An oral preparation of paclitaxel amorphous solid dispersion and its preparation method

Abstract

The present invention discloses an oral preparation of paclitaxel amorphous solid dispersion and a preparation method thereof. The oral preparation of paclitaxel amorphous solid dispersion of the present invention is as follows (I) or (II): (I) comprising paclitaxel and cocamidopropyl betaine (CAPB); (II) comprising paclitaxel, vitamin E polyethylene glycol succinate (TPGS) and cocamidopropyl betaine (CAPB). The present invention uses CAPB, or the combination of TPGS and CAPB as a carrier for paclitaxel, and enables the drug to be uniformly dispersed in the excipient in an amorphous state, which can significantly improve the oral bioavailability of paclitaxel. During preparation, only the drug and the excipient need to be dissolved in ethanol together, and the solvent is removed by simple techniques such as spray drying or rotary evaporation, and a paclitaxel / TPGS / CAPB amorphous solid dispersion with good uniformity can be obtained. The process is simple and the quality is controllable.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to an oral preparation of paclitaxel amorphous solid dispersion and a preparation method thereof. Background Art

[0002] Paclitaxel is a broad-spectrum anti-tumor drug, which mainly inhibits the proliferation of tumor cells by promoting the aggregation of tubulin in the mitotic phase of cells and inhibiting its depolymerization. Paclitaxel is used as a first-line anti-cancer drug clinically and is widely used in the treatment of cancers such as ovarian cancer, breast cancer, and non-small cell lung cancer. At present, the commonly used paclitaxel, albumin-bound paclitaxel, and paclitaxel liposome in clinics are all administered intravenously. However, paclitaxel for intravenous use needs to be wrapped with castor oil, which may cause hypersensitivity reactions; in addition, long-term intravenous use of paclitaxel requires a high economic cost. The compliance of patients receiving intravenous infusion is also extremely poor. Oral administration has become the first choice for formulation development due to its advantages such as convenient administration, painless, relatively safe, patients can take drugs independently, and easy to store and transport.

[0003] However, the development of oral paclitaxel is difficult. First, from the physicochemical properties of the drug itself, the water solubility of paclitaxel is extremely low (~0.12 μg / mL), its lipophilicity is very strong (log P: 3.96), and its gastrointestinal permeability is poor, belonging to BCS class IV drugs. Second, from the physiological and biochemical barriers of the human gastrointestinal tract, the gastrointestinal tract has a rich enzyme environment, resulting in the drug being easily degraded and inactivated after entering the gastrointestinal tract. The surface of gastrointestinal epithelial cells is covered with a layer of mucus secreted by goblet cells. Since its components such as mucin are negatively charged, nano-drugs with positive charges or surface hydrophobicity are easily entangled by mucus, resulting in the inability to penetrate to the surface of intestinal villi for effective absorption. The intestinal epithelial tissue is mainly composed of intestinal epithelial cells, and the tight junction state between cells forms a serious cell barrier to the absorption of nano-drugs, resulting in low bioavailability. Finally, from the perspective of the drug absorption mechanism, in the liver, paclitaxel is easily metabolized by cytochrome P450 (CYP) 2C8; paclitaxel is also a substrate of P-glycoprotein (P-gp), and the efflux pump function of P-gp highly expressed in the gastrointestinal tract and tumor cells leads to the difficulty of achieving an effective therapeutic concentration of paclitaxel in tumor cells. Considering the above factors, although the development of oral paclitaxel has a long history, there is still no marketed oral paclitaxel drug in China due to the unresolved problem of oral absorption.

[0004] Regarding the above factors that make it difficult for paclitaxel to be orally absorbed, the commonly used solutions in current research reports are as follows: ① Designing nanoformulations, such as polymer micelles, polymer nanoparticles, liposome nanoparticles, lipid-polymer hybrid nanoparticles, nanoemulsions and other nano-delivery systems to improve the solubility of paclitaxel; ② Using polymer carriers with inhibitory activity against P-gp to deliver drugs, or combining with P-gp inhibitors (such as cyclosporine A, verapamil, etc.) to improve the oral absorption of drugs. However, P-gp inhibitors (such as cyclosporine A, verapamil, etc.) themselves have pharmacological activities and may cause side effects. In addition, the above methods still cannot overcome the physiological and biochemical barriers of paclitaxel absorption through the gastrointestinal tract. Therefore, developing new drug delivery technologies to improve the solubility and dissolution rate of paclitaxel, and overcome various physiological and biochemical barriers of the gastrointestinal tract, so as to improve the oral bioavailability of paclitaxel is the focus and difficulty of current pharmaceutical researchers. Summary of the Invention

