Oral drug nano-carrier capable of realizing lymphatic transport as well as preparation method and application of oral drug nano-carrier

Abstract

The invention discloses an oral drug nano-carrier capable of realizing lymphatic transport as well as a preparation method and application thereof, the oral drug nano-carrier is prepared from polylactic acid-glycolic acid copolymer, platycodon grandiflorum fatty acid, distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 and soya bean lecithin according to the mass ratio of (10-20): (5-15): (1-3): (0-5) in sequence, and the oral drug nano-carrier is prepared by mixing the polylactic acid-glycolic acid copolymer, the platycodon grandiflorum fatty acid, the distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 and the soya bean lecithin. The nano-particle dispersion liquid with the average particle size smaller than 300 nm is prepared by combining a nano-precipitation method and a post-insertion method. Experiments prove that the oral drug nano-carrier not only can realize lymphatic transport and remarkably improve oral bioavailability, but also can remarkably improve lung enrichment, has important significance and application value for solving the problem of low lung enrichment of oral indissolvable drugs, can be used as a carrier of the indissolvable oral drugs, and has wide application prospects. Especially a drug carrier for treating lung diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to an oral drug nanocarrier, in particular to an oral drug nanocarrier capable of realizing lymphatic transport, a preparation method and application thereof, and belongs to the technical field of pharmaceutical targeting carriers. BACKGROUND

[0002] As a drug delivery carrier, oral nanoparticles can effectively overcome the multiple physiological barriers of the gastrointestinal tract by protecting drugs from gastrointestinal degradation, enhancing mucosal adhesion, and promoting transmembrane transport, thereby improving the oral absorption of drugs.

[0003] However, after traditional oral administration, the drug is easily affected by the liver first-pass effect after entering the blood through intestinal capillaries, resulting in a significant decrease in the efficiency of pulmonary targeted delivery. Studies have shown that the lymphatic transport pathway can effectively avoid the liver first-pass metabolism of drugs; and drugs absorbed through the lymphatic system can enter the systemic circulation through the subclavian vein and preferentially distribute to the lung tissue after the lymph fluid merges into the blood circulation. Therefore, promoting the transport of drug-loaded oral nanoparticles through the intestinal lymphatic system is of great significance to improve the delivery efficiency of drugs to the lungs.

[0004] After oral administration, oral nanoparticles can be endocytosed by intestinal epithelial cells, then transported intracellularly or degraded and excreted from the cell, and then enter the intestinal capillaries or capillary lymphatic vessels. Among them, the drugs absorbed through the intestinal capillaries will directly face the liver first-pass metabolism, limiting their effective distribution in the lungs; and nanoparticles transported through the lymphatic system can avoid the first-pass effect, thereby enriching in the lungs. At present, the strategies to promote the lymphatic transport of drugs through the intestinal tract mainly include: constructing lipid prodrugs, using lipid-based carriers (such as emulsions, micelles), and designing nanoparticles targeting M cells, etc.

[0005] However, the existing technology still has the following shortcomings: (1) lipid prodrugs need to be chemically modified, which may introduce safety risks; (2) lipid-based carriers are easily affected by gastrointestinal lipid-digesting enzymes, resulting in unstable structure; (3) the effective action of the M cell targeting strategy is limited by the number of M cells in the intestinal tract. Therefore, the development of an oral nanodelivery system that does not require complex chemical modification, is safe and structurally stable, and has delivery efficiency that is not limited by the number of specific cells in the intestinal tract, and can realize lymphatic transport, will be of great significance to solve the problem of low pulmonary enrichment of poorly soluble oral drugs. SUMMARY

[0006] In view of the above problems and needs existing in the prior art, the purpose of the present application is to provide an oral drug nanocarrier capable of realizing lymphatic transport, a preparation method and application thereof.

[0007] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0008] The application discloses an oral drug nano-carrier capable of realizing lymphatic transportation, which is prepared by combining a nano precipitation method with a post-insertion method and is a nano particle dispersion liquid with an average particle size of less than 300 nm, and is prepared from poly (lactic-co-glycolic acid) (PLGA), jiegeng fatty acid, distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) and soybean lecithin in a mass ratio of (10-20):(5-15):(1-3):(0-5).

[0009] In an embodiment, the poly (lactic-co-glycolic acid) (PLGA) is selected from ester-terminated or carboxyl-terminated polymers.

[0010] In an embodiment, the poly (lactic-co-glycolic acid) (PLGA) has a weight average molecular weight (Mw) of 50000±5000 Da.

[0011] In an embodiment, the poly (lactic-co-glycolic acid) (PLGA) is selected from polymers with a lactic acid and glycolic acid monomer ratio of 50:50.

[0012] In an embodiment, the jiegeng fatty acid is a mixture of multiple saturated fatty acids and multiple unsaturated fatty acids, and the unsaturated fatty acid accounts for 70% to 80% by mass.

[0013] In an embodiment, the saturated fatty acids include palmitic acid, stearic acid, arachidic acid, behenic acid and lignoceric acid, and the unsaturated fatty acids include linoleic acid, linolenic acid and eicosapentaenoic acid.

[0014] In an embodiment, the jiegeng fatty acid contains 21% to 22% of palmitic acid by mass, 64% to 65% of linoleic acid by mass and 5% to 6% of linolenic acid by mass.

[0015] In an embodiment, the preparation of the jiegeng fatty acid comprises the following steps:

[0016] 1. A Soxhlet extraction method is used to reflux extract jiegeng decoction pieces for 10 to 12 hours by taking diethyl ether as a solvent and a material-liquid ratio of 1:8 to 1:12 g / mL;

[0017] 2. The extraction liquid is concentrated at 35 to 45 DEG C under reduced pressure to remove the solvent, and jiegeng fatty oil is obtained;

[0018] 3. A 0.1 to 1.0 mol / L KOH-ethanol solution is added to the obtained jiegeng fatty oil in a material-liquid ratio of 1:8 to 1:12 g / mL, and then the solution is heated to reflux in a water bath, and after refluxing for 10 to 30 minutes, the solution is cooled to room temperature, an equal volume of water is added, and diethyl ether / n-hexane is used for extraction to remove unsaponifiable matter, and the water phase is collected;

[0019] IV. The pH of the collected water phase is adjusted to about 2 with 1-3 mol / L hydrochloric acid to precipitate mixed free fatty acids; the organic phase is extracted with diethyl ether, and the extracted organic phase is washed with water until neutral, dried over anhydrous Na2SO4, and then the solvent is concentrated under reduced pressure to obtain the platycodon fatty acid.

