PRODUCTION SYSTEM AND METHOD FOR PRODUCING NANOPARTICLES

Abstract

Disclosed in the present invention are a production system and method for producing nanoparticles. Particularly disclosed is a production system, which comprising (1) a first pipeline, (2) a second pipeline, (3) a combined pipeline, and a fluid outlet; wherein the first pipeline and the second pipeline are connected to the combined pipeline, a first phase solution enters the combined pipeline through an outlet of the first pipeline, a second phase solution enters the combined pipeline through an outlet of the second pipeline, and the first phase solution and the second phase solution are mixed in the combined pipeline to form a combined phase; which combined phase flows out through the outlet of the combined pipeline. The production system and method of the present invention can realize the continuous, large-scale and controllable production of composite nanoparticles for a photosensitizer/an anti-tumor drug.

Claims

1. A production system, which includes (1) a first pipeline, (2) a second pipeline, (3) a combined pipeline and their outlets; wherein, the first pipeline and the second pipeline are connected to the combined pipeline, the first phase solution enters the combined pipeline through the first pipeline outlet, the second phase solution enters the combined pipeline through the second pipeline outlet, the first phase solution and the second phase solution are mixed in the combined pipeline to form a combined phase; the combined phase flows out through the outlet of the combined pipeline; the first pipeline outlet is a spray hole with a certain shape and diameter, and the first phase solution passes through the first pipeline and enters the combined pipeline through the spray hole; The spray hole diameter D.sub.1(S) is 0.3-0.6 mm; The combined pipeline inner diameter D.sub.3(IN) is 5.4-50.0 mm.

2. The system of claim 1, wherein the core part of the production system includes: (1) a first pipeline; (2) a second pipeline; (3) a combined pipeline; (4) turbulent mixing device; (5) fluid outlet; wherein, the first pipeline and the second pipeline are connected to the combined pipeline, the first phase solution enters the combined pipeline through the first pipeline outlet, the second phase solution enters the combined pipeline through the second pipeline outlet, the first phase solution and the second phase solution are mixed in the combined pipeline to form a combined phase. The combined phase is fully mixed by a turbulent mixing device. After the mixing, the composite nanoparticles are collected into a suitable container through the outlet of the combined pipeline.

3. The system of claim 1, wherein the production system fulfills one or more of the following: (1) the first pipeline is coaxial with the combined pipeline and the second pipeline is perpendicular to the combined pipeline; (2) the mixing is turbulent mixing; The turbulent mixing can be achieved by adding a turbulent mixing device in the combined pipeline; (3) the first pipeline outlet is positioned within the combined pipeline.

4. The system of claim 3, wherein the production system fulfills one or more of the following: (1) the second pipeline inner diameter D.sub.2(IN) is selected from 0.3-50.0 mm; (2) the combined pipeline length is selected from 6 to 120 cm; (3) the ratio of the combined pipeline length to the combined pipeline inner diameter is (16-17):1; (4) the second pipeline inner diameter D.sub.2(IN) is the same as the combined pipeline inner diameter D.sub.3(IN); (5) the ratio of the spray hole diameter D.sub.1(S) to the combined pipeline inner diameter D.sub.3(IN) is 1:(2-50); (6) the turbulent mixing achieved by turbulent mixing device includes but not limited to: increasing the fluid flow velocity, changing the degree of pipeline twisting, or adding baffles or special-shaped objects within the pipeline.

5. The system of claim 4, wherein the production system fulfills one or more of the following: (1) the second pipeline inner diameter D.sub.2(IN) is 5.4 mm; (2) the combined pipeline inner diameter D.sub.3(IN) is 5.4 mm; (3) the combined pipeline length is 9 cm; (4) the ratio of the combined pipeline length to the combined pipeline inner diameter is 16.7:1; (5) the ratio of the spray hole diameter D.sub.1(S) to the combined pipeline inner diameter D.sub.3(IN) is 1:9 or 1:18; (6) the first pipeline outer diameter D.sub.1(O) is 2 mm; (7) the second pipeline outer diameter D.sub.2(O) is 6 mm; (8) the combined pipeline outer diameter D.sub.3(O) is 6 mm; (9) the turbulent mixing device is static mixer, and the Reynolds number calculated based on the fluid in the circular tube is selected from 500-100000; (10) the amount of turbulent mixing device can be one or more; (11) the materials used in the first pipeline, the second pipeline, the combined pipeline, the turbulent mixing device, and the fluid outlet are each selected from one or more of stainless steel, polytetrafluoroethylene, polyethylene, polypropylene, latex, silicone, or other polymer materials.

6. A production method for producing photosensitizer/anti-tumor drug composite nanoparticles, which includes the following steps: in the production system of claim 1, the first phase solution and the second phase solution are mixed, and the photosensitizer/anti-tumor drug composite nanoparticles are collected from combined phase through the fluid outlet; the solvent in the first phase solution is a good solvent for an anti-tumor drug or its pharmaceutically acceptable salt, and the solute is (1) an anti-tumor drug or its pharmaceutically acceptable salt and a photosensitizer, or (2) an anti-tumor drug or its pharmaceutically acceptable salt; the solvent in the second phase solution is an anti-solvent of the anti-tumor drug or its pharmaceutically acceptable salt, and the solute is (1) absent, or (2) a photosensitizer; when the solute in the first phase solution is an anti-tumor drug or its pharmaceutically acceptable salt and a photosensitizer, the solute in the second phase solution does not exist; when the solute in the first phase solution is an anti-tumor drug or its pharmaceutically acceptable salt, the solute in the second phase solution is a photosensitizer.