[0005] To solve the problems of poor water solubility and difficult oral absorption of paclitaxel, the present invention adopts the amorphous solid dispersion drug delivery technology, screens the combination of carriers and surfactants of the amorphous solid dispersion, and optimizes the formulation and process technology, which can significantly improve the oral bioavailability of paclitaxel. Therefore, the object of the present invention is to provide an oral preparation of paclitaxel amorphous solid dispersion and its preparation method. By selecting a suitable class of polymer materials and a suitable class of surfactants in combination as the carrier for preparing the paclitaxel amorphous solid dispersion, and using a suitable method, the drug is uniformly dispersed in the excipient in an amorphous state, thereby improving the dissolution and absorption behavior of the drug in the gastrointestinal tract.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] In the first aspect, the present invention provides an oral preparation of paclitaxel amorphous solid dispersion, which is as follows Ⅰ) or Ⅱ):

[0008] Ⅰ) Comprising paclitaxel and cocamidopropyl betaine;

[0009] Ⅱ) Comprising paclitaxel, vitamin E polyethylene glycol succinate and cocamidopropyl betaine.

[0010] Based on this, the present invention screens out an amphoteric ionic surfactant, cocamidopropyl betaine (CAPB), as a carrier for paclitaxel, or a combination of a polymer material, vitamin E polyethylene glycol succinate (TPGS), and an amphoteric ionic surfactant, cocamidopropyl betaine (CAPB), as a carrier for paclitaxel.

[0011] TPGS is a water-soluble vitamin E derivative composed of a polar polyethylene glycol (PEG) head and a non-polar vitamin E tail. Due to its amphiphilic structure, TPGS can carry hydrophobic drugs. Due to the presence of its hydrophilic head, it can reduce the affinity with the mononuclear phagocyte system (MPS), can stably exist in the circulatory system and prolong the half-life. At the same time, TPGS has the activity of inhibiting the efflux transporter P-gp, reducing the efflux effect of intestinal epithelial cells, and thus promoting the absorption of drugs through the gastrointestinal tract.

[0012] CAPB is an amphoteric ionic surfactant with a quaternary ammonium salt group in its molecular structure. CAPB has a weak affinity with mucin in the mucus layer covering the surface of gastrointestinal epithelial cells. Therefore, the drug carried by CAPB is more likely to penetrate through the mucus layer, reach the surface of intestinal epithelial cells and be absorbed by the cells.

[0013] Since TPGS and CAPB are used in combination as carriers, the nanoparticles formed after the amorphous solid dispersion of paclitaxel / TPGS / CAPB dissolves in water have good mucus penetration performance, and at the same time can reduce the P-gp efflux activity. Therefore, the absorption of drugs through the gastrointestinal tract is significantly increased. In addition, the nanoparticles can change the intestinal absorption mechanism of drug molecules, and can be transported and absorbed through the lymphatic system via Peyer's patches on the intestinal surface. The drugs absorbed through the lymph can avoid hepatic metabolism. Therefore, the amorphous solid dispersion preparation of paclitaxel of the present invention can significantly improve the oral bioavailability of paclitaxel.

[0014] In the above oral preparation of the amorphous solid dispersion of paclitaxel, further, the mass percentage content of paclitaxel in the oral preparation is 9% to 17%;

[0015] The mass percentage content of vitamin E polyethylene glycol succinate in the oral preparation is 0% to 45.5%;

[0016] The mass percentage content of cocamidopropyl betaine in the oral preparation is 45.5% to 83%.

[0017] That is, the mass ratio of the paclitaxel, the vitamin E polyethylene glycol succinate, and the cocamidopropyl betaine in the oral preparation is 1:(0-5):(3-5).

[0018] In the first embodiment of the present invention, the mass percentage content of the paclitaxel in the oral preparation is 17%;

[0019] The mass percentage content of the cocamidopropyl betaine in the oral preparation is 83%.

[0020] That is, the mass ratio of the paclitaxel and the cocamidopropyl betaine in the oral preparation is 1:5.

[0021] In the second embodiment of the present invention, the mass percentage content of the paclitaxel in the oral preparation is 17%;

[0022] The mass percentage content of the vitamin E polyethylene glycol succinate in the oral preparation is 33%;

[0023] The mass percentage content of the cocamidopropyl betaine in the oral preparation is 50%.

[0024] That is, the mass ratio of the paclitaxel, the vitamin E polyethylene glycol succinate, and the cocamidopropyl betaine in the oral preparation is 1:2:3.