[0020] In an embodiment, the mass fraction of phosphatidylcholine in the soybean lecithin is greater than 90%.

[0021] In an embodiment, the preparation of the oral drug nanocarrier comprises the following steps:

[0022] a) dissolving polylactic acid-glycolic acid copolymer (PLGA) in acetone to obtain an oil phase with a PLGA concentration of 4-8 mg / mL;

[0023] b) dissolving platycodon fatty acid in anhydrous ethanol to obtain a platycodon fatty acid ethanol solution with a platycodon fatty acid concentration of 40-60 mg / mL, for standby use;

[0024] c) dissolving DSPE-PEG2000 in anhydrous ethanol to obtain a DSPE-PEG2000 ethanol solution with a DSPE-PEG2000 concentration of 90-110 mg / mL; or dissolving DSPE-PEG2000 and soybean lecithin in anhydrous ethanol to obtain a DSPE-PEG2000 and soybean lecithin ethanol solution with a DSPE-PEG2000 and soybean lecithin concentration of 90-110 mg / mL;

[0025] d) combining the platycodon fatty acid ethanol solution obtained in step b) and the DSPE-PEG2000 ethanol solution or the DSPE-PEG2000 and soybean lecithin ethanol solution obtained in step c) and adding them into deionized water preheated to 60-70℃, stirring at 100-300 r / min for 20-40 min to obtain an aqueous phase;

[0026] e) adding the oil phase into the aqueous phase, stirring at 100-300 r / min at 25℃ for 1-3 h to obtain a dispersion;

[0027] f) rotary evaporation of the dispersion at 35-45℃ to remove the organic solvent, and the obtained nanoparticle dispersion is the oral drug nanocarrier.

[0028] In an embodiment, the volume ratio of the oil phase to the aqueous phase is 1:1-1:3.

[0029] In an embodiment, the oral drug nanocarrier is used as a carrier for a poorly soluble oral drug.

[0030] In an embodiment, the poorly soluble oral drug is a drug for treating lung diseases.

[0031] An embodiment dissolves the poorly soluble oral drug and polylactic acid-glycolic acid copolymer (PLGA) in acetone to prepare an oil phase, and the rest of the steps are the same as the preparation of the oral drug nanocarrier, so that the drug-loaded nanoparticle dispersion capable of realizing lymphatic transport of the poorly soluble oral drug is prepared.

[0032] Compared with the prior art, the present application has the following remarkable beneficial effects:

[0033] Experiments prove that the oral drug nanocarrier can significantly promote the secretion of chylomicrons, not only realizing lymphatic transport, but also significantly improving the oral bioavailability and lung enrichment, which has important significance and application value for solving the problem of low lung enrichment of poorly soluble oral drugs, and can be used as a carrier for poorly soluble oral drugs, especially a drug carrier for treating lung diseases; in addition, the oral drug nanocarrier has the advantages of good biological safety, high stability, easy-to-obtain raw materials, and simple preparation method. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The GC-MS chromatogram of the platycodon grandiflorum fatty acid prepared in Example 1.

[0035] Figure 2 The sample graph of the oral drug nanocarrier prepared in Example 2, wherein: the left graph is a real object graph; and the right graph is a real object graph under laser pen irradiation.

[0036] Figure 3 The sample graph of the oral drug nanocarrier prepared in Example 3, wherein: the left graph is a real object graph; and the right graph is a real object graph under laser pen irradiation.

[0037] Figure 4 The sample graph of the oral drug nanocarrier prepared in Example 4, wherein: the left graph is a real object graph; and the right graph is a real object graph under laser pen irradiation.

[0038] Figure 5 The in-vivo analysis standard curve of the drug SLB established in Example 9.

[0039] Figure 6 The drug concentration-time curve obtained in Example 9.

[0040] Figure 7 The drug concentration-time curve obtained in Example 10.

[0041] Figure 8 The fluorescence distribution semi-quantitative analysis graph, wherein: A is the fluorescence distribution of liver tissue; B is the fluorescence distribution of lung tissue; and C is the ratio of fluorescence intensity (lung fluorescence intensity / liver fluorescence intensity). DETAILED DESCRIPTION

[0042] The present application will be further described in conjunction with the specific embodiments. It should be understood that these embodiments are only used to illustrate but not to limit the scope of the present application. The experimental methods in the following examples without specific conditions are generally according to the conventional conditions or according to the conditions suggested by the manufacturers. The reagents, methods and equipment used in the following examples, if not specifically stated, are the conventional reagents, methods and equipment in the technical field, which can be obtained by commercial purchase.

[0043] Example 1: Preparation of the Platycodon fatty acid according to the present application

[0044] ① 100 g of the Platycodon root slice (dried root) was weighed and added with 1000 mL of diethyl ether, and heated to reflux in water bath, then reflux extraction was carried out for 12 hours;

[0045] ② The extraction liquid was concentrated at 40℃ under reduced pressure to dry the solvent, and 2.47 g of Platycodon fatty oil was obtained;

[0046] ③ 25 mL of 0.5 mol / L KOH-ethanol solution was added to the obtained Platycodon fatty oil, and heated to reflux in water bath. After 20 minutes, the temperature was lowered to room temperature, 25 mL of water was added, and diethyl ether was used to extract the unsaponifiable matter, and the water phase was collected;

[0047] ④ The collected water phase was adjusted to pH≈2 with 2 mol / L hydrochloric acid, and the mixed free fatty acid was precipitated. The organic phase was extracted with diethyl ether, and the extracted organic phase was washed with water until neutral. After drying with anhydrous Na2SO4, the solvent was concentrated under reduced pressure to obtain 2.23 g of Platycodon fatty acid.

[0048] The composition of the obtained Platycodon fatty acid was analyzed, and the specific method was as follows:

[0049] 100 mg of the obtained Platycodon fatty acid was weighed and added with 6 mL of 5% (v / v) hydrochloric acid-methanol solution. After heating at 80℃ water bath for 60 min, the temperature was lowered to room temperature. 5 mL of distilled water and 5 mL of n-hexane were added, and after shaking and standing to separate the layers, the supernatant was filtered through a 0.22 μm microporous filter membrane, and the obtained filtrate was determined by gas chromatography-mass spectrometry.

