Paclitaxel-phospholipid compound oral preparation and preparation method thereof

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a paclitaxel-phospholipid compound oral preparation and a preparation method thereof.The oral preparation comprises paclitaxel, marine phospholipid and auxiliary materials, and the mass ratio of paclitaxel to marine phospholipid to auxiliary materials is 2: (1-20): (1-20). According to the oral preparation, the water solubility and the bioavailability of the paclitaxel raw medicine are improved; the paclitaxel oral solution can replace a paclitaxel injection, so that the compliance of a patient is improved, and the treatment burden is relieved. The preparation method is simple and time-saving, the preparation process does not involve harmful organic reagents, and the process is economical and environment-friendly.

Description

[0001] This patent claims priority to the following patent: Patent Application No. 202411893345.4, Patent Application Date 2024-12-20, Patent Title: A Method for Preparing an Oral Formulation of Paclitaxel-Phospholipid Complex. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to an oral formulation of paclitaxel-phospholipid complex and its preparation method. Background Technology

[0003] Paclitaxel (PTX) is a tricyclic diterpenoid compound derived from the bark and needles of the yew tree. Due to its unique anticancer mechanism and biological activity, it is one of the most widely used natural anticancer drugs.

[0004] Currently, paclitaxel is mainly used for the treatment of breast cancer, colorectal cancer, and bladder squamous cell carcinoma via injection. It also exhibits strong toxicity against other malignant tumor cells and possesses broad-spectrum anticancer activity. However, due to its poor water solubility and low bioavailability, the world's first injectable paclitaxel (Taxol) required polyoxyethylene castor oil and alcohol for solubilization, necessitating pre-administration and regular injections. This not only increases the burden on the healthcare system and patients but also leads to severe hypersensitivity reactions, neutropenia, and other adverse effects.

[0005] To address the problems associated with paclitaxel injections (Taxol), pharmaceutical experts both domestically and internationally have conducted extensive research, such as preparing paclitaxel into liposomes and micelles for injection. However, issues such as low drug encapsulation efficiency, easy leakage, and difficulty in completely removing organic solvents remain. Furthermore, the pharmacokinetics of injections are complex, and frequent dosing may lead to fluctuations in drug levels, thereby increasing the risk of toxicity. Therefore, the need for oral paclitaxel formulations is extremely urgent.

[0006] In 2016, the world's first oral paclitaxel solution (Liporaxel) was approved for marketing in South Korea. Reports indicate that the absolute bioavailability of Liporaxel in mice after oral administration was only 22.7%; 10.2% of patients who took the drug developed infectious pneumonia, and the drug also increased liver damage. Therefore, further development of oral paclitaxel formulations is needed to improve its water solubility, bioavailability, and reduce its toxic side effects.

[0007] Phospholipid complexes are integral entities formed by the active ingredient and phospholipids through weak interactions. Under certain conditions, some poorly soluble drug molecules interact with phospholipid molecules through electron gain or loss, forming phospholipid complexes via charge migration. This alters the original physical properties of the drug (such as molecular solubility and in vitro dissolution rate), resulting in greater stability than liposomes. Pharmacokinetic studies have shown that phospholipid complexes can increase the concentration of active molecules in vivo, slow their elimination rate, and thus exhibit higher bioavailability, allowing the active molecules to better exert their pharmacological effects in vivo.

[0008] Currently, phospholipid complexes are all prepared using soybean phospholipids as raw materials. Soybean phospholipids mainly contain ω-6 fatty acids (such as linoleic acid), which are easily oxidized during long-term storage, generating free radicals that damage the complex structure and accelerate the degradation of paclitaxel. Therefore, it is necessary to add antioxidants such as vitamin E or use inert gas packaging, which increases cost and process complexity. Soy is a common allergen, and soybean-derived phospholipid complexes may cause adverse reactions in people with soybean allergies. Summary of the Invention

[0009] To address the aforementioned issues, this invention proposes an oral formulation of a paclitaxel-phospholipid complex and its preparation method. This oral formulation improves the water solubility and bioavailability of paclitaxel; it is convenient to administer orally, thus enhancing patient compliance.