7. The method of claim 6, wherein the production method is any of the following: method I: (1a). one or more of the anti-tumor drugs or their pharmaceutically acceptable salts and one or more of the photosensitizers are dissolved in a first phase solvent to form a first phase solution, and the first phase solution is a good solvent for the anti-tumor drug or its pharmaceutically acceptable salt and the photosensitizer; (1b). the second phase solution is an anti-solvent for anti-tumor drugs or their pharmaceutically acceptable salts and photosensitizers; (1c). the first phase solution with the quantity of flow Q.sub.1 and the second phase solution with the quantity of flow Q.sub.2 are mixed in the combined phase. Under turbulent shear, the two phase solutions mix rapidly to form a mixed solvent of the first phase and the second phase, and produce a stably dispersed composite nano formulation of photosensitizer and anti-tumor drug with a certain particle size and distribution coefficient; or, method II: (2a). one or more of the anti-tumor drugs or their pharmaceutically acceptable salts are dissolved in first phase solvent to form first phase solution, and the first phase solvent is good solvent for anti-tumor drugs or their pharmaceutically acceptable salts; (2b). one or more of the photosensitizers are dissolved in second phase solvent to form second phase solution, and the second phase solvent is anti-solvent for anti-tumor drugs or their pharmaceutically acceptable salts; (2c). the first phase solution with quantity of flow Q.sub.1 and the second phase solution with quantity of flow Q.sub.2 are mixed in the combined phase. Under turbulent shear, the two phase solutions mix rapidly to form a mixed solvent of the first phase and the second phase, and produce a stably dispersed composite nano formulation of photosensitizer and anti-tumor drug with a certain particle size and distribution coefficient.

8. The method of claim 6, wherein the quantity of flow Q.sub.1 of the first phase solution through the first pipeline is selected from 1-1000 ml/min; the temperature T.sub.1 of the first phase solution is selected from 0-90 C.; the quantity of flow Q.sub.2 of the second phase solution through the second pipeline is selected from 10-10000 ml/min; the temperature T.sub.2 of the second phase solution is selected from 0-90 C.

9. The method of claim 6, wherein the production method fulfills one or more of the following: (1) the temperature of the first phase solution is 0-90 C.; (2) the temperature of the second phase solution is 0-90 C.; (3) the Reynolds number Re of fluid in the combined phase is 800 to 7700; (4) the flow velocity ratio FVR between the first phase solution and the combined phase is 5 to 26; (5) when the Re of the combined phase is less than 3000, the FVR of the production system is 17 to 26, and/or the production system further includes a static mixer; (6) when the FVR of the production system is less than 17, the Re of the combined phase is 3000 to 7700, and/or the production system further includes a static mixer.

10. The method of claim 6, wherein the production method fulfills one or more of the following: (1) the temperature of the first phase solution is 25 C.; (2) the temperature of the second phase solution is 25 C.; (3) the Reynolds number Re of fluid in the combined phase is 3000 to 7700; (4) the flow velocity ratio FVR between the first phase solution and the combined phase is 17 to 26; (5) when the Re of the combined phase is less than 3868, the FVR of the production system is 20.8 to 26, and/or the production system further includes a static mixer; (6) when the FVR of the production system is less than 20.8, the Re of the combined phase is 3868 to 7659, and/or the production system further includes a static mixer.

11. The method of claim 6, wherein the production method fulfills one or more of the following: (1) the photosensitizer is selected from one or more of cyanine type molecules, porphyrin type molecules, porphyrin precursors, phthalocyanine type molecules and chlorin type molecules; (2) the anti-tumor drug contains one or more of aromatic rings or aromatic heterocycles in its structure. The aromatic rings or aromatic heterocycles have conjugated planar ring systems covered by delocalized electrons. The anti-tumor drugs are selected from one or more of camptothecin type compounds, paclitaxel type compounds, anthracycline type compounds, targeted drugs or other anti-tumor drugs; (3) the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (1-15):1; (4) the solvent used in the first phase solution and the second phase solution is water, an aqueous buffer solution with a certain pH value, or an organic solvent miscible with water. Further, the organic solvent is one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, DMF, DMAc, N-methylpyrrolidone, DMSO, butyl sulfone, tetramethylene sulfone, THF, 2-methyltetrahydrofuran, acetonitrile, acetone, ethylene glycol, ethylene glycol methyl ether, ethylene glycol ethyl ether, HMPA, dioxane, formic acid, acetic acid, hydroxypropionic acid, ethylamine, ethylenediamine, glycerol or pyridine; (5) the molar concentration of the anti-tumor drug or its pharmaceutically acceptable salt in the first phase solution is 0.01-0.3M; (6) the molar concentration of the photosensitizer in the first phase solution or the second phase solution is 0.01-0.3M.

12. The method of claim 11, wherein the production method fulfills one or more of the following: (1) the cyanine type molecules are selected from one or more of IR780, IR820, indocyanine green and indocyanine green analogs; (2) the porphyrin type molecules are selected from hematoporphyrin monomethyl ether; (3) the porphyrin precursors are selected from 5-aminolevulinic acid and/or 5-aminolevulinic acid esters; (4) the phthalocyanine type molecules are selected from one or more of copper phthalocyanine, cobalt phthalocyanine, aluminum phthalocyanine, nickel phthalocyanine, calcium phthalocyanine, sodium phthalocyanine, magnesium phthalocyanine, zinc phthalocyanine, indium phthalocyanine, oxytitanium phthalocyanine, manganese phthalocyanine or phthalocyanine derivatives; (5) the chlorin type molecules are selected from one or more of chlorins, talaporfin, verteporfin, temoporfin, rostaporfin, porfimer sodium, hemoporfin and HPPH. (6) the camptothecin type molecules are selected from one or more of camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, lurtotecan, gimatecan, belotecan, 10-hydroxycamptothecin, SN-38, exatecan, irinotecan, topotecan and deruxtecan; (7) the paclitaxel type compounds are selected from one or more of paclitaxel, docetaxel, cabazitaxel, 7-epipaclitaxel, 2-acetylpaclitaxel, 10-deacetylpaclitaxel, 7-epi-10-deacetyltaxol, 7-xylosyltaxol, 10-deacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylacetaxel and larotaxel; (8) the anthracycline type compounds are selected from one or more of doxorubicin, epirubicin, daunorubicin, pirarubicin and aclacinomycin; (9) the targeted drugs are selected from one or more of gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, vandetanib, neratinib, osimertinib, imatinib, sorafenib, sunitinib, lapatinib, dasatinib, olaparib, niraparib, rucaparib, fluzoparib, pamiparib, veliparib, talazoparib and apatinib; (10) the other anti-tumor drugs are selected from one or more of etoposide, teniposide, vinblastine, vincristine, vinorelbine, vindesine, maytansine, curcumin, harringtonine, homoharringtonine, gemcitabine, capecitabine, fludarabine, cladribine, pemetrexed, bortezomib, carfilzomib, ixazomib, carmustine, fluorouracil, cytarabine, cyclosporine A, eribulin and trabectedin; (11) the solvent in the first phase solution is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, DMF, DMAc, N-methylpyrrolidone, DMSO, butyl sulfone, tetramethylene sulfone, THF, 2-methyltetrahydrofuran, acetonitrile, acetone, ethylene glycol, ethylene glycol methyl ether, ethylene glycol ethyl ether, HMPA, dioxane, formic acid, acetic acid, hydroxypropionic acid, ethylamine, ethylenediamine, glycerol and pyridine; (12) the solvent in the second phase solution is water or a buffer with a pH of 210; (13) the molar concentration of the anti-tumor drug or its pharmaceutically acceptable salt in the first phase solution is 0.05-0.1M; (14) the molar concentration of the photosensitizer in the first phase solution or the second phase solution is 0.05-0.1M.