[0025] In the third embodiment of the present invention, the mass percentage content of the paclitaxel in the oral preparation is 12.5%;

[0026] The mass percentage content of the vitamin E polyethylene glycol succinate in the oral preparation is 25%;

[0027] The mass percentage content of the cocamidopropyl betaine in the oral preparation is 62.5%.

[0028] That is, the mass ratio of the paclitaxel, the vitamin E polyethylene glycol succinate, and the cocamidopropyl betaine in the oral preparation is 1:2:5.

[0029] In the fourth embodiment of the present invention, the mass percentage content of the paclitaxel in the oral preparation is 9%;

[0030] The mass percentage content of the vitamin E polyethylene glycol succinate in the oral preparation is 45.5%;

[0031] The mass percentage content of the cocamidopropyl betaine in the oral preparation is 45.5%.

[0032] That is, the mass ratio of the paclitaxel, the vitamin E polyethylene glycol succinate, and the cocamidopropyl betaine in the oral preparation is 1:5:5.

[0033] Among them, in the third embodiment, the dosage of CAPB in the preparation is further increased, and the oral bioavailability of paclitaxel / TPGS / CAPB (1:2:5, w / w / w) (F7) is significantly improved. However, on the basis of the third embodiment, when the content of TPGS in the preparation is further increased, the oral bioavailability of paclitaxel / TPGS / CAPB (1:5:5, w / w / w) (F8) is decreased, indicating that the content of TPGS should be controlled within a certain range. It can be seen from the pharmacokinetic parameters of paclitaxel in different preparation groups in Table 1 that when the mass ratio of paclitaxel to cocamidopropyl betaine is 1:5, its absolute bioavailability (F%) is 45.61%, which is higher than the absolute bioavailability of paclitaxel / TPGS / CAPB (1:2:3, w / w / w), and the absolute oral bioavailability of paclitaxel / TPGS / CAPB (1:2:5, w / w / w) and paclitaxel / TPGS / CAPB (1:5:5, w / w / w) is higher.

[0034] Further, preferably, the mass percentage content of the paclitaxel in the oral preparation is 17%;

[0035] The mass percentage content of the cocamidopropyl betaine in the oral preparation is 83%.

[0036] Further, preferably, the mass percentage content of the paclitaxel in the oral preparation is 9% - 12.5%;

[0037] The mass percentage content of the vitamin E polyethylene glycol succinate in the oral preparation is 25% - 45.5%;

[0038] The mass percentage content of the cocamidopropyl betaine in the oral preparation is 45.5% - 62.5%.

[0039] More preferably, the mass percentage content of the paclitaxel in the oral preparation is 12.5%;

[0040] The mass percentage content of the vitamin E polyethylene glycol succinate in the oral preparation is 25%;

[0041] The mass percentage content of the cocamidopropyl betaine in the oral preparation is 62.5%.

[0042] In the above paclitaxel amorphous solid dispersion oral preparation, further, in the oral preparation, the paclitaxel, the vitamin E polyethylene glycol succinate, and the cocamidopropyl betaine are all in an amorphous state.

[0043] In the above oral preparation of paclitaxel amorphous solid dispersion, the mass percentage content of paclitaxel in the oral preparation is calculated based on the mass percentage content of paclitaxel crystalline raw material drug in the oral preparation.

[0044] In the above oral preparation of paclitaxel amorphous solid dispersion, the molecular formula of vitamin E polyethylene glycol succinate is C 33 H 54 O 5 ·(C 2 H 4 O) n , CAS No.: 9002-96-4; the mass percentage content of vitamin E polyethylene glycol succinate in the oral preparation is calculated based on the mass percentage content of reagent-grade vitamin E polyethylene glycol succinate in the oral preparation.

[0045] In the above oral preparation of paclitaxel amorphous solid dispersion, as an example, the solid content of cocoamidopropyl betaine is 95% (reagent grade). The mass percentage content of cocoamidopropyl betaine in the oral preparation is calculated based on the mass percentage content of cocoamidopropyl betaine with the above solid content in the oral preparation.

[0046] In a second aspect, the present invention provides a preparation method of the oral preparation of paclitaxel amorphous solid dispersion according to any one of the above, which is as follows 1) or 2):

[0047] 1) It includes the following steps: uniformly dispersing paclitaxel in cocoamidopropyl betaine to obtain the oral preparation of paclitaxel amorphous solid dispersion;

[0048] 2) It includes the following steps: uniformly dispersing paclitaxel in two excipients, vitamin E polyethylene glycol succinate and cocoamidopropyl betaine, to obtain the oral preparation of paclitaxel amorphous solid dispersion.