[0050] 1. Gas chromatography conditions

[0051] Chromatographic column: Agilent DB-5MS quartz capillary column (30 m x 250 μm x 1 μm);

[0052] Injection port temperature: 260℃;

[0053] Temperature rising program: 120℃, rising to 300℃ at 4℃ / min, and maintaining for 10 min;

[0054] Carrier gas (He) flow rate: 3 mL / min;

[0055] Pressure: 0.116 MPa;

[0056] Injection volume: 1 μL;

[0057] Split ratio 50:1, solvent cutoff 2 min.

[0058] 2. Mass spectrometry conditions

[0059] Electron impact ion source (EI); electron energy -70 eV; transmission line temperature 250℃; ion source temperature 230℃; mass scan range m / z 35~400; acquisition time 4~55 min.

[0060] 3. Measurement Method

[0061] A 0.2 μL sample of fatty acid methyl esterification was analyzed using an Agilent 7000B GC-QQQ gas chromatograph-triple quadrupole mass spectrometer. The NIST11 spectral library was searched using the GC-MS Solution chromatographic workstation data processing system, and the chemical components were identified by manual spectral analysis in conjunction with relevant literature. After qualitative analysis, quantitative analysis was performed using the GC-MS Solution chromatographic workstation data processing system according to the area normalization method to determine the relative percentage content of each fatty acid component.

[0062] Figure 1 The GC-MS chromatogram of the obtained Platycodon grandiflorus fatty acids is shown in Table 1. The fatty acid composition and their relative contents are shown in Table 1.

[0063] Table 1. Compositional analysis results of fatty acids obtained from Platycodon grandiflorus.

[0064]

[0065] Depend on Figure 1 As shown in Table 1, the platycodon fatty acids prepared in this embodiment are a mixture of various saturated fatty acids (specifically: palmitic acid, stearic acid, arachidic acid, 9,10-dihydroxyoctadecanoic acid, behenic acid, pentadecanoic acid, lignoceric acid, and octadecanoic acid) and various unsaturated fatty acids (specifically: linoleic acid, linolenic acid, 10-octadecenoic acid, and eicosapentaenoic acid). The mass percentage of unsaturated fatty acids is 73.55%, the mass percentage of palmitic acid is 21.19%, the mass percentage of linoleic acid is 64.09%, and the mass percentage of linolenic acid is 5.67%.

[0066] Example 2: Preparation of the oral drug nanocarrier of the present invention

[0067] a) Weigh 30 mg of polylactic acid-glycolic acid copolymer (PLGA, 50:50, Mw 50kD, purchased from Dalian Meilun Biotechnology Co., Ltd.), dissolve it in acetone, and prepare 5 mL of oil phase with a PLGA concentration of 6 mg / mL.

[0068] b) Weigh 20 mg of Platycodon grandiflorum fatty acid (prepared in Example 1), dissolve it in anhydrous ethanol to obtain a Platycodon grandiflorum fatty acid ethanol solution with a concentration of 50 mg / mL.

[0069] c) Weigh 3.2 mg of distearylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG 2000, purchased from Shanghai Avete Pharmaceutical Technology Co., Ltd.), dissolve it in anhydrous ethanol to prepare a DSPE-PEG2000 ethanol solution with a concentration of 100 mg / mL.

[0070] d) Combine the ethanol solution of Platycodon grandiflorum fatty acids obtained in step b) and the ethanol solution of DSPE-PEG2000 obtained in step c) and add them to deionized water preheated to 65°C. Stir at 200 r / min for 30 min to obtain 10 mL of aqueous phase.

[0071] e) Add the oil phase dropwise to the aqueous phase and stir at 200 r / min for 2 h at 25 °C to obtain a dispersion;

[0072] f) The organic solvent is removed by rotary evaporation at 40°C, and the resulting nanoparticle dispersion is the oral drug nanocarrier described in this invention.

[0073] The particle size and particle size distribution of three parallel nanoparticles were determined using a Malvern particle size analyzer. The results are shown in Table 2.

[0074] Table 2. Particle size and particle size distribution of the nanoparticles obtained in this embodiment.

[0075]

[0076] As shown in Table 2, the oral drug nanocarrier prepared in this embodiment is a uniformly dispersed nanoparticle dispersion with an average particle size of less than 200 nm.

[0077] Figure 2 Images of the oral drug nanocarriers prepared in this embodiment are shown, where: the left image is a photograph of the actual product; the right image is a photograph of the actual product under laser illumination; and the images are derived from... Figure 2 As shown, the prepared oral drug nanocarrier can produce the Tyndall effect and is a nanosystem.

[0078] Example 3: Preparation of the oral drug nanocarrier of the present invention

[0079] a) Weigh 40 mg of polylactic acid-glycolic acid copolymer (PLGA, 50:50, Mw 50kD, purchased from Dalian Meilun Biotechnology Co., Ltd.), dissolve it in acetone, and prepare 5 mL of oil phase with a PLGA concentration of 8 mg / mL.

[0080] b) Weigh 30 mg of Platycodon grandiflorum fatty acid (prepared in Example 1), dissolve it in anhydrous ethanol to obtain a Platycodon grandiflorum fatty acid ethanol solution with a concentration of 60 mg / mL.

[0081] c) Weigh 6 mg of distearate phosphatidylethanolamine-polyethylene glycol (DSPE-PEG 2000, purchased from Shanghai Avete Pharmaceutical Technology Co., Ltd.), dissolve it in anhydrous ethanol to prepare a DSPE-PEG2000 ethanol solution with a concentration of 90 mg / mL.

[0082] d) Combine the ethanol solution of Platycodon grandiflorum fatty acid obtained in step b) and the ethanol solution of DSPE-PEG2000 obtained in step c) and add them to deionized water preheated to 65°C. Stir at 300 r / min for 20 min to obtain 10 mL of aqueous phase.

[0083] e) Add the oil phase dropwise to the aqueous phase and stir at 300 r / min for 1 h at 25 °C to obtain a dispersion;

[0084] f) The organic solvent is removed by rotary evaporation at 40°C, and the resulting nanoparticle dispersion is the oral drug nanocarrier described in this invention.

[0085] The particle size and particle size distribution of three parallel nanoparticles were determined using a Malvern particle size analyzer. The results are shown in Table 3.