13. The method of claim 6, wherein the production method fulfills one or more of the following: (1) the photosensitizer is indocyanine green or chlorin e6; (2) the anti-tumor drug is camptothecin, 10-hydroxycamptothecin, exatecan, Dxd, paclitaxel, sorafenib or curcumin.

14. The method of claim 6, wherein in the photosensitizer/anti-tumor drug composite nanoparticles, the combination of the photosensitizer and the anti-tumor drug is a combination of indocyanine green and camptothecin, indocyanine green and 10-hydroxycamptothecin, indocyanine green and 7-ethylcamptothecin, indocyanine green and 7-ethyl-10-hydroxycamptothecin, indocyanine green and exatecan, indocyanine green and Dxd, indocyanine green and paclitaxel, indocyanine green and docetaxel, indocyanine green and cabazitaxel, indocyanine green and sorafenib, indocyanine green and curcumin, chlorin e6 and 7-ethyl-10-hydroxycamptothecin; the preferable combination of the photosensitizer and the anti-tumor drug is a combination of indocyanine green and camptothecin, indocyanine green and 10-hydroxycamptothecin, indocyanine green and exatecan, indocyanine green and Dxd, indocyanine green and paclitaxel, indocyanine green and sorafenib, indocyanine green and curcumin, indocyanine green and 7-ethyl-10-hydroxycamptothecin, chlorin e6 and 7-ethyl-10-hydroxycamptothecin.

15. The method of claim 6, wherein the production method fulfills one or more of the following: (1) when the anti-tumor drug is 7-ethyl-10-hydroxycamptothecin and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (2-15):1; (2) when the anti-tumor drug is camptothecin and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (1-10):1; (3) when the anti-tumor drug is 10-hydroxycamptothecin and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (1-10):1; (4) when the anti-tumor drug is exatecan and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (2-15):1; (5) when the anti-tumor drug is Dxd and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (5-10):1; (6) when the anti-tumor drug is sorafenib and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (6-8):1; (7) when the anti-tumor drug is paclitaxel and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (1-10):1; (8) when the anti-tumor drug is curcumin and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (5-8):1; (9) when the anti-tumor drug is 7-ethyl-10-hydroxycamptothecin and the photosensitizer is chlorin e6, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is 2:1.

16. The method of claim 6, wherein the production method also includes the following post-reaction processing steps: adding water to the prepared mixed solution and ultrafiltration; or further concentration and ultrafiltration. wherein, the ultrafiltration uses 2-100 kDa ultrafiltration membrane.

17. The method of claim 6, wherein the production method fulfills one or more of the following: (1) the particle size of the nanoparticles is less than 1000 nm; (2) the polydispersity index of the nanoparticle is less than 0.4.

18. A photosensitizer/anti-tumor drug composite nanoparticle, which is prepared by the method of claim 6; the photosensitizer/anti-tumor drug composite nanoparticle is SN-38/ICG composite nanoparticles, wherein the SN-38 encapsulation efficiency is greater than 80%.

19. The system of claim 4, wherein the static mixer is selected from one or more of SV type static mixer, SX type static mixer, SL type static mixer, SH type static mixer and SK type static mixer.

20. The method of claim 6, wherein the production method fulfills one or more of the following: (1) the Reynolds number Re of fluid in the combined phase is 3868 to 7659; (2) the flow velocity ratio FVR between the first phase solution and the combined phase is 20.8 to 26; (3) when the anti-tumor drug is 7-ethyl-10-hydroxycamptothecin and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is 2:1, 5:1, 10:1 or 15:1; (4) when the anti-tumor drug is camptothecin and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is 1:1, 2:1, 5:1 or 10:1; (5) when the anti-tumor drug is 10-hydroxycamptothecin and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is 1:1, 2:1, 5:1 or 10:1; (6) when the anti-tumor drug is exatecan and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is (2-10): 1; (7) when the anti-tumor drug is paclitaxel and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is 1:1, 2:1, 5:1 or 10:1; (8) when the anti-tumor drug is curcumin and the photosensitizer is indocyanine green, the molar ratio of the anti-tumor drug or its pharmaceutically acceptable salt to the photosensitizer is 5:1, 6:1, 7:1 or 8:1; (9) the ultrafiltration uses 30 kDa ultrafiltration membrane; (10) the particle size of the nanoparticles is less than 500 nm.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0101] FIG. 1. Schematic diagram of the core part of the production system for the continuous production of photosensitizers and anti-tumor drug composite nano formulations (D.sub.1(S)=0.3 mm, D.sub.3(IN)=5.4 mm)