[0010] Krill phospholipids, derived from Antarctic krill, are rich in phospholipid omega-3 fatty acids and astaxanthin. Their EPA and DHA content is significantly higher than that of soybean phospholipids. This not only synergizes with the physiological activity of paclitaxel but also enhances the permeability of cell membranes and organelle membranes, facilitating phospholipid transport and improving the bioavailability of poorly soluble drugs. Furthermore, astaxanthin in krill phospholipids acts as a natural antioxidant, maintaining the stability of the phospholipid complex. This invention further improves the physical stability and enhances the water solubility of the phospholipid complex by introducing excipients into the phospholipid complex system.

[0011] The first objective of this invention is to provide a novel paclitaxel-marine phospholipid complex solid dosage form by replacing ordinary low-content krill phospholipids and soybean-derived phospholipids with high-purity marine phospholipids, thereby increasing the water solubility of paclitaxel and thus improving its bioavailability. The second objective of this invention is to provide a method for preparing the aforementioned paclitaxel-marine phospholipid complex solid dosage form. The third objective of this invention is to provide physicochemical characterization results, such as water solubility, particle size, and dissolution rate, as well as an evaluation of the bioavailability of the aforementioned paclitaxel phospholipid complex.

[0012] The technical solution of the present invention is as follows: An oral formulation of a paclitaxel-phospholipid complex comprises paclitaxel, marine phospholipids, and excipients; wherein the mass ratio of paclitaxel, marine phospholipids, and excipients is 2:1-20:1-20. The preferred mass ratio of paclitaxel to marine phospholipids is 1:1-4. More preferably, the mass ratio of paclitaxel to marine phospholipids is 1:2. Preferably, the marine phospholipids include krill phospholipids.

[0013] Preferably, the marine phospholipids are derived from high-purity krill phospholipids (PPC) from Antarctic krill.

[0014] Preferably, the marine phospholipid contains ≥50% phosphatidylcholine.

[0015] Preferably, the marine phospholipid contains ≥70% phosphatidylcholine.

[0016] Preferably, the marine phospholipid contains ≥80% phosphatidylcholine.

[0017] Preferably, the marine phospholipid contains ≥95% phosphatidylcholine.

[0018] Preferably, the excipients are selected from one or more of povidone K30 (PVP-K30), povidone K90 (PVP-K90), Tween 20, Tween 80, poloxamer 188, and hydroxypropyl β-cyclodextrin.

[0019] The preferred further auxiliary material is PVP-K30.

[0020] This application provides a method for preparing an oral formulation of a paclitaxel-phospholipid complex, comprising the following steps: A. Dissolve paclitaxel in an organic solvent to prepare an organic paclitaxel solution; the concentration of the organic paclitaxel solution is 1-20 mg / mL; B. Dissolve the excipients and marine phospholipids separately in deionized water to prepare excipient aqueous solutions and phospholipid aqueous solutions; the concentration of the excipient aqueous solution is 1-20 mg / mL; the concentration of the phospholipid aqueous solution is 10 mg / mL. C. Mix the excipient aqueous solution with the phospholipid aqueous solution to form an excipient-phospholipid aqueous solution; the mass ratio of the excipient aqueous solution to the phospholipid aqueous solution is 1:1-10; D. Add paclitaxel organic solution to the excipient-phospholipid aqueous solution, remove the solvent after ultrasonic treatment, and dry to obtain an oral formulation of paclitaxel-phospholipid complex.

[0021] This application provides another method for preparing an oral formulation of paclitaxel-krill phospholipid complex, which is carried out according to the following steps: Paclitaxel and marine phospholipids were placed in an organic solvent at a mass concentration of 2-20 mg / ml. The mixture was stirred at 30-70℃ for 1-3 hours, then rotary evaporated. Unreacted paclitaxel was removed by adding diethyl ether, excipients were added, and anhydrous ethanol was added. The mixture was stirred for 1-3 hours, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then dried under vacuum to obtain an oral formulation of the paclitaxel-phospholipid complex.