[0086] Table 3. Particle size and particle size distribution of the nanoparticles obtained in this embodiment.

[0087]

[0088] As shown in Table 3, the oral drug nanocarrier prepared in this embodiment is a uniformly dispersed nanoparticle dispersion with an average particle size of less than 200 nm.

[0089] Figure 3 Images of the oral drug nanocarriers prepared in this embodiment are shown, where: the left image is a photograph of the actual product; the right image is a photograph of the actual product under laser illumination; and the images are derived from... Figure 3 As shown, the prepared oral drug nanocarrier can produce the Tyndall effect and is a nanosystem.

[0090] Example 4: Preparation of the oral drug nanocarrier of the present invention

[0091] a) Weigh 20 mg of polylactic acid-glycolic acid copolymer (PLGA, 50:50, Mw 50kD, purchased from Dalian Meilun Biotechnology Co., Ltd.), dissolve it in acetone, and prepare 5 mL of oil phase with a PLGA concentration of 4 mg / mL.

[0092] b) Weigh 10 mg of Platycodon grandiflorum fatty acid (prepared from Example 1), dissolve it in anhydrous ethanol to prepare a Platycodon grandiflorum fatty acid ethanol solution with a concentration of 40 mg / mL.

[0093] c) Weigh 2 mg of distearate phosphatidylethanolamine-polyethylene glycol (DSPE-PEG 2000, purchased from Shanghai Avete Pharmaceutical Technology Co., Ltd.), dissolve it in anhydrous ethanol to prepare a DSPE-PEG2000 ethanol solution with a concentration of 110 mg / mL.

[0094] d) Combine the ethanol solution of Platycodon grandiflorum fatty acids obtained in step b) and the ethanol solution of DSPE-PEG2000 obtained in step c) and add them to deionized water preheated to 65°C. Stir at 100 r / min for 40 min to obtain 10 mL of aqueous phase.

[0095] e) Add the oil phase dropwise to the aqueous phase and stir at 100 r / min for 3 h at 25 °C to obtain a dispersion;

[0096] f) The organic solvent is removed by rotary evaporation at 40°C, and the resulting nanoparticle dispersion is the oral drug nanocarrier described in this invention.

[0097] The particle size and particle size distribution of three parallel samples of nanoparticles were determined using a Malvern particle size analyzer. The results are shown in Table 4.

[0098] Table 4. Particle size and particle size distribution of the nanoparticles obtained in this embodiment.

[0099]

[0100] As shown in Table 4, the oral drug nanocarrier prepared in this embodiment is a uniformly dispersed nanoparticle dispersion with an average particle size of less than 200 nm.

[0101] Figure 4 Images of the oral drug nanocarriers prepared in this embodiment are shown, where: the left image is a photograph of the actual product; the right image is a photograph of the actual product under laser illumination; and the images are derived from... Figure 4 As shown, the prepared oral drug nanocarrier can produce the Tyndall effect and is a nanosystem.

[0102] Example 5: Preparation of the oral drug nanocarrier of the present invention

[0103] a) Weigh 30 mg of polylactic acid-glycolic acid copolymer (PLGA, 50:50, Mw 50kD, purchased from Dalian Meilun Biotechnology Co., Ltd.), dissolve it in acetone, and prepare 5 mL of oil phase with a PLGA concentration of 6 mg / mL.

[0104] b) Weigh 20 mg of Platycodon grandiflorum fatty acid (prepared in Example 1), dissolve it in anhydrous ethanol to obtain a Platycodon grandiflorum fatty acid ethanol solution with a concentration of 50 mg / mL.

[0105] c) Weigh 3.2 mg of distearylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG 2000, purchased from Shanghai Avete Pharmaceutical Technology Co., Ltd.), dissolve it in anhydrous ethanol to prepare a DSPE-PEG2000 ethanol solution with a concentration of 100 mg / mL; separately weigh 10 mg of soy lecithin (using Lipoid S100 produced by Lipoid GmbH, Germany, with a phosphatidylcholine mass fraction greater than 94%), dissolve it in anhydrous ethanol to prepare a soy lecithin ethanol solution with a concentration of 100 mg / mL.

[0106] d) Combine the ethanol solution of Platycodon grandiflorum fatty acid obtained in step b) with the ethanol solution of DSPE-PEG2000 and the ethanol solution of soybean lecithin obtained in step c) and add them to deionized water preheated to 65°C. Stir at 200 r / min for 30 min to obtain 10 mL of aqueous phase.

[0107] e) Add the oil phase dropwise to the aqueous phase and stir at 200 r / min for 2 h at 25 °C to obtain a dispersion;

[0108] f) The organic solvent is removed by rotary evaporation at 40°C, and the resulting nanoparticle dispersion is the oral drug nanocarrier described in this invention.

[0109] The nanoparticle size and particle size distribution of the oral drug nanocarrier prepared in this embodiment are shown in Table 5.

[0110] Example 6: Preparation of the oral drug nanocarrier of the present invention

[0111] a) Weigh 30 mg of polylactic acid-glycolic acid copolymer (PLGA, 50:50, Mw 50kD, purchased from Dalian Meilun Biotechnology Co., Ltd.), dissolve it in acetone, and prepare 5 mL of oil phase with a PLGA concentration of 6 mg / mL.

[0112] b) Weigh 20 mg of Platycodon grandiflorum fatty acid (prepared in Example 1), dissolve it in anhydrous ethanol to obtain a Platycodon grandiflorum fatty acid ethanol solution with a concentration of 50 mg / mL.

[0113] c) Weigh 3.2 mg of distearylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG 2000, purchased from Shanghai Avete Pharmaceutical Technology Co., Ltd.), dissolve it in anhydrous ethanol to prepare a DSPE-PEG2000 ethanol solution with a concentration of 100 mg / mL; separately weigh 5 mg of soy lecithin (using Lipoid S100 produced by Lipoid GmbH, Germany, with a phosphatidylcholine mass fraction greater than 94%), dissolve it in anhydrous ethanol to prepare a soy lecithin ethanol solution with a concentration of 100 mg / mL.

[0114] d) Combine the ethanol solution of Platycodon grandiflorum fatty acids obtained in step b) with the ethanol solution of DSPE-PEG2000 and the ethanol solution of soybean lecithin obtained in step c) and add them to 10 mL of deionized water preheated to 65 °C. Stir at 200 r / min for 30 min to obtain 10 mL of aqueous phase.