[0102] FIG. 2. Schematic diagram of the core part of the production system for the continuous production of photosensitizers and anti-tumor drug composite nano formulations (D.sub.1(S)=0.3 mm, D.sub.3(IN)=5.4 mm, SK static mixer)

[0103] FIG. 3. Particle size and distribution of SN-38/ICG nanoparticles (Example 5)

[0104] FIG. 4. Particle size and distribution of SN-38/ICG nanoparticles (Example 6)

[0105] FIG. 5. Particle size and distribution of SN-38/ICG nanoparticles (Example 7)

[0106] FIG. 6. Particle size and distribution of SN-38/ICG nanoparticles (Example 8)

[0107] FIG. 7. Particle size and distribution of SN-38/ICG nanoparticles (Example 9)

[0108] FIG. 8. Particle size and distribution of SN-38/ICG nanoparticles (Example 10)

[0109] FIG. 9. Particle size and distribution of SN-38/ICG nanoparticles (Example 11)

[0110] FIG. 10. Particle size and distribution of SN-38/ICG nanoparticles (Example 12)

[0111] FIG. 11. Particle size and distribution of SN-38/ICG nanoparticles (Example 13)

[0112] FIG. 12. Particle size and distribution of SN-38/ICG nanoparticles (Example 14)

[0113] FIG. 13. Particle size and distribution of SN-38/ICG nanoparticles (Example 15)

[0114] FIG. 14. Particle size and distribution of SN-38/ICG nanoparticles (Example 16)

[0115] FIG. 15. Particle size and distribution of SN-38/ICG nanoparticles (Example 17)

[0116] FIG. 16. Particle size and distribution of SN-38/ICG nanoparticles (Example 18)

[0117] FIG. 17. Particle size and distribution of SN-38/ICG nanoparticles (Example 19)

[0118] FIG. 18. Particle size and distribution of SN-38/ICG nanoparticles (Example 20)

[0119] FIG. 19. Particle size and distribution of SN-38/ICG nanoparticles (Example 21)

[0120] FIG. 20. Particle size and distribution of SN-38/ICG nanoparticles (Example 22)

[0121] FIG. 21. Particle size and distribution of SN-38/ICG nanoparticles (Example 23)

[0122] FIG. 22. Particle size and distribution of SN-38/ICG nanoparticles (Example 24)

[0123] FIG. 23. Particle size and distribution of SN-38/ICG nanoparticles (Example 25)

[0124] FIG. 24. Particle size and distribution of SN-38/ICG nanoparticles (Example 26)

[0125] FIG. 25. Particle size and distribution of SN-38/ICG nanoparticles (Example 27)

[0126] FIG. 26. Particle size and distribution of SN-38/ICG nanoparticles (Example 28)

[0127] FIG. 27. Particle size and distribution of SN-38/ICG nanoparticles (Example 29)

[0128] FIG. 28. Particle size and distribution of SN-38/ICG nanoparticles (Example 30)

[0129] FIG. 29. Particle size and distribution of SN-38/ICG nanoparticles (Example 31)

[0130] FIG. 30. Particle size and distribution of SN-38/ICG nanoparticles (Example 32)

[0131] FIG. 31. Particle size and distribution of SN-38/ICG nanoparticles (Example 33)

[0132] FIG. 32. Particle size and distribution of SN-38/ICG nanoparticles (Example 34)

[0133] FIG. 33. Particle size and distribution of SN-38/ICG nanoparticles (Example 35)

[0134] FIG. 34. Particle size and distribution of SN-38/ICG nanoparticles (Example 36)

[0135] FIG. 35. Particle size and distribution of SN-38/ICG nanoparticles (Example 37)

[0136] FIG. 36. Particle size and distribution of SN-38/ICG nanoparticles (Example 38)

[0137] FIG. 37. Particle size and distribution of SN-38/ICG nanoparticles (Example 39) before ultrafiltration

[0138] FIG. 38. Particle size and distribution of SN-38/ICG nanoparticles (Example 39) after ultrafiltration

[0139] FIG. 39. Comparative Example 2 production of SN-38/ICG nanoparticles (SN-38:ICG=10:1-1:1, molar ratio), small amount of SN-38/ICG nanoparticles was prepared by nanoprecipitation method

[0140] FIG. 40. Production of SN-38/ICG nanoparticles in Example 40 (SN-38:ICG=15:1-5:1, molar ratio) particle size distribution graph

[0141] FIG. 41. Production of camptothecin/ICG nanoparticles in Example 41 (camptothecin:ICG=10:1-1:1, molar ratio) particle size distribution graph

[0142] FIG. 42. Production of 10-hydroxycamptothecin/ICG nanoparticles in Example 42 (10-hydroxycamptothecin:ICG=10:1-1:1, molar ratio) particle size distribution graph

[0143] FIG. 43. Production of exatecan/ICG nanoparticles in Example 43 (exatecan:ICG=2:1-10:1, molar ratio) particle size distribution graph

[0144] FIG. 44. Production of sorafenib/ICG nanoparticles in Example 45 (sorafenib:ICG=1:1-8:1, molar ratio) solution after centrifugation and precipitation

[0145] FIG. 45. Production of sorafenib/ICG nanoparticles in Example 45 (sorafenib:ICG=6:1-8:1, molar ratio) particle size distribution graph

[0146] FIG. 46. Production of PTX/ICG nanoparticles in Example 46 (PTX:ICG=5:1-10:1, molar ratio) particle size distribution graph

[0147] FIG. 47. Production of curcumin/ICG nanoparticles in Example 47 (curcumin:ICG=5:1-8:1, molar ratio) particle size distribution graph

[0148] FIG. 48. Production of SN-38/Ce6 nanoparticles in Example 48 (SN-38/Ce6=2:1, molar ratio) chlorin e6 particle size distribution graph

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0149] The abbreviations used in the present invention are shown in Table 1.