[0022] Preferably, the organic solvent can be one of tetrahydrofuran, acetone, ethyl acetate or anhydrous ethanol.

[0023] Anhydrous ethanol is preferred. Preferably, the reaction temperature is 50°C. Preferably, the mass concentration of the reactant is 10 mg / ml, and the reaction time is 2 h.

[0024] This invention uses marine phospholipids and paclitaxel as raw materials to prepare an oral formulation of paclitaxel-phospholipid complex, which improves the water solubility and bioavailability of paclitaxel; oral administration is convenient and improves patient compliance.

[0025] This invention uses high-purity krill phospholipids to replace ordinary low-content krill phospholipids, soybean-derived phospholipids, and Antarctic krill oil to prepare an oral formulation of paclitaxel-krill phospholipid complex, thereby improving the water solubility and bioavailability of paclitaxel.

[0026] In this invention, krill phospholipids have strong surfactant properties, thus greatly reducing the amount of solid carriers used and avoiding allergic reactions or other health risks. The use of high-purity marine krill phospholipids (PPC) significantly improves the bioavailability of paclitaxel raw materials, thereby reducing the dosage.

[0027] This invention provides a paclitaxel-phospholipid complex with excellent water dispersibility. When dissolved in water, it forms an oral paclitaxel solution, which can replace paclitaxel injections, improving patient compliance and reducing the burden of treatment. The preparation method of this invention is simple and time-saving, and the process does not involve harmful organic reagents, making it economical and environmentally friendly. Attached Figure Description

[0028] The accompanying drawings, which are included to provide a further understanding of this application and form part of this application, illustrate exemplary embodiments and are used to explain this application, but do not constitute an undue limitation of this application. In the drawings: Figure 1 The images show X-ray diffraction patterns, where a. paclitaxel; b. krill phospholipids; c. control sample 1; d. complex 1. Figures 2-4 The image shows the results of the in vitro dissolution experiment. Detailed Implementation

[0029] The following embodiments are provided to further illustrate the present invention. Obviously, the described embodiments are only some, not all, of the embodiments described in this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without inventive effort are within the scope of protection claimed in this application.

[0030] Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available products.

[0031] A method for preparing an oral formulation of paclitaxel-phospholipid complex: Paclitaxel is dissolved in anhydrous ethanol to a concentration of 10 mg / mL and set aside. Krill phospholipids and povidone K30 are each prepared into 10 mg / mL aqueous solutions using deionized water. These solutions are then mixed to form a povidone K30-phospholipid aqueous solution. The povidone K30-phospholipid aqueous solution is added to the paclitaxel ethanol solution, and the mixture is sonicated at 400 W for 4 min. After drying, the oral formulation of paclitaxel-phospholipid complex is obtained.

[0032]

[0033] The encapsulation efficiency was tested as follows: The dried phospholipid complex oral formulation was dissolved in water to prepare a 1 mg / mL nano-suspension. The suspension was placed in an ultrafiltration centrifuge tube (MWCO = 10 kDa), centrifuged at 4000 rpm for 20 min, and the filtrate was collected to determine and calculate the amount of free paclitaxel (Wf). Separately, the phospholipid complex nano-suspension was ultrasonically demulsified with methanol and brought to a final volume. The total amount of paclitaxel (Wt) was then determined and calculated.

[0034] Encapsulation efficiency EE = (1 - Wf / Wt) * 100% When the feed ratio of paclitaxel:krill phospholipid:povidone K30 = 1:6:3, the encapsulation efficiency of the phospholipid complex nanoparticles is the highest. This indicates that adding povidone K30 can promote the dissolution of paclitaxel, and adding krill phospholipid can cause paclitaxel to react with the polar ends of the phospholipids to form a stable phospholipid complex. However, if there is too much phospholipid, the complex will become viscous, which is not conducive to improving the encapsulation efficiency.