[0115] e) Add the oil phase dropwise to the aqueous phase and stir at 200 r / min for 2 h at 25 °C to obtain a dispersion;

[0116] f) The organic solvent is removed by rotary evaporation at 40°C, and the resulting nanoparticle dispersion is the oral drug nanocarrier described in this invention.

[0117] The nanoparticle size and particle size distribution of the oral drug nanocarrier prepared in this embodiment are shown in Table 5.

[0118] Example 7: Preparation of the oral drug nanocarrier of the present invention

[0119] a) Weigh 30 mg of polylactic acid-glycolic acid copolymer (PLGA, 50:50, Mw 50kD, purchased from Dalian Meilun Biotechnology Co., Ltd.), dissolve it in acetone, and prepare 5 mL of oil phase with a PLGA concentration of 6 mg / mL.

[0120] b) Weigh 20 mg of Platycodon grandiflorum fatty acid (prepared in Example 1), dissolve it in anhydrous ethanol to obtain a Platycodon grandiflorum fatty acid ethanol solution with a concentration of 50 mg / mL.

[0121] c) Weigh 3.2 mg of distearylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG 2000, purchased from Shanghai Avete Pharmaceutical Technology Co., Ltd.), dissolve it in anhydrous ethanol to prepare a DSPE-PEG2000 ethanol solution with a concentration of 100 mg / mL; separately weigh 2.5 mg of soy lecithin (using Lipoid S100 produced by Lipoid GmbH, Germany, with a phosphatidylcholine mass fraction greater than 94%), dissolve it in anhydrous ethanol to prepare a soy lecithin ethanol solution with a concentration of 100 mg / mL.

[0122] d) Combine the ethanol solution of Platycodon grandiflorum fatty acids obtained in step b) with the ethanol solution of DSPE-PEG2000 and the ethanol solution of soybean lecithin obtained in step c) and add them to 10 mL of deionized water preheated to 65 °C. Stir at 200 r / min for 30 min to obtain 10 mL of aqueous phase.

[0123] e) Add the oil phase dropwise to the aqueous phase and stir at 200 r / min for 2 h at 25 °C to obtain a dispersion;

[0124] f) The organic solvent is removed by rotary evaporation at 40°C, and the resulting nanoparticle dispersion is the oral drug nanocarrier described in this invention.

[0125] The nanoparticle size and particle size distribution of the oral drug nanocarrier prepared in this embodiment are shown in Table 5.

[0126] Table 5. Particle size and particle size distribution of the nanoparticles obtained in Examples 5-7

[0127]

[0128] A comparison of the results shown in Table 5 and Table 2 reveals that, under the same conditions, the appropriate addition of soybean lecithin is beneficial to reducing the particle size of nanoparticles; however, the optimal addition ratio of soybean lecithin to quinoa fatty acids is 1:8.

[0129] Example 8: Preparation of drug-loaded nanoparticle dispersion

[0130] The poorly soluble oral drug was dissolved together with polylactic-co-glycolic acid copolymer (PLGA) in acetone to prepare an oil phase. The remaining steps were the same as those for the preparation of oral drug nanocarriers, thus preparing a drug-loaded nanoparticle dispersion that can achieve lymphatic transport and encapsulate the poorly soluble oral drug.

[0131] This embodiment takes the poorly soluble oral drug "silymarin (SLB)" as an example. The specific preparation method of the drug-loaded nanoparticle dispersion encapsulating silymarin is as follows:

[0132] a) Weigh 270 mg of polylactic acid-glycolic acid copolymer (PLGA, 50:50, Mw 50kD, purchased from Dalian Meilun Biotechnology Co., Ltd.) and 27 mg of silymarin (SLB), dissolve them in acetone, and prepare 45 mL of oil phase with a PLGA concentration of 6 mg / mL and a silymarin (SLB) concentration of 0.6 mg / mL;

[0133] b) Weigh 224 mg of Platycodon grandiflorum fatty acid (prepared from Example 1), dissolve it in anhydrous ethanol to obtain a Platycodon grandiflorum fatty acid ethanol solution with a concentration of 50 mg / mL.

[0134] c) Weigh 28 mg of distearate phosphatidylethanolamine-polyethylene glycol (DSPE-PEG 2000, purchased from Shanghai Avete Pharmaceutical Technology Co., Ltd.) and 28 mg of soybean lecithin (using Lipoid S100 produced by Lipoid GmbH, Germany, in which the mass fraction of phosphatidylcholine is greater than 94%), dissolve them in anhydrous ethanol to prepare an ethanol solution of DSPE-PEG2000 and soybean lecithin with a concentration of 100 mg / mL.

[0135] d) Combine the ethanol solution of euphorbia fatty acids obtained in step b) and the ethanol solution of DSPE-PEG2000 and soybean lecithin obtained in step c) and add them to deionized water preheated to 65°C. Stir at 200 r / min for 30 min to obtain 90 mL of aqueous phase.

[0136] e) Add the oil phase dropwise to the aqueous phase and stir at 200 r / min for 2 h at 25 °C to obtain a dispersion;

[0137] f) The organic solvent was removed by rotary evaporation at 40°C, and the resulting nanoparticle dispersion was the drug-loaded nanoparticle dispersion containing silymarin.

[0138] The particle size and particle size distribution of three parallel nanoparticles were determined using a Malvern particle size analyzer. The results are shown in Table 6.

[0139] Table 6. Particle size and particle size distribution of the nanoparticles obtained in this embodiment.

[0140]

[0141] As shown in Table 6, the drug-loaded nanoparticle dispersion prepared in this embodiment is a uniformly dispersed nanoparticle dispersion with an average particle size of less than 200 nm.

[0142] Take 1 mL of the prepared drug-loaded nanoparticle dispersion, add 9 mL of methanol to it, sonicate to break the emulsion for 15 min, filter the broken emulsion through a 0.45 µm filter membrane, and then determine the total drug mass A by HPLC.

[0143] Another 1 mL of the prepared drug-loaded nanoparticle dispersion was subjected to ultrafiltration centrifugation twice at 3980×g for 30 min each time. The filtrate was taken and the mass B of the free drug in it was detected by HPLC.

[0144] The drug loading was calculated according to the following formula:

[0145] .