TABLE-US-00001 TABLE 1 Abbreviation Full name D.sub.1(S) Diameter of a spray hole in the end of the first pipeline D.sub.2(IN) Inner diameter of the second pipeline D.sub.3(IN) Inner diameter of the combined pipeline Re Reynolds number Q.sub.1 The quantity of flow of the first pipeline Q.sub.2 The quantity of flow of the second pipeline T.sub.1 First phase solution temperature T.sub.2 Second phase solution temperature IR780 2-[2-[2-Chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2H- indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3- dimethyl-1-propylindolium iodide IR820 New indocyanine green ICG Indocyanine green HPPH Photochlor SN-38 7-Ethyl-10-hydroxycamptothecin DMF N,N-dimethylformamide DMAc N,N-dimethylacetamide DMSO Dimethyl sulfoxide THF Tetrahydrofuran HMPA Hexamethylphosphoramide siRNA Small interfering RNA Ce6 Chlorin e6 DOX Doxorubicin HCPT 10-Hydroxycamptothecin PTX Paclitaxel UA Ursolic acid LA Lactobionic acid FNP Flash nanoprecipitation CIJM Confined impinging jet mixer MIVM Multi-inlet vortex mixer TEM Transmission electron microscope FVR The flow velocity ratio of the first phase solution to the combined phase solution

[0150] The corresponding structures of materials used in the present invention are shown in Table 2.

TABLE-US-00002 TABLE 2 SN-38 [00001] ICG [00002] Camptothecin [00003] 10-Hydroxycamptothecin [00004] Exatecan [00005] Dxd [00006]

[0151] The present invention is further described below by examples, but the present invention is not limited to the scope of the described examples.

[0152] Experimental methods that do not indicate specific conditions in the following examples should be selected according to conventional methods and conditions, or according to product specifications.

[0153] The endpoints of ranges and any values disclosed herein are not limited to the precise range or value, but these ranges or values are to be understood to include values close to such ranges or values. For numerical ranges, the endpoint values of each range, the endpoint values of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges. These numerical ranges shall be deemed to be specifically disclosed herein.

[0154] The turbulent mixing part in this application is a circular pipe with a certain diameter and length, and turbulent flow conditions are achieved through one or more of the following methods:

[0155] Increase flow velocity: [0156] Thorough mixing requires turbulence, Re>4000 [0157] Quantity of flow Q=d.sup.2/4* [0158] Re=d/=4Q/(d)>4000 [0159] When d=0.25 mm [0160] Q>d=2.8 L/h [0161] When d=4 mm [0162] Q>45 L/h [0163] When d=40 mm [0164] Q>450 L/h

[0165] Wherein, Re is the Reynolds number, Q is the quantity of flow, d is the pipeline diameter, is the fluid flow velocity in the pipe, is the fluid viscosity, 20 C. water=10.sup.3 Pa.Math.s

[0166] It should be pointed out that for the preparation of certain composite nanoparticles of photosensitizers and anti-tumor drugs, nano-formulations with a certain particle size and particle size distribution can also be obtained with Re in the range of 500-4000.

[0167] Change the shape of the pipeline:

[0168] By increasing the tortuosity of the pipeline, the direction of fluid flow is forcibly changed, which enhances the fluid mixing.

[0169] Add a static mixer to the pipeline:

[0170] The static mixer can include but is not limited to: SV type static mixer, SX type static mixer, SL type static mixer, SH type static mixers, SK type static mixers, etc. that can divide the fluid through turbulent mixing elements, change the flow direction of the fluid, enhance the convection of the fluid, and increase the mixing of the fluid.

[0171] The SV type static mixer unit is a cylinder assembled from certain regular wave plates.

[0172] The SX type static mixer unit consists of many X-shaped units composed of crossed horizontal bars according to certain rules.

[0173] The SL type static mixer unit is composed of crossed horizontal bars according to a certain pattern to form a single X-shaped unit.

[0174] The SK type static mixer unit is composed of single-channel left and right twisted spiral plates welded together.

[0175] SH type static mixer unit is composed of double channels, with a fluid redistribution chamber between the units.

Example 1: Preparation of First Phase Solution and Second Phase Solution

Example: Preparation of the First Phase Solution of SN-38:ICG=2:1 (Molar Ratio)

[0176] Preparation of the first phase solution: ICG 1.30 g and SN-38 1.30 g were dissolved in 35.1 g DMSO, total weight 37.7 g, SN-38 content: 3.4 wt. %, ICG content: 3.4 wt. %, SN-38 and ICG molar ratio is 2:1.

[0177] Unless otherwise specified, the second phase solution is water.

Example 2: Determination of SN-38 and ICG Concentration

[0178] Instrument: Agilent1260 HPLC

[0179] Column: Waters XBridge C18 4.6*150 mm, 3.5 m

[0180] Mobile phase: Use 10 mmol/L sodium dihydrogen phosphate solution (adjust to pH 4.0 with phosphoric acid) as phase A, use acetonitrile as phase B, and perform gradient elution according to the following table:

TABLE-US-00003 Time (min) A % B % 0 80 20 10 20 80 11 80 20 16 80 20

[0181] Chromatographic parameters: flow rate: 1 ml/min; column temperature: 35 C.; detection wavelength: 264 nm; injection volume: 10 l

[0182] Diluent: DMSO

[0183] Test solution: Use a pipette to accurately take 200 l of the SN-38/ICG nano-formulation solution, place it in a 10 ml volumetric flask, add DMSO to dissolve and quantitatively dilute to the mark and shake well.

[0184] Reference substance solution: Take about 10 mg of ICG or SN-38 reference substance, weigh it accurately, put it in a 100 ml volumetric flask, add DMSO to dissolve it and quantitatively dilute it to the mark and shake well.

[0185] Calculation method: Peak area external standard method

[0186] Unless otherwise specified, all other compounds are measured using this mobile phase, and the wavelength depends on the specific compound.