[0035] Weigh an appropriate amount of the dried paclitaxel-phospholipid complex oral formulation sample from Example 4 into pure water, and sonicate at 50°C for 15 min to fully dissolve it. Characterize its particle size, polydispersity index (PdI), and zeta potential using a Malvern particle size analyzer.

[0036]

[0037] Paclitaxel monomer, physical mixture, and the oral formulation of paclitaxel-phospholipid complex from Example 4 were respectively placed in pure water, sonicated, and then placed in a 37°C constant temperature shaking water bath for 48 hours. The solutions were centrifuged (10000 rpm, 10 min), and the supernatant was diluted with an appropriate amount of methanol, filtered through a 0.22 μm filter membrane, and its solubility was determined and calculated by high performance liquid chromatography (HPLC).

[0038] The physical mixture consisted of the same amounts of paclitaxel, krill phospholipids, and povidone K30 as in Example 4, which were thoroughly mixed in a mortar.

[0039]

[0040] As shown in the table above, the oral formulation of paclitaxel-phospholipid complex prepared in this application has the highest solubility, which is much higher than that of paclitaxel raw materials and physical mixtures. This indicates that the oral formulation prepared in this application can greatly improve the water solubility of paclitaxel, thereby improving the bioavailability of paclitaxel. This application provides another method for preparing a paclitaxel-phospholipid complex, which is carried out according to the following steps: paclitaxel and krill phospholipids are placed in an organic solvent, the mass concentration of the reactants is 2-20 mg / ml, the mixture is stirred at 30-70℃ for 1-3 h, then rotary evaporated, ether is added to remove unreacted paclitaxel, and the mixture is vacuum dried for 12 h to obtain the paclitaxel-phospholipid complex.

[0041] Krill phospholipids can be commercially available products, or they can be prepared in-house or using existing technologies. Products that meet the requirements of having a phospholipid content of not less than 50 wt% and a phosphatidylcholine content of not less than 50 wt% can be used in this application.

[0042] This application lists several commonly used technical methods: 1. Organic solvent extraction (using acetone or ethanol to remove neutral lipids and free fatty acids from krill; using polar solvents to extract phospholipids from the defatted residue, evaporating the solvent, and then increasing the PC content through column chromatography or low-temperature crystallization). 2. Supercritical fluid extraction, utilizing the solubility of supercritical CO2 to selectively extract lipids; combining it with an entrainer (ethanol) can improve the phospholipid recovery rate. 3. Column chromatography purification, using silica gel, alumina, or reversed-phase chromatography columns to separate PC. Specific examples are detailed in the table below.

[0043]

[0044] Characterization of the paclitaxel-phospholipid complex 1. Composite rate Taking advantage of the fact that paclitaxel is insoluble in diethyl ether, while phospholipids and their complexes are readily soluble in diethyl ether, paclitaxel and phospholipids are compounded under certain conditions. The reaction solvent is removed under reduced pressure, and the residue is dissolved in an appropriate amount of diethyl ether. After centrifugation, the supernatant is collected and dried under reduced pressure to obtain the paclitaxel-phospholipid complex. The precipitate is collected, dried, and weighed. The difference between the initial amount of paclitaxel added (Wt) and the amount of precipitate (Wf) represents the amount of paclitaxel compounded with the phospholipid. The compounding percentage is calculated using the following formula: Composite rate (%) = (Wt - Wf) / Wt × 100 2. Equilibrium solubility Samples were dissolved in pure water to obtain supersaturated solutions, which were then sonicated and placed in a 37°C constant temperature shaking water bath. After shaking for 10 hours, undissolved matter was observed, and shaking was continued overnight. The next day, the solutions were centrifuged (10,000 rpm, 10 min), and the supernatant was diluted with an appropriate amount of methanol, filtered through a 0.22 μm filter membrane, and its solubility was determined and calculated by high performance liquid chromatography (HPLC).

[0045] 3. X-ray diffraction (XRD) X-ray diffraction (XRD) was performed on paclitaxel, krill phospholipids, complex 1, and control sample 1. The voltage and current were 40 kV and 30 mA, respectively. The scanning speed was 4 (°) / min, and the scanning range was 5°–60°. The XRD patterns are shown below. Figure 1 As shown.