[0146] The analytical conditions for determining the drug SLB concentration by HPLC were as follows:

[0147] Chromatographic column: Diamonsil Plus C18 (5μm, 250×4.6 mm);

[0148] Mobile phase: 1% acetic acid water - acetonitrile - methanol (50:9.6:40.4, v / v / v);

[0149] Flow rate: 0.8 mL / min;

[0150] Injection volume: 10 μL;

[0151] Column temperature: 30°C;

[0152] Detection wavelength: 288 nm.

[0153] After detection, the drug loading of the prepared drug-loaded nanoparticle dispersion was 4.03%.

[0154] Example 9: Investigating the lymphatic transport effect of the oral drug nanocarrier described in this invention using the chylomicron blockade model

[0155] Because the operation steps of the chylomicron blockade model are simple and the success rate is high, it has been used by medical workers as a research model for the lymphatic transport effect of drugs. The construction of the chylomicron blockade model is achieved by intragastric administration of a certain amount of cycloheximide to rats to inhibit the secretion of chylomicrons in rats, thereby ultimately blocking the entry of drugs into the lymphatic system.

[0156] SD rats (200±20 g), female rats, SPF grade, were purchased from Shanghai Bikai Keyi Biotechnology Co., Ltd., with the production license number SCXK (Shanghai) 2023-0009; The animals were raised under standard conditions in the Experimental Animal Center of Shanghai University of Traditional Chinese Medicine.

[0157] Ten female SD rats were randomly divided into two groups: one group without the blocker and the other group with the blocker. The rats were fasted for 12 hours before administration. One hour before administration, the rats in the blocker group were injected intraperitoneally with cycloheximide (3 mg / kg) to block lymphatic transport, while the rats in the non-blocker group were given an equal volume of physiological saline. One hour later, both groups of rats were administered the drug-loaded nanoparticle dispersion containing silymarin prepared in Example 8 by gavage. The dosage was 30 mg / kg based on SLB.

[0158] Blood was collected from the retro-orbital venous plexus of rats at predetermined time points after drug administration. Whole blood was collected in centrifuge tubes containing heparin sodium and centrifuged at 5000 rpm for 8 min. The supernatant plasma was collected and stored at -80℃.

[0159] The SLB content in plasma samples was determined by HPLC. The specific determination method is as follows:

[0160] 1. Establishment of the standard curve

[0161] Take 100 μL of SLB reference solution, blow dry with N2, add 100 μL of rat blank plasma, vortex mix for 3 min to obtain standard plasma samples with concentrations of 0.01, 0.025, 0.10, 0.20, 0.50, 1.00, 2.00, 2.50, 3.00 and 5.00 μg / mL;

[0162] Take 100 μL of a standard plasma sample of a certain concentration, add 0.2 M phosphate buffer (pH=5.0) and 2500 U / mL β-glucuronidase working solution, mix well and incubate at 37 °C with shaking for 18 h; add 1.0 M sodium carbonate solution and 0.1 M borate buffer (pH=8.0), vortex to mix; then add methyl tert-butyl ether for extraction: vortex for 5 min, then centrifuge at 4000 rpm for 10 min, collect the upper extract (organic phase), repeat the operation 3 times, combine the 3 extracts, and dry with N2; add 100 μL of chromatographic methanol to reconstitute, vortex for 3 min, then centrifuge at 4 °C and 12000 rpm for 10 min, take the upper liquid, and analyze by HPLC (specific analysis conditions are the same as described in Example 8), record the peak area, and calculate the SLB content;

[0163] A standard curve was obtained by linear regression of the SLB peak area A against the plasma SLB concentration C. See details below. Figure 5 As shown; by Figure 5 As shown, the standard curve for SLB in the range of 0.025–5.00 μg / mL is A = 28.335C - 1.0135 (R = 0.9993), indicating a good linear relationship.

[0164] 2. Take 100 μL of the collected plasma sample, add 0.2 M phosphate buffer (pH=5.0) and 2500 U / mL β-glucuronidase working solution, mix well and incubate at 37 °C with shaking for 18 h; add 1.0 M sodium carbonate solution and 0.1 M borate buffer (pH=8.0), vortex to mix; then add methyl tert-butyl ether for extraction: vortex for 5 min, then centrifuge at 4000 rpm for 10 min, collect the upper extract (organic phase), repeat the operation 3 times, combine the 3 extracts, and blow dry with N2; add 100 μL of chromatographic methanol to reconstitute, vortex for 3 min, then centrifuge at 4 °C and 12000 rpm for 10 min, take the upper liquid, and detect by HPLC (specific analysis conditions are the same as described in Example 8), record the peak area, and then calculate the SLB content in the collected plasma according to the established standard curve.

[0165] Statistical analysis of the data was performed using Graphpad Prism 8.0.1 software, and pharmacokinetic curves were plotted (see details). Figure 6 As shown in the figure, t-tests or one-way ANOVA were used, and the results are expressed as Mean ± SD. P < 0.05 indicates that the results are statistically significant.

[0166] Depend on Figure 6 As shown, at the same time point, the blood drug concentration in the group containing the blocker was significantly lower than that in the group without the blocker. This indicates that under the action of the chylomicron blocker, the promoting effect of the drug-loaded nanoparticles prepared in this invention on chylomicron secretion is inhibited, which will affect the absorption of the drug in vivo. This demonstrates that the drug-loaded nanoparticles prepared in this invention can improve the absorption of the drug (SLB) by promoting the secretion of chylomicrons and their transport via the lymphatic system.

[0167] The drug concentration data in rat plasma were processed using WinNonLin 6.1 software to obtain the corresponding pharmacokinetic parameters, as shown in Table 7.

[0168] Table 7. Pharmacokinetic parameters of rat plasma SLB (Mean ± SD, n=5)

[0169]

[0170] Note: * indicates P < 0.05 compared to the group containing the blocking agent; ** indicates P < 0.01 compared to the group containing the blocking agent.

[0171] As shown in Table 7, C in the group without the blocking agent max The concentration was 1.76 mg / L, which is 5.03 times that of the group containing the blocker, and the oral relative bioavailability AUC of the group without the blocker was also higher. (0-t)The efficacy was 173.33% higher than that of the group containing the blocker; this further demonstrates that the drug-loaded nanoparticles prepared in this invention can improve the oral bioavailability of the drug by promoting the secretion of chylomicrons and mediating lymphatic transport.