Example 3: Determination of Nanoparticle Size

[0187] Dynamic light scattering method: The concentration of nanoparticles is 10-100 g/ml, and the particle size and distribution of nanoparticles are measured with a nanoparticle sizer (laser light source 633 nm). Each sample is measured three times, and the average and variance of the nanoparticle size are calculated. The particle size distribution of different nanoparticles is shown in FIGS. 3 to 43 and FIGS. 45 to 48. The three different curves in the attached figures represent the results of three measurements of the samples.

[0188] Since the photosensitizer molecules usually absorb the laser light source (633 nm) of the dynamic light scattering instrument to a certain extent, the intercept in the fitting diagram is low, and there is a certain deviation between the three measurement results of the same sample. Therefore, the average of the three measurements is used to reduce the deviation. The peaks in the micron range in the figure are usually caused by dust.

Example 4: Determination of Hydrophobic Drug Encapsulation Efficiency

Example: Determination of SN-38 Encapsulation Efficiency

[0189] Take 1 ml of SN-38/ICG solution, filter with a 0.22 m nylon needle filter, and measure the SN-38 concentration by HPLC.

[00001]$\mathrm{SN}-38\mathrm{encapsulation}\mathrm{effciency}\%=\frac{\mathrm{SN}38\mathrm{concentration}\mathrm{after}\mathrm{filtration}}{\mathrm{SN}38\mathrm{concentration}\mathrm{before}\mathrm{filtration}}100\%$

[0190] Unless otherwise specified, the encapsulation efficiency of hydrophobic drugs was measured according to this method.

Example 5: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 13 ml/min, Second Phase 203 ml/min)

[0191] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0192] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0193] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0194] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0195] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0196] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0197] Combined phase length=90 mm; [0198] First phase solution temperature T.sub.1=25 C.; [0199] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00004 First phase Second phase ml/min ml/min 13 203

[0200] Calculated based on the fluid in the circular pipeline, the combined phase Re=839, with no static mixer. [0201] The first phase outlet flow velocity is: 3.1 m/s [0202] The second phase flow velocity is: 0.15 m/s [0203] FVR=20.8 [0204] Production quantity: 15 ml-20 ml

TABLE-US-00005 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 61 4 71 5 90 15 123 18 96.0%

Example 6: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 30 ml/min, Second Phase 468 ml/min)

[0205] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0206] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0207] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0208] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0209] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0210] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0211] Combined phase length=90 mm; [0212] First phase solution temperature T.sub.1=25 C.; [0213] Second phase solution temperature T.sub.2=25 C.,

TABLE-US-00006 First phase Second phase ml/min ml/min 30 468

[0214] Calculated based on the fluid in the circular pipeline, the combined phase Re-1934, with no static mixer. [0215] The first phase outlet flow velocity is: 7.1 m/s [0216] The second phase flow velocity is: 0.34 m/s [0217] FVR=20.8 [0218] Production quantity: 15 ml-20 ml

TABLE-US-00007 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 68 6 79 8 93 11 101 6 94.3%

Example 7: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 40 ml/min, Second Phase 624 ml/min)

[0219] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0220] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0221] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0222] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0223] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0224] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0225] Combined phase length=90 mm; [0226] First phase solution temperature T.sub.1=25 C.; [0227] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00008 First phase Second phase ml/min ml/min 40 624

[0228] Calculated based on the fluid in the circular pipeline, the combined phase Re=2579, with no static mixer. [0229] The first phase outlet flow velocity is: 9.43 m/s [0230] The second phase flow velocity is: 0.45 m/s [0231] FVR=20.8 [0232] Production quantity: 15 ml-20 ml

TABLE-US-00009 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 85 5 101 5 118 7 99 5 92.0%

Example 8: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 60 ml/min, Second Phase 936 ml/min)

[0233] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0234] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0235] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0236] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0237] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0238] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0239] Combined phase length=90 mm; [0240] First phase solution temperature T.sub.1=25 C.; [0241] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00010 First phase Second phase ml/min ml/min 60 936

[0242] Calculated based on the fluid in the circular pipeline, the combined phase Re=3868, with no static mixer. [0243] The first phase outlet flow velocity is: 14.1 m/s [0244] The second phase flow velocity is: 0.68 m/s [0245] FVR=20.8 [0246] Production quantity: 15 ml-20 ml

TABLE-US-00011 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 86 5 103 6 126 10 108 9 96.0%

Example 9: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 80 ml/min, Second Phase 1248 ml/min)

[0247] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0248] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0249] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0250] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0251] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0252] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0253] Combined phase length=90 mm; [0254] First phase solution temperature T.sub.1=25 C.; [0255] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00012 First phase Second phase ml/min ml/min 80 1248

[0256] Calculated based on the fluid in the circular pipeline, the combined phase Re=5158, with no static mixer. [0257] The first phase outlet flow velocity is: 18.9 m/s [0258] The second phase flow velocity is: 0.91 m/s [0259] FVR=20.8 [0260] Production quantity: 15 ml-20 ml

TABLE-US-00013 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 88 15 109 22 138 34 99 5 97.8%

Example 10: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1560 ml/min)

[0261] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0262] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0263] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0264] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0265] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0266] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0267] Combined phase length=90 mm; [0268] First phase solution temperature T.sub.1=25 C.; [0269] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00014 First phase Second phase ml/min ml/min 100 1560

[0270] Calculated based on the fluid in the circular pipeline, the combined phase Re-6477, with no static mixer. [0271] The first phase outlet flow velocity is: 23.6 m/s [0272] The second phase flow velocity is: 1.14 m/s [0273] FVR=20.8 [0274] Production quantity: 15 ml-20 ml

TABLE-US-00015 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 76 16 89 20 107 27 104 4 95.3%

Example 11: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 13 ml/min, Second Phase 203 ml/min)

[0275] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0276] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0277] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0278] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0279] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0280] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0281] Combined phase length=90 mm; [0282] First phase solution temperature T.sub.1=25 C.; [0283] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00016 First phase Second phase ml/min ml/min 13 203