[0046] from Figure 1 It can be seen that the paclitaxel monomer (line a) has sharp peaks and is a small molecule with polycrystalline properties. In the paclitaxel-phospholipid complex, i.e., complex 1 (line d), the crystal diffraction peaks of PTX completely disappear. This means that paclitaxel has changed from a polycrystalline form to an amorphous form or is dispersed in the paclitaxel-phospholipid complex in a molecular state, so that its crystal properties cannot be displayed. This indicates that the paclitaxel-phospholipid complex was successfully prepared.

[0047] Dispersibility: Weigh an appropriate amount of sample into pure water, sonicate at 50℃ for 15 min to fully dissolve it, and characterize its particle size and polydispersity index (PdI) using a Malvern particle size analyzer.

[0048]

[0049] The data analysis in the table above shows that: 1. Comparing complexes 1-3, the paclitaxel phospholipid complex obtained when using anhydrous ethanol as the organic solvent exhibits the best composite rate, water solubility, and dispersion performance. 2. Comparison of complex 1 and complexes 4-6 shows that when the molar ratio of paclitaxel to phospholipid is 1:2, the resulting paclitaxel-phospholipid complex exhibits the best composite rate, water solubility, and dispersion performance. 3. Comparing complex 1 and complex 7-11, the paclitaxel phospholipid complex obtained with a reactant mass concentration of 10 mg / ml showed the best composite rate, water solubility, and dispersibility. 4. Comparing complex 1 and complexes 12-14, the paclitaxel phospholipid complex obtained at a reaction temperature of 50℃ showed the best composite rate, water solubility, and dispersion performance. 5. Comparison of complex 1 and complexes 15-17 shows that the paclitaxel phospholipid complex obtained when the phosphatidylcholine content in the krill phospholipid is 95% has the best composite rate, water solubility and dispersion performance. 6. Compared with control sample 1, it can be seen that simply physically mixing paclitaxel and phospholipids will result in a significant decrease in the water solubility and dispersibility of the product.

[0050] 7. Compared with control sample 3, it can be seen that the use of krill phospholipids is more beneficial to the product's compounding rate, water solubility, and dispersion performance. Using the technical parameters of the above-mentioned compound 1, an oral formulation of paclitaxel-phospholipid complex solid dispersion was prepared. The specific preparation steps were as follows: 0.5 g of paclitaxel and 1.0 g of krill phospholipid were placed in anhydrous ethanol, with a reactant concentration of 10 mg / ml. The mixture was magnetically stirred at 50 °C for 2 h. After that, the mixture was rotary evaporated, and diethyl ether was added to remove unreacted paclitaxel. Excipients were added, followed by anhydrous ethanol. The mixture was stirred for 2 h, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then vacuum dried for 12 h. The powder sample was then filled into capsules to obtain the paclitaxel-phospholipid complex solid dispersion. Specific samples are shown in the table below.

[0051]

[0052] Characterization of Paclitaxel-Phospholipid Complex Oral Formulations - Solid Dispersions 1. In vitro dissolution test The in vitro dissolution rate of the sample in the dissolution medium (PBS at pH 6.8) was determined using the paddle method, with a paddle speed of 100 rpm and a water bath temperature of 37°C.

[0053] Samples of solid dispersions 1-3 of the same mass of paclitaxel were added to a dissolution vessel. At 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, 2 mL samples were taken (with an equal volume of fresh medium added at the same temperature). The samples were then filtered sequentially through 0.45 μm and 0.22 μm microporous membranes. The cumulative dissolution rate was determined by high-performance liquid chromatography (HPLC). Chromatographic conditions: Column: ODS2C18 column (250 mm × 4.6 mm, 5 μm); Mobile phase: methanol-water-acetonitrile (23:41:36, v / v); Flow rate: 1.0 mL / min; Column temperature: 25℃; Injection volume: 10 µL; Detection wavelength: 227 nm. Figure 2 As shown.