[0049] Further, the dispersion step in the method 1) is as follows: dissolving paclitaxel and cocoamidopropyl betaine together in an organic solvent to prepare a drug solution, and removing the organic solvent from the drug solution;

[0050] The dispersion step in the method 2) is as follows: dissolving paclitaxel, vitamin E polyethylene glycol succinate and cocoamidopropyl betaine together in an organic solvent to prepare a drug solution, and then removing the organic solvent from the drug solution.

[0051] Furthermore, the solvent is ethanol; the method for removing the solvent can be a suitable solvent evaporation method such as spray drying or rotary evaporation.

[0052] In the present invention, the dispersion step may also be directly mixing paclitaxel with vitamin E polyethylene glycol succinate and cocamidopropyl betaine and then performing melt extrusion, so that the drug is highly dispersed in the preparation.

[0053] The present invention has the following beneficial effects:

[0054] ① Significantly improve the oral bioavailability of paclitaxel. The paclitaxel preparation was orally administered (40 mg / kg) to Sprague-Dawley male rats (180 - 200 g). When the paclitaxel crystalline raw material drug was directly orally administered, or directly orally administered with an injection preparation (paclitaxel / Cremophor EL), the oral bioavailability was very low, and the maximum plasma drug concentration (C max ) was less than 40 ng / mL, and the absolute bioavailability was less than 2%. However, in the present invention, by optimizing the ratio of paclitaxel and excipients, after a single oral administration of the paclitaxel / TPGS / CAPB amorphous solid dispersion, the C max of the drug can be as high as ~3788 ng / mL, and the F% is as high as 86.4%, greatly improving the oral bioavailability of paclitaxel.

[0055] Since both TPGS and CAPB have good compatibility with paclitaxel and can form strong intermolecular interactions between the drug and the excipients. In the paclitaxel / TPGS / CAPB amorphous solid dispersion, the drug is dispersed in the excipients in a molecular state, and the excipients can effectively inhibit the recrystallization of the amorphous drug and can significantly improve the solubility and dissolution rate of the drug in water. In vitro experimental studies have shown that the solubility of paclitaxel crystals in water is 0.12 μg / mL. In the present invention, the paclitaxel / TPGS / CAPB amorphous solid dispersion was gavaged to rats at a drug concentration of 4 mg / mL, and the drug was completely dissolved in water and could remain supersaturated for a long time without recrystallization of the drug. In addition, when the paclitaxel / TPGS / CAPB amorphous solid dispersion is dissolved in water, very small and uniform nanoparticles can be formed, which can change the intestinal absorption mechanism of the drug and avoid the first-pass effect of the liver. At the same time, due to the introduction of TPGS and CAPB, the permeability of the drug through the mucus layer on the surface of gastrointestinal epithelial cells can be increased, and the P-gp drug efflux effect can be inhibited, thereby overcoming a series of physiological and biochemical barriers to the gastrointestinal absorption of paclitaxel. Animal in vivo experiments have proved that this formulation design is very conducive to the intestinal absorption of paclitaxel.

[0056] ② The preparation process of the preparation is simple and the quality is controllable. Since paclitaxel, TPGS, and CAPB in the present invention are all easily soluble in ethanol solvent, the drug and excipients only need to be dissolved in ethanol solvent together, and the solvent can be removed by simple techniques such as spray drying or rotary evaporation to prepare a paclitaxel / TPGS / CAPB amorphous solid dispersion with good homogeneity. The solvent used is also very green and environmentally friendly, reducing the harm to the human body and the environment. In addition, since TPGS is a good plasticizer, it can significantly reduce the glass transition temperature (T g ) of the paclitaxel / TPGS / CAPB system. Therefore, the paclitaxel preparation of the present invention can also be prepared by hot melt extrusion method. In the paclitaxel / TPGS / CAPB amorphous solid dispersion, the drug and excipients can form strong intermolecular interactions. Therefore, during the preparation, storage, and in vitro and in vivo dissolution processes of the preparation, the excipients can effectively inhibit the recrystallization of paclitaxel, maintaining the drug in an amorphous state and supersaturated state, and increasing the physical stability and in vivo absorption behavior of the preparation.

[0057] ③ Low toxicity. TPGS used in the present invention has good safety and can be used for intravenous injection. CAPB also has good safety and can be used for skin administration preparations. After the paclitaxel / TPGS / CAPB amorphous solid dispersion prepared in the present invention is administered to rats by gavage, no adverse reactions are found in the rats. In the acute toxicity experiment of mice, no toxic dose is measured either. Description of the Drawings

[0058] Figure 1 PXRD spectra of CAPB (A), TPGS (B), paclitaxel crystals (C), paclitaxel / TPGS oil micelles (D), and paclitaxel / TPGS / CAPB amorphous solid dispersion (E) in Example 1.

