ratio of the pharmacokinetic enhancer to the docetaxel is 2:1 to 5:

1.

9. The docetaxel oral self-microemulsification composition according to any one of claims 1 to 8, characterized in that: The particle size of the docetaxel oral self-microemulsification composition after emulsification is 54-77 nm.

10. The method for preparing the docetaxel oral self-microemulsification composition according to any one of claims 1 to 9, comprising the following steps: The oil phase and the surfactant are mixed to obtain a first solution, the stabilizer is uniformly dispersed with a co-surfactant other than anhydrous ethanol to obtain a second solution, and the first solution and the second solution are mixed to obtain a premixed solution 1; Mixing the antioxidant, anhydrous ethanol and docetaxel to obtain a premix 2; The premix solution 1 and the premix solution 2 are mixed to obtain a docetaxel oral self-microemulsification composition.

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