[0054] Samples of solid dispersions 1 and 4-7 of the same mass of paclitaxel were added to a dissolution vessel. At 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, 2 mL samples were taken (with an equal volume of fresh medium added at the same temperature). The samples were then filtered sequentially through 0.45 μm and 0.22 μm microporous membranes, and the cumulative dissolution rate was determined and calculated by high-performance liquid chromatography (HPLC). Figure 3 As shown.

[0055] Take capsules containing the same mass of paclitaxel, a physical mixture (0.5 g of paclitaxel, 1.0 g of krill phospholipids, and 0.6 g of PVP-K30 mixed thoroughly in a mortar), and solid dispersions 1, 2, 3, and 4 (comparative solid dispersions 1, 2, and 3) and place them into dissolution vessels. Take 2 mL samples at 5, 10, 15, 20, 30, 45, 60, 90, and 120 min respectively (simultaneously replenishing with an equal volume of fresh medium at the same temperature). Filter sequentially through 0.45 μm and 0.22 μm microporous membranes. Determine and calculate the cumulative dissolution rate using high-performance liquid chromatography (HPLC). Figure 4 As shown.

[0056] Because paclitaxel monomer has very poor solubility, its dissolution is relatively slow. When prepared as a physical mixture, phospholipids act as surfactants, promoting paclitaxel dissolution to some extent, but the effect is not significant. After forming the paclitaxel-phospholipid complex solid dispersion, complete release was achieved after 30 minutes of administration, while no release of the monomer was detected, showing a highly significant difference. At 30 minutes, the cumulative dissolution rate of solid dispersion 1 was 3.66 times that of control solid dispersion 1, 2.48 times that of control solid dispersion 2, and 1.48 times that of control solid dispersion 3; that is, the phospholipid complex solid dispersion prepared from high-purity krill phospholipids exhibited the best dissolution rate.

[0057] 2. Bioavailability Animal experiments: Thirty healthy male SD rats (weighing 180-200 g) were randomly divided into 5 groups. Before administration, the rats were fasted for 12 hours but had free access to water. The rats were administered 25 mg / kg (based on the amount of paclitaxel) by gavage, along with an aqueous solution of free paclitaxel and a paclitaxel-phospholipid complex. Blank blood samples were collected before administration. At 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, 0.3 mL of blood was collected from the retro-orbital venous plexus of the rats and placed in centrifuge tubes containing heparin sodium. The samples were centrifuged at 3000 rpm for 10 min at 4°C to separate the plasma, which was then stored at -80°C. LC-MS / MS was used for analysis.

[0058] Preparation of the standard curve: Using blank plasma as a matrix, a standard curve was prepared: First, a standard solution of paclitaxel (1 mg / mL dissolved in methanol) was prepared and serially diluted with acetonitrile to obtain standard curves at concentrations of 2000 ng, 1000 ng, 500 ng, 200 ng, 100 ng, 50 ng, and 20 ng / mL. Then, blank plasma was used as the matrix. 20 μL of plasma was added to the standard curve (180 μL), and after shaking, the mixture was centrifuged at 4℃ and 13000 rpm for 10 min. 70 μL of the supernatant was collected, and 70 μL of acetonitrile was added. After shaking and centrifugation, 120 μL of the supernatant was transferred to a vial for analysis.

[0059] Plasma sample processing: Take 20 μL of plasma, dissolve it in 80 μL of acetonitrile solution, shake for 2 min, centrifuge at 13000 rpm for 10 min at 4℃, collect 80 μL of supernatant, add another 80 μL of acetonitrile, shake, centrifuge, collect 100 μL of supernatant, dry under nitrogen at 30℃ for 5-10 min, and then reconstitute the sample with 50 μL of methanol solution. Finally, transfer to a vial and store at -80℃ for analysis.

[0060] Liquid chromatography-mass spectrometry (LC-MS) conditions: Mobile phase: A: 900mL water (containing 0.1% formic acid) + 900μL formic acid B: Acetonitrile (containing 0.1% formic acid) 900mL acetonitrile + 900μL formic acid Elution gradient:

[0061] Conditions: C18 (4.6 mm × 250 mm, 5 μm) column Flow rate: 0.3 mL / min; positive ion detection mode. Ion pairs used for quantitative analysis: m / z 854→105.