[0059] Figure 2 Physical structure characterization of the nanoparticles formed after the paclitaxel / TPGS / CAPB amorphous solid dispersion in Example 1 is dissolved in water: a) Dynamic light scattering for measuring the particle size of the nanoparticles; b) Dynamic light scattering for measuring the ζ-potential of the nanoparticles; c) Transmission electron micrograph of the nanoparticles.

[0060] Figure 3 Plasma concentration-time curves of paclitaxel in formulation groups F2, F3, and F4 (the inset is an enlarged view from 0 - 4 h).

[0061] Figure 4 Plasma concentration-time curves of paclitaxel in formulation groups F1, F5, F6, F7, and F8 (the inset is an enlarged view from 0 - 4 h). Detailed Embodiments

[0062] The present invention will be further described in detail below in conjunction with specific embodiments. The provided embodiments are only for clarifying the present invention, rather than limiting the scope of the present invention. The following provided embodiments can be used as a guide for those of ordinary skill in the art to make further improvements, and do not limit the present invention in any way.

[0063] Unless otherwise specified, the methods used in the following embodiments are all conventional methods, carried out according to the techniques or conditions described in the literature in this field or according to the product instructions. The materials, reagents, etc. used in the following embodiments, unless otherwise specified, can all be obtained from commercial sources.

[0064] The paclitaxel in the following embodiments is all paclitaxel crystal raw material medicine, which is a product of Wuhan Beileye Biopharmaceutical Technology Co., Ltd., with a solid content exceeding 99%.

[0065] The TPGS in the following embodiments is a product of Shanghai Macklin Biochemical Co., Ltd., with the product name of vitamin E polyethylene glycol succinate, reagent grade, and the product lot number is Lot:C15168997.

[0066] The CAPB in the following embodiments is a product of Shanghai Macklin Biochemical Co., Ltd., with the product name of cocamidopropyl betaine, reagent grade, the product lot number is Lot:C16478324, and the solid content is 95%.

[0067] Example 1

[0068] This example provides an oral preparation group of paclitaxel / TPGS / CAPB amorphous solid dispersion. The preparation steps are as follows: Paclitaxel, TPGS, and CAPB are dissolved in an ethanol solvent at a weight ratio of 1:2:3 (w / w / w), 1:2:5, or 1:5:5 (w / w / w), and the solvent is removed using a rotary evaporator to prepare paclitaxel / TPGS / CAPB amorphous solid dispersion.

[0069] Comparative Example 1

[0070] This comparative example provides a paclitaxel crystal raw material medicine preparation group. The preparation steps are as follows: Weigh the paclitaxel crystal raw material medicine. Dissolve sodium carboxymethylcellulose in pure water to prepare a 0.5% sodium carboxymethylcellulose solution. Add the paclitaxel crystal raw material medicine to the sodium carboxymethylcellulose suspension to obtain a 4 mg / mL paclitaxel crystal drug suspension.

[0071] Comparative Example 2

[0072] This comparative example provides a generic Formulation group, the preparation steps are as follows: Dissolve paclitaxel and polyoxyethylene castor oil EL (Cremophor EL) (Shanghai Macklin Biochemical Technology Co., Ltd.) at a weight ratio of 1:10 (w / w) in an ethanol solvent, and remove the solvent using a rotary evaporator to prepare paclitaxel / polyoxyethylene castor oil EL oily micelles, that is, the imitation formulation.

[0073] Comparative Example 3

[0074] This comparative example provides a paclitaxel / TPGS formulation group, and the preparation steps are as follows: Dissolve paclitaxel and TPGS at a weight ratio of 1:10 (w / w) in an ethanol solvent, and remove the solvent using a rotary evaporator to prepare paclitaxel / TPGS oily micelles.

[0075] Example 2

[0076] This example provides a paclitaxel / CAPB formulation group, and the preparation steps are as follows: Dissolve paclitaxel and CAPB at a weight ratio of 1:5 (w / w) in an ethanol solvent, and remove the solvent using a rotary evaporator to prepare paclitaxel / CAPB amorphous solid dispersion.

[0077] From Figure 1 the PXRD patterns of each group, it can be seen that paclitaxel, TPGS, and CAPB in the formulation of this example are all amorphous. The raw materials of PTX, TPGS, and CAPB all have characteristic crystal diffraction peaks, while in paclitaxel / TPGS or paclitaxel

[0078] / TPGS / CAPB formulations, these crystal diffraction peaks disappear.