[0172] Example 10: Investigating the effect of the oral drug nanocarrier described in this invention on oral bioavailability

[0173] Preparation of drug suspension: Weigh 15 mg of silybin, add 45 mL of 0.5% sodium carboxymethyl cellulose solution, and stir at 300 r / min for 2 h at 25 °C to obtain silybin suspension.

[0174] Ten female SD rats were randomly divided into two groups: a drug suspension group and a drug-loaded nanoparticle dispersion group. The rats were fasted for 12 hours before administration. The drug suspension group was administered the prepared silymarin suspension by gavage, and the drug-loaded nanoparticle dispersion group was administered the drug-loaded nanoparticle dispersion containing silymarin prepared in Example 8 by gavage. The dosage was 30 mg / kg (calculated as SLB) for both groups.

[0175] Blood was collected from the retro-orbital venous plexus of rats at predetermined time points after drug administration. Whole blood was collected in centrifuge tubes containing heparin sodium and centrifuged at 5000 rpm for 8 min. The supernatant plasma was collected and stored at -80℃.

[0176] The SLB content in plasma was determined by HPLC according to the method described in Example 9.

[0177] Statistical analysis of the data was performed using Graphpad Prism 8.0.1 software, and pharmacokinetic curves were plotted (see details). Figure 7 As shown in the figure, t-tests or one-way ANOVA were used, and the results are expressed as Mean ± SD. P < 0.05 indicates that the results are statistically significant.

[0178] Depend on Figure 7 As shown, compared with the drug suspension group, the drug-loaded nanoparticle dispersion group had higher blood drug concentrations at all time points, and the drug (SLB) reached its maximum blood drug concentration at 0.5 h.

[0179] The drug concentration data in rat plasma were further processed using WinNonLin 6.1 software to obtain the corresponding pharmacokinetic parameters, as shown in Table 8.

[0180] Table 8. Pharmacokinetic parameters of rat plasma SLB (Mean ± SD, n=5)

[0181]

[0182] Note: * indicates P < 0.05 compared to the drug suspension group; ** indicates P < 0.01 compared to the drug suspension group; **** indicates P < 0.0001 compared to the drug suspension group.

[0183] As shown in Table 8, the T values ​​of the drug-loaded nanoparticle dispersion group are as follows: max The concentration of C in the drug-loaded nanoparticle dispersion group was significantly lower than that in the drug suspension group, indicating that the drug-loaded nanoparticle dispersion prepared in this invention can improve the absorption of the drug (SLB) in vivo and shorten the time to peak concentration; in addition, the C concentration of the drug-loaded nanoparticle dispersion group was significantly lower than that in the drug suspension group. max It is 13.54 times that of the drug suspension group, and the oral relative bioavailability (AUC) of the drug-loaded nanoparticle dispersion group is also higher. (0-t) The bioavailability was increased by 256.52% compared to the drug suspension group; this result indicates that the oral drug nanocarrier described in this invention can significantly improve the oral bioavailability of poorly soluble drugs (such as SLB).

[0184] Example 11: Investigating the enrichment effect of the oral drug nanocarrier of the present invention on the lungs.

[0185] 1,1-Dioctadecyl-3,3,3,3-Tetramethylindocyanine iodide (DiR) dye is a lipophilic NIR fluorescent anthocyanin dye with excitation and emission wavelengths of 748 nm / 780 nm. It is environmentally sensitive, and its fluorescence intensity is significantly enhanced when it binds to lipophilic biomolecules. The NIR properties of DiR enable it to be used for in vivo imaging. The infrared light emitted by DiR can penetrate cells and tissues efficiently, and the autofluorescence level of the organism itself is very low in the near-infrared region, thus it can be used to trace the distribution of nanoparticles in vivo.

[0186] The nanoparticles prepared in this invention are now labeled with the fluorescent probe DiR. The preparation of the DiR-loaded nanoparticle dispersion is as follows:

[0187] a) Weigh 30 mg of polylactic acid-glycolic acid copolymer (PLGA, 50:50, Mw 50kD, purchased from Dalian Meilun Biotechnology Co., Ltd.) and 1.5 mg of DiR (purchased from Dalian Meilun Biotechnology Co., Ltd.), dissolve them in acetone, and prepare 5 mL of oil phase with a PLGA concentration of 6 mg / mL and a DiR concentration of 0.3 mg / mL;

[0188] b) Weigh 24 mg of Platycodon grandiflorum fatty acid (prepared from Example 1), dissolve it in anhydrous ethanol to prepare a Platycodon grandiflorum fatty acid ethanol solution with a concentration of 50 mg / mL.

[0189] c) Weigh 3 mg of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol (DSPE-PEG 2000, purchased from Shanghai Avert Pharmaceutical Technology Co., Ltd.) and 3 mg of soybean lecithin (Lipoid S100 produced by Lipoid GmbH in Germany, with the mass fraction of phosphatidylcholine greater than 94%), dissolve them in absolute ethanol, and prepare an ethanol solution of DSPE-PEG2000 and soybean lecithin with a concentration of 100 mg / mL for both DSPE-PEG2000 and soybean lecithin;

[0190] d) Combine the platycodon fatty acid ethanol solution obtained in step b) and the ethanol solution of DSPE-PEG2000 and soybean lecithin obtained in step c), add them to deionized water preheated to 65 °C, stir at 200 r / min for 30 min, and prepare 10 mL of the aqueous phase;

[0191] e) Drop the oil phase into the aqueous phase, stir at 200 r / min at 25 °C for 2 h to obtain a dispersion;

[0192] f) Remove the organic solvent from the dispersion by rotary evaporation at 40 °C, and the obtained nanoparticle dispersion is the nanoparticle dispersion loaded with DiR.

[0193] Ten female BALB / c mice (20 ± 2 g, SPF grade, purchased from Shanghai SLAC Laboratory Animal Co., Ltd., production license number: SCXK (Shanghai) 2022-0004) were randomly divided into two groups, one group was the control group, and the other group was the fluorescently labeled nanoparticle group; they were fasted for 12 h before the experiment and had free access to water.

[0194] Each mouse in the control group was intragastrically administered 200 μL of normal saline, and each mouse in the fluorescently labeled nanoparticle group was intragastrically administered 200 μL of the nanoparticle dispersion loaded with DiR (the final concentration of DiR was 100 μg / mL).