[0062] Results analysis: Blood drug concentrations were measured at different time points, and bioavailability was calculated. The results are as follows:

[0063] The table shows that the AUC of the paclitaxel-phospholipid complex solid dispersion is... 0-t and C maxThe bioavailability of the paclitaxel complex was 10.37 times and 8.50 times that of free paclitaxel, respectively; 4.30 times and 3.55 times that of control solid dispersion 1, respectively; 3.15 times and 2.25 times that of control solid dispersion 2, respectively; and 1.68 times and 1.53 times that of control solid dispersion 3, respectively. This demonstrates that the paclitaxel-phospholipid complex solid dispersion prepared from high-purity krill phospholipids can effectively improve drug bioavailability and is significantly superior to soybean phospholipids and low-purity krill phospholipids.

[0064] The various embodiments in this specification are described in a progressive manner. Similar or identical parts between embodiments can be referred to interchangeably. Each embodiment focuses on describing the differences from other embodiments. In particular, the system embodiments are basically similar to the method embodiments, so the description is relatively simple; relevant parts can be referred to the descriptions in the method embodiments.

[0065] The above description is merely an embodiment of this application and is not intended to limit the scope of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of the claims of this application.

Claims

1. An oral formulation of a paclitaxel-phospholipid complex, characterized in that, It contains paclitaxel, marine phospholipids, and excipients; the mass ratio of paclitaxel, marine phospholipids, and excipients is 2:1-20:1-20.

2. The oral formulation of paclitaxel-phospholipid complex according to claim 1, characterized in that, The marine phospholipids mentioned are krill phospholipids.

3. The oral formulation of a paclitaxel-phospholipid complex according to claim 1, characterized in that, The excipients are one or more of the following: povidone K30, povidone K90, Tween 20, Tween 80, poloxamer 188, and hydroxypropyl β-cyclodextrin.

4. The oral formulation of a paclitaxel-phospholipid complex according to claim 1, characterized in that, The marine phospholipid contains more than 50 wt% phosphatidylcholine; preferably, the marine phospholipid contains more than 70 wt% phosphatidylcholine; preferably, the marine phospholipid contains more than 80 wt% phosphatidylcholine.

5. The oral formulation of a paclitaxel-phospholipid complex according to claim 1, characterized in that, The marine phospholipids contain more than 95 wt% phosphatidylcholine.

6. A method for preparing an oral formulation of a paclitaxel-phospholipid complex, characterized in that, Includes the following steps: A. Dissolve paclitaxel in an organic solvent to prepare an organic paclitaxel solution; the concentration of the organic paclitaxel solution is 1-20 mg / mL; B. Dissolve the excipients and marine phospholipids separately in deionized water to prepare excipient aqueous solutions and phospholipid aqueous solutions; the concentration of the excipient aqueous solution is 1-20 mg / mL; the concentration of the phospholipid aqueous solution is 10 mg / mL. C. Mix the excipient aqueous solution with the phospholipid aqueous solution to form an excipient-phospholipid aqueous solution; the mass ratio of the excipient aqueous solution to the phospholipid aqueous solution is 1:1-10; D. Add paclitaxel organic solution to the excipient-phospholipid aqueous solution, remove the solvent after ultrasonic treatment, and dry to obtain an oral formulation of paclitaxel-phospholipid complex.

7. The preparation method according to claim 6, characterized in that, The organic solvent is one or more of tetrahydrofuran, acetone, ethyl acetate, or anhydrous ethanol.

8. The preparation method according to claim 7, characterized in that, The organic solvent is anhydrous ethanol.

9. The oral formulation of paclitaxel-phospholipid complex according to any one of claims 1-5 or the oral formulation of paclitaxel-phospholipid complex prepared according to any one of claims 6-8, characterized in that, The oral preparation is a solid dispersion.

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