[0284] Calculated based on the fluid in the circular pipeline, the combined phase Re=839, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0285] The first phase outlet flow velocity is: 3.1 m/s [0286] The second phase flow velocity is: 0.15 m/s [0287] FVR=20.8 [0288] Production quantity: 15 ml-20 ml

TABLE-US-00017 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 85 15 113 22 192 12 139 12 91.8%

Example 12: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 30 ml/min, Second Phase 468 ml/min)

[0289] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0290] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0291] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0292] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0293] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0294] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0295] Combined phase length=90 mm; [0296] First phase solution temperature T.sub.1=25 C.; [0297] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00018 First phase Second phase ml/min ml/min 30 468

[0298] Calculated based on the fluid in the circular pipeline, the combined phase Re=1934, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0299] The first phase outlet flow velocity is: 7.1 m/s [0300] The second phase flow velocity is: 0.34 m/s [0301] FVR=20.8 [0302] Production quantity: 15 ml-20 ml

TABLE-US-00019 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 98 3 119 2 152 4 107 13 95.6%

Example 13: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 40 ml/min, Second Phase 624 ml/min)

[0303] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0304] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0305] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0306] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0307] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0308] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0309] Combined phase length=90 mm; [0310] First phase solution temperature T.sub.1=25 C.; [0311] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00020 First phase Second phase ml/min ml/min 40 624

[0312] Calculated based on the fluid in the circular pipeline, the combined phase Re=2579, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0313] The first phase outlet flow velocity is: 9.43 m/s [0314] The second phase flow velocity is: 0.45 m/s [0315] FVR=20.8 [0316] Production quantity: 15 ml-20 ml

TABLE-US-00021 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 84 11 99 13 119 18 118 1 95.7%

Example 14: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 60 ml/min, Second Phase 936 ml/min)

[0317] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0318] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0319] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0320] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0321] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0322] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0323] Combined phase length=90 mm; [0324] First phase solution temperature T.sub.1=25 C.; [0325] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00022 First phase Second phase ml/min ml/min 60 936

[0326] Calculated based on the fluid in the circular pipeline, the combined phase Re=3868, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0327] The first phase outlet flow velocity is: 14.1 m/s [0328] The second phase flow velocity is: 0.68 m/s [0329] FVR=20.8 [0330] Production quantity: 15 ml-20 ml

TABLE-US-00023 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 88 5 110 6 157 9 104 9 94.8%

Example 15: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 80 ml/min, Second Phase 1248 ml/min)

[0331] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0332] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0333] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0334] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0335] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0336] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0337] Combined phase length=90 mm; [0338] First phase solution temperature T.sub.1=25 C.; [0339] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00024 First phase Second phase ml/min ml/min 80 1248

[0340] Calculated based on the fluid in the circular pipeline, the combined phase Re=5158, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0341] The first phase outlet flow velocity is: 18.9 m/s [0342] The second phase flow velocity is: 0.91 m/s [0343] FVR=20.8 [0344] Production quantity: 15 ml-20 ml

TABLE-US-00025 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 98 3 119 2 152 4 107 13 99.7%

Example 16: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 100 ml/min, Second Phase 1560 ml/min)

[0345] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0346] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0347] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0348] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0349] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0350] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0351] Combined phase length=90 mm; [0352] First phase solution temperature T.sub.1=25 C.; [0353] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00026 First phase Second phase ml/min ml/min 100 1560

[0354] Calculated based on the fluid in the circular pipeline, the combined phase Re-6477, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0355] The first phase outlet flow velocity is: 23.6 m/s [0356] The second phase flow velocity is: 1.14 m/s [0357] FVR=20.8 [0358] Production quantity: 15 ml-20 ml

TABLE-US-00027 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 98 3 119 2 152 4 107 13 95.9%

Example 17: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, First Phase 13 ml/min, Second Phase 203 ml/min)

[0359] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0360] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0361] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0362] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0363] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0364] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0365] Combined phase length=90 mm; [0366] First phase solution temperature T.sub.1=25 C.; [0367] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00028 First phase Second phase ml/min ml/min 13 203

[0368] Calculated based on the fluid in the circular pipeline, the combined phase Re=839, with no static mixer. [0369] The first phase outlet flow velocity is: 0.77 m/s [0370] The second phase flow velocity is: 0.15 m/s [0371] FVR=5.2 [0372] Production quantity: 15 ml-20 ml

TABLE-US-00029 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 123 9 269 11 457 25 222 2 29.1% 85.3%

Example 18: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, First Phase 30 ml/min, Second Phase 468 ml/min)

[0373] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0374] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0375] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0376] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0377] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0378] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0379] Combined phase length=90 mm; [0380] First phase solution temperature T.sub.1=25 C.; [0381] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00030 First phase Second phase ml/min ml/min 30 468

[0382] Calculated based on the fluid in the circular pipeline, the combined phase Re=1934, with no static mixer. [0383] The first phase outlet flow velocity is: 1.77 m/s [0384] The second phase flow velocity is: 0.34 m/s [0385] FVR=5.2 [0386] Production quantity: 15 ml-20 ml

TABLE-US-00031 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 130 15 199 20 303 62 161 13 61.9% 91.8%

Example 19: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, First Phase 60 ml/min, Second Phase 936 ml/min)

[0387] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0388] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0389] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0390] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0391] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0392] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0393] Combined phase length=90 mm; [0394] First phase solution temperature T.sub.1=25 C.; [0395] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00032 First phase Second phase ml/min ml/min 60 936

[0396] Calculated based on the fluid in the circular pipeline, the combined phase Re=3868, with no static mixer. [0397] The first phase outlet flow velocity is: 3.54 m/s [0398] The second phase flow velocity is: 0.68 m/s [0399] FVR=5.2 [0400] Production quantity: 15 ml-20 ml

TABLE-US-00033 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 79 7 96 8 124 13 98 4 98.4% 98.0%