[0079] From Figure 2 it can be seen that the paclitaxel / TPGS / CAPB amorphous solid dispersion can significantly improve the solubility and dissolution rate of paclitaxel. After the formulation is dissolved in water, a uniform nanoparticle will be formed, with a particle size of ~7.5 nm and a Zeta potential of -4.3 mV. After the amorphous solid dispersion is dissolved in water, paclitaxel is encapsulated in the TPGS / CAPB carrier, which can avoid the contact between paclitaxel and gastrointestinal metabolic enzymes and reduce drug metabolism and degradation. At the same time, this nanostructure can also inhibit the recrystallization of paclitaxel, increase the physical stability of the drug, and maintain the maximum supersaturation of the drug in water.

[0080] TPGS has the activity of inhibiting the efflux transporter P-gp, reducing the efflux effect of intestinal epithelial cells, and thus promoting the gastrointestinal absorption of drugs. CAPB is an amphoteric surfactant with strong surface activity and is relatively easy to penetrate through the mucus layer. When TPGS and CAPB are used in combination as carriers to prepare paclitaxel / TPGS / CAPB amorphous solid dispersions, we speculate that the nanoparticles formed after dissolution in water have good mucus penetration performance and can also reduce the P-gp efflux activity. Therefore, the gastrointestinal absorption of drugs is significantly increased. In addition, the nanoparticles can change the intestinal absorption mechanism of drug molecules, and can be transported and absorbed through the lymphatic system via Peyer's patches on the intestinal surface. The drugs absorbed through the lymph can avoid hepatic metabolism. Due to the above reasons, the paclitaxel amorphous solid dispersion designed in the present invention can significantly improve the oral bioavailability of paclitaxel.

[0081] Test Example 1

[0082] Using SD rats as an animal model, liquid chromatography-mass spectrometry was used with acetaminophen as an internal standard to conduct an oral pharmacokinetic study of paclitaxel to verify the effect of the paclitaxel / TPGS / CAPB amorphous solid dispersion formulation on improving the oral absorption of paclitaxel. Among them, the high-performance liquid chromatography-mass spectrometer used was the 5500 QTRAP from AB SCIEX, USA. The chromatographic column used was ACQUITY UPLC BEH C18 (1.7 μm, 2.1 mm X 150 mm), the injection volume was 5 μL; the flow rate was 0.2 mL / min; the column temperature was 40 °C; the mobile phases selected were A (water, 0.1% formic acid) and B (acetonitrile); the elution gradient is shown in Table 2. The resolution and separation time of PTX and its internal standard (acetaminophen) were investigated to determine the appropriate LC-MS chromatographic separation conditions. In the mass spectrometry conditions, an electrospray ionization source was used, and the positive ion mode of multiple reaction monitoring (MRM) was used to investigate and determine the mass spectrometry detection parameters of PTX and APAP, as shown in Table 3. The pharmacokinetic study data results were analyzed by the statistical moment method using DAS 2.0 for the experimental data, and the main pharmacokinetic parameters were calculated, including the peak time (T max ) and peak concentration (C max)Use the measured values. Statistical analysis was performed using GraphPad Prism 7 software, and the parameters of each group were expressed as mean ± standard deviation. According to the non-compartmental model, pharmacokinetic parameters were calculated. The absolute bioavailability F(%) was calculated according to the normalized AUC ratio, i.e., (AUCP.O×DOSAGEI.V. / AUC I.V.×DOSAGEP.O), and the meanings of each physical quantity are as follows: AUCP.O is the area under the plasma concentration-time curve of the oral formulation group, DOSAGEI.V. is the dosage of the intravenous injection formulation group, AUC I.V. is the area under the plasma concentration-time curve of the intravenous injection formulation group, and DOSAGEP.O is the dosage of the oral formulation group.

[0083] Sprague-Dawley male rats (180 - 200 g) were selected for the generic formulation by intravenous injection (F1), paclitaxel crystal raw material by oral administration (F2), generic formulation by oral administration (F3), paclitaxel / TPGS (1:10, w / w) by oral administration (F4), paclitaxel / CAPB (1:5, w / w) by oral administration (F5), paclitaxel / TPGS / CAPB (1:2:3, w / w / w) by oral administration (F6), paclitaxel / TPGS / CAPB (1:2:5, w / w / w) by oral administration (F7), paclitaxel / TPGS / CAPB (1:5:5, w / w / w) by oral administration (F8) for blood drug concentration testing and pharmacokinetic studies respectively. The specific operations are as follows:

[0084] Before use, the generic formulation was prepared into a solution with a paclitaxel concentration of 4 mg / mL using normal saline. In the intravenous injection group, each SD rat was injected with 0.5 mL of the drug solution via the tail vein, equivalent to a dosage of 10 mg / kg, denoted as formulation group F1. In the oral administration group, each SD rat was gavaged with 2 mL of the drug solution, equivalent to a dosage of 40 mg / kg, denoted as formulation group F3. Blood was collected from the retro-orbital venous plexus at the scheduled time for corresponding blood drug concentration analysis.