[0195] The mice were sacrificed 1 h after administration, the liver and lung organs were dissected and separated, the tissues were minced (about 1 - 10 mm 3 ), and images were taken using a small animal in vivo imaging system in the Cy5.5 channel to observe the fluorescence distribution and perform semi-quantitative analysis. The detailed results are shown in Figure 8 as follows: A is the fluorescence distribution of liver tissue; B is the fluorescence distribution of lung tissue; C is the ratio of fluorescence intensities (lung fluorescence intensity / liver fluorescence intensity); * indicates P < 0.05 compared with the control group; *** indicates P < 0.001 compared with the control group; **** indicates P < 0.0001 compared with the control group.

[0196] From Figure 8As shown, the fluorescence distribution of the oral drug nanocarrier described in this invention in the liver is significantly higher than that in the control group (P<0.05, see Figure A), and the fluorescence distribution in the lung tissue is much higher than that in the control group (P<0.0001, see Figure B). Furthermore, the ratio of lung fluorescence intensity to liver fluorescence intensity is also significantly higher than that in the control group (P<0.001, see Figure C). This reveals that the oral drug nanocarrier described in this invention enhances the distribution in lung tissue, and therefore has important value in solving the problem of poor enrichment in the lungs after oral administration.

[0197] The experimental results above show that the oral drug nanocarrier described in this invention can significantly promote the secretion of chylomicrons, not only achieving lymphatic transport but also significantly improving oral bioavailability and lung enrichment. This is of great significance and application value in solving the problem of low lung enrichment of poorly soluble oral drugs, and can be used as a carrier for poorly soluble oral drugs, especially for treating lung diseases. In addition, the oral drug nanocarrier described in this invention also has the advantages of good biosafety, high stability, readily available raw materials, and simple preparation method.

[0198] Finally, it should be noted that the above are only some preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention shall fall within the scope of protection of the present invention.

Claims

1. An oral drug nanocarrier capable of lymphatic transport, characterized in that: It is a nanoparticle dispersion with an average particle size of less than 300 nm, prepared by combining the nanoprecipitation method and the post-insertion method with polylactic acid-hydroxyacetic acid copolymer (PLGA), platycodon fatty acid, distearate phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) and soybean lecithin in the following mass ratios: (10-20):(5-15):(1-3):(0-5).

2. The oral drug nanocarrier capable of lymphatic transport according to claim 1, characterized in that: The polylactic acid-glycolic acid copolymer (PLGA) is selected from ester-terminated or carboxyl-terminated polymers.

3. The oral drug nanocarrier capable of lymphatic transport according to claim 1, characterized in that: The fatty acids from the platycodon root are a mixture of various saturated fatty acids and various unsaturated fatty acids, wherein the mass percentage of unsaturated fatty acids is 70% to 80%.

4. The oral drug nanocarrier capable of lymphatic transport according to claim 3, characterized in that: Of the fatty acids in the platycodon, palmitic acid accounts for 21% to 22% by mass, linoleic acid accounts for 64% to 65% by mass, and linolenic acid accounts for 5% to 6% by mass.

5. The oral drug nanocarrier capable of lymphatic transport according to claim 1, 3, or 4, characterized in that, The preparation of the platycodon fatty acid includes the following steps: ① The Platycodon grandiflorus slices were extracted by refluxing for 10 to 12 hours using Soxhlet extraction with ether as solvent and a solid-liquid ratio of 1:8 to 1:12 g / mL. ② The extract was concentrated under reduced pressure at 35-45℃ to dry the solvent, thus obtaining Platycodon grandiflorum fatty oil; ③ Add 0.1-1.0 mol / L KOH-ethanol solution to the obtained Platycodon grandiflorum fatty oil, with a ratio of 1:8-1:12 g / mL. Then heat in a water bath to reflux. After refluxing for 10-30 minutes, cool to room temperature, add an equal volume of water, and extract with diethyl ether / n-hexane to remove unsaponifiable matter. Collect the aqueous phase. ④ Adjust the pH of the collected aqueous phase to ≈2 with 1-3 mol / L hydrochloric acid to precipitate mixed free fatty acids; extract with diethyl ether, wash the extracted organic phase with water until neutral, dry with anhydrous Na2SO4 and concentrate under reduced pressure to obtain the platycodon fatty acids.

6. A method for preparing an oral drug nanocarrier capable of lymphatic transport as described in claim 1, characterized in that, Includes the following steps: a) Dissolve polylactic acid-glycolic acid copolymer (PLGA) in acetone to obtain an oil phase with a PLGA concentration of 4-8 mg / mL; b) Dissolve the platycodon fatty acids in anhydrous ethanol to prepare a platycodon fatty acid ethanol solution with a concentration of 40-60 mg / mL for later use. c) Dissolve DSPE-PEG2000 in anhydrous ethanol to prepare an ethanol solution of DSPE-PEG2000 with a concentration of 90–110 mg / mL; or, dissolve both DSPE-PEG2000 and soybean lecithin in anhydrous ethanol to prepare an ethanol solution of DSPE-PEG2000 and soybean lecithin with a concentration of 90–110 mg / mL. d) Combine the ethanol solution of euphorbia fatty acids obtained in step b) and the ethanol solution of DSPE-PEG2000 obtained in step c) or the ethanol solution of DSPE-PEG2000 and soybean lecithin, add them to deionized water preheated to 60-70°C, and stir at 100-300 r / min for 20-40 min to obtain an aqueous phase. e) Add the oil phase dropwise to the aqueous phase and stir at 100-300 r / min for 1-3 h at 25°C to obtain a dispersion; f) The organic solvent is removed by rotary evaporation at 35-45°C, and the resulting nanoparticle dispersion is the oral drug nanocarrier.

7. The preparation method according to claim 6, characterized in that: The volume ratio of the oil phase to the water phase is 1:1 to 1:

3.

8. The application of the oral drug nanocarrier capable of lymphatic transport as described in claim 1, characterized in that: Used as a carrier for poorly soluble oral drugs.

9. The application according to claim 8, characterized in that: The poorly soluble oral medication is a drug for treating lung diseases.

10. The application according to claim 8, characterized in that: The poorly soluble oral drug was dissolved together with polylactic-co-glycolic acid copolymer (PLGA) in acetone to prepare an oil phase. The remaining steps were the same as those for the preparation of oral drug nanocarriers, thus preparing a drug-loaded nanoparticle dispersion that can achieve lymphatic transport and encapsulate the poorly soluble oral drug.

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