[0085] Before use, the paclitaxel crystal raw material was suspended with 0.5% sodium carboxymethylcellulose to prepare a suspension with a paclitaxel concentration of 4 mg / mL. Each SD rat was gavaged with 2 mL of the drug solution, equivalent to a dosage of 40 mg / kg, denoted as formulation group F2. Blood was collected from the retro-orbital venous plexus at the scheduled time for corresponding blood drug concentration analysis.

[0086] Before use, the generic formulation was prepared into a solution with a paclitaxel concentration of 4 mg / mL using pure water. Each SD rat was gavaged with 2 mL of the drug solution, equivalent to a dosage of 40 mg / kg, denoted as formulation group F3. Blood was collected from the retro-orbital venous plexus at the scheduled time for corresponding blood drug concentration analysis.

[0087] Before use, the paclitaxel / TPGS (1:10, w / w) micelle preparation was dissolved in pure water to prepare a solution with a paclitaxel concentration of 4 mg / mL. Each SD rat was gavaged with 2 mL of the drug solution, corresponding to a dosage of 40 mg / kg, denoted as formulation group F4. Blood was collected from the retro-orbital venous plexus at a predetermined time for corresponding blood drug concentration analysis.

[0088] Before use, the paclitaxel / CAPB amorphous solid dispersion was dissolved in pure water to prepare a solution with a paclitaxel concentration of 4 mg / mL. Each SD rat was gavaged with 2 mL of the drug solution, corresponding to a dosage of 40 mg / kg, denoted as formulation group F5. Blood was collected from the retro-orbital venous plexus at a predetermined time for corresponding blood drug concentration analysis.

[0089] The formulation groups with a paclitaxel / TPGS / CAPB weight ratio of 1:2:3 (w / w / w) were denoted as F6, those with a weight ratio of 1:2:5 (w / w / w) were denoted as F7, and those with a weight ratio of 1:5:5 (w / w / w) were denoted as F8. Before use, the above three different ratios of paclitaxel / TPGS / CAPB amorphous solid dispersions were dissolved in pure water to prepare a solution with a paclitaxel concentration of 4 mg / mL. Each SD rat was gavaged with 2 mL of the drug solution, corresponding to a dosage of 40 mg / kg. Blood was collected from the retro-orbital venous plexus at a predetermined time for corresponding blood drug concentration analysis.

[0090] For each formulation group, the plasma drug concentration-time curves of SD rats after drug administration are as Figure 3 shown, and the pharmacokinetic parameters are summarized in Table 1.

[0091] Table 1 Pharmacokinetic parameters of paclitaxel in different formulation groups (n = 6, M ± SD)

[0092]

[0093] Table 2 Paclitaxel gradient elution program

[0094] Time (min) Water (0.1% formic acid) A (%) Acetonitrile B (%) 0 85 15 1.0 80 20 7.0 20 80 10.0 5 95 12.0 85 15

[0095] Table 3 Main mass spectrometry detection parameters

[0096]

[0097] From Figure 3 - 4 and Table 1, it can be seen that the oral bioavailability of paclitaxel raw material is extremely low (F2), the maximum blood drug concentration (C max ) is only 7.3 ng / mL, and the absolute bioavailability (F%) is only 0.2%. Using generic When the preparation is administered directly by oral route (F3), the oral bioavailability of paclitaxel remains very low, with C max being only 58.2 ng / mL and F% being only 1.3%. Similarly, the paclitaxel / TPGS preparation (F4) prepared using only TPGS as the carrier and the generic preparation (F3) prepared using only Cremophor EL as the carrier have similar oral bioavailabilities, with C max being only 69.7 ng / mL and F% being only 2.6%. The oral bioavailability of the paclitaxel / CAPB amorphous solid dispersion (F5) prepared using only CAPB as the carrier is improved compared to F4, with C max being 1209.8 ng / mL and F% being increased to 45.6%. If the paclitaxel / TPGS / CAPB amorphous solid dispersion is prepared using both TPGS and CAPB as carriers, the oral bioavailability of the drug is further significantly improved. For paclitaxel / TPGS / CAPB (1:2:3, w / w / w) (F6), C max is 1316.2 ng / mL and F% is 18.1%. However, if the amount of CAPB in the preparation is further increased, the oral bioavailability of the drug is greatly improved. The oral absorption effect of paclitaxel / TPGS / CAPB (1:2:5, w / w / w) (F6) is very good, with C max being as high as 3788.2 ng / mL and F% being as high as 86.4%. However, if the content of TPGS is further increased based on F7, the oral bioavailability of the drug cannot be further improved, with C max being 2627.0 ng / mL and F% being 73.2%. This shows that in the paclitaxel drug preparation, the ratio of TPGS to CAPB should be controlled within a reasonable range to achieve the best effect.

[0098] The present invention has been described in detail above. For those skilled in the art, without departing from the spirit and scope of the present invention, the present invention can be implemented within a relatively wide range under equivalent parameters, concentrations and conditions. Although specific embodiments of the present invention are given, it should be understood that the present invention can be further improved. In short, according to the principle of the present invention, this application intends to cover any changes, uses or improvements to the present invention, including changes made using conventional techniques known in the art that depart from the scope disclosed in this application.

Claims

1. A paclitaxel amorphous solid dispersion oral preparation, characterized in that: It consists of paclitaxel and cocamidopropyl betaine; The mass percentage of paclitaxel in the oral preparation is 17%; The mass percentage of the cocamidopropyl betaine in the oral preparation is 83%.

2. A paclitaxel amorphous solid dispersion oral preparation, characterized in that: It consists of paclitaxel, vitamin E polyethylene glycol succinate, and cocamidopropyl betaine; The mass percentage of paclitaxel in the oral preparation is 9% to 17%; The mass percentage of the vitamin E polyethylene glycol succinate in the oral preparation is greater than 0% and less than or equal to 45.5%; The mass percentage of the cocamidopropyl betaine in the oral preparation is 45.5% to 83%.

3. The paclitaxel amorphous solid dispersion oral preparation according to claim 2, characterized in that: The mass percentage of paclitaxel in the oral preparation is 9% to 12.5%; The mass percentage of the vitamin E polyethylene glycol succinate in the oral preparation is 25% to 45.5%; The mass percentage of the cocamidopropyl betaine in the oral preparation is 45.5% to 62.5%.

4. The paclitaxel amorphous solid dispersion oral preparation according to claim 2, characterized in that: The mass percentage of paclitaxel in the oral preparation is 12.5%; The mass percentage of the vitamin E polyethylene glycol succinate in the oral preparation is 25%; The mass percentage of the cocamidopropyl betaine in the oral preparation is 62.5%.

5. The paclitaxel amorphous solid dispersion oral preparation according to claim 2, characterized in that: The mass percentage of paclitaxel in the oral preparation is 9%; The mass percentage of the vitamin E polyethylene glycol succinate in the oral preparation is 45.5%; The mass percentage of the cocamidopropyl betaine in the oral preparation is 45.5%.

6. The paclitaxel amorphous solid dispersion oral preparation according to claim 2, characterized in that: In the oral preparation, paclitaxel, vitamin E polyethylene glycol succinate and cocamidopropyl betaine are all in amorphous state.

7. The method for preparing the paclitaxel amorphous solid dispersion oral preparation according to claim 1, characterized in that: The method comprises the following steps: uniformly dispersing paclitaxel in cocamidopropyl betaine to obtain the paclitaxel amorphous solid dispersion oral preparation.

8. The method for preparing the paclitaxel amorphous solid dispersion oral preparation according to claim 7, characterized in that: The dispersion step is as follows: dissolving paclitaxel and cocamidopropyl betaine in an organic solvent to prepare a drug solution, and removing the organic solvent in the drug solution.

9. The method for preparing the paclitaxel amorphous solid dispersion oral preparation according to any one of claims 2 to 6, characterized in that: The method comprises the following steps: uniformly dispersing paclitaxel in two auxiliary materials, namely, vitamin E polyethylene glycol succinate and cocamidopropyl betaine, to obtain the paclitaxel amorphous solid dispersion oral preparation.

10. The method for preparing the paclitaxel amorphous solid dispersion oral preparation according to claim 9, characterized in that: The dispersion step is as follows: dissolving paclitaxel, vitamin E polyethylene glycol succinate and cocamidopropyl betaine in an organic solvent to prepare a drug solution, and removing the organic solvent in the drug solution.

11. The method for preparing the paclitaxel amorphous solid dispersion oral preparation according to claim 8 or 10, characterized in that: The solvent is ethanol; The method of removing the solvent is solvent volatilization method.

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