Example 20: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, First Phase 80 ml/min, Second Phase 1248 ml/min)

[0401] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0402] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0403] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0404] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0405] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0406] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0407] Combined phase length=90 mm; [0408] First phase solution temperature T.sub.1=25 C.; [0409] Second phase solution temperature T.sub.2=25 C.:

TABLE-US-00034 First phase Second phase ml/min ml/min 80 1248

[0410] Calculated based on the fluid in the circular pipeline, the combined phase Re=5158, with no static mixer. [0411] The first phase outlet flow velocity is: 4.72 m/s [0412] The second phase flow velocity is: 0.91 m/s [0413] FVR=5.2 [0414] Production quantity: 15 ml-20 ml

TABLE-US-00035 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 78 6 93 9 111 12 99 4 100.0% 98.7%

Example 21: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1560 ml/min)

[0415] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0416] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0417] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0418] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0419] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0420] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0421] Combined phase length=90 mm; [0422] First phase solution temperature T.sub.1=25 C.; [0423] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00036 First phase Second phase ml/min ml/min 100 1560

[0424] Calculated based on the fluid in the circular pipeline, the combined phase Re=6477, with no static mixer. [0425] The first phase outlet flow velocity is: 5.89 m/s [0426] The second phase flow velocity is: 1.14 m/s [0427] FVR=5.2 [0428] Production quantity: 15 ml-20 ml

TABLE-US-00037 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 88 2 105 2 133 10 97 14 94.1% 93.6%

Example 22: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 13 ml/min, Second Phase 203 ml/min)

[0429] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0430] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0431] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0432] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0433] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0434] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0435] Combined phase length=90 mm; [0436] First phase solution temperature T.sub.1=25 C.; [0437] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00038 First phase Second phase ml/min ml/min 13 203

[0438] Calculated based on the fluid in the circular pipeline, the combined phase Re-839, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0439] The first phase outlet flow velocity is: 0.77 m/s [0440] The second phase flow velocity is: 0.15 m/s [0441] FVR=5.2 [0442] Production quantity: 15 ml-20 ml

TABLE-US-00039 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 99 20 166 11 232 26 152 2 67.4% 88.8%

Example 23: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 30 ml/min, Second Phase 468 ml/min)

[0443] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0444] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0445] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0446] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0447] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0448] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0449] Combined phase length=90 mm; [0450] First phase solution temperature T.sub.1=25 C.; [0451] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00040 First phase Second phase ml/min ml/min 30 468

[0452] Calculated based on the fluid in the circular pipeline, the combined phase Re-1934, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0453] The first phase outlet flow velocity is: 1.77 m/s [0454] The second phase flow velocity is: 0.34 m/s [0455] FVR=5.2 [0456] Production quantity: 15 ml-20 ml

TABLE-US-00041 Filtration Filtration Average encapsulation encapsulation D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 103 2 128 4 172 7 119 8 93.4% 95.3%

Example 24: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 60 ml/min, Second Phase 936 ml/min)

[0457] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0458] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0459] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0460] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0461] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0462] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0463] Combined phase length=90 mm; [0464] First phase solution temperature T.sub.1=25 C.; [0465] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00042 First phase Second phase ml/min ml/min 60 936

[0466] Calculated based on the fluid in the circular pipeline, the combined phase Re=3868, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0467] The first phase outlet flow velocity is: 3.54 m/s [0468] The second phase flow velocity is: 0.68 m/s [0469] FVR=5.2 [0470] Production quantity: 15 ml-20 ml

TABLE-US-00043 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 90 4 113 2 159 29 110 3 97.5% 97.6%

Example 25: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 80 ml/min, Second Phase 1248 ml/min)

[0471] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0472] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0473] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0474] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0475] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0476] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0477] Combined phase length=90 mm; [0478] First phase solution temperature T.sub.1=25 C.; [0479] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00044 First phase Second phase ml/min ml/min 80 1248

[0480] Calculated based on the fluid in the circular pipeline, the combined phase Re-5158, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0481] The first phase outlet flow velocity is: 4.72 m/s [0482] The second phase flow velocity is: 0.91 m/s [0483] FVR=5.2 [0484] Production quantity: 15 ml-20 ml

TABLE-US-00045 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 83 17 101 23 126 35 109 5 98.8% 98.2%

Example 26: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 100 ml/min, Second Phase 1560 ml/min)

[0485] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0486] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0487] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0488] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0489] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0490] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0491] Combined phase length=90 mm; [0492] First phase solution temperature T.sub.1=25 C.; [0493] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00046 First phase Second phase ml/min ml/min 100 1560

[0494] Calculated based on the fluid in the circular pipeline, the combined phase Re-6477, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0495] The first phase outlet flow velocity is: 5.89 m/s [0496] The second phase flow velocity is: 1.14 m/s [0497] FVR=5.2 [0498] Production quantity: 15 ml-20 ml

TABLE-US-00047 Filtration Filtration encapsula- encapsula- Average tion tion D10 D50 D90 diameter efficiency efficiency nm nm nm nm (SN-38) (ICG) 93 9 113 12 143 17 111 8 98.8% 100.3%

Example 27: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1248 ml/min)

[0499] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0500] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0501] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0502] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0503] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0504] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0505] Combined phase length=90 mm; [0506] First phase solution temperature T.sub.1=25 C.; [0507] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00048 First phase Second phase ml/min ml/min 100 1248

[0508] Calculated based on the fluid in the circular pipeline, the combined phase Re-5236, with no static mixer. [0509] The first phase outlet flow velocity is: 23.6 m/s [0510] The second phase flow velocity is: 0.91 m/s [0511] FVR=26.0 [0512] Production quantity: 15 ml-20 ml

TABLE-US-00049 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 89 7 106 7 133 5 109 3 95.2%

Example 28: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1326 ml/min)

[0513] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0514] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0515] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0516] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0517] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0518] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0519] Combined phase length=90 mm; [0520] First phase solution temperature T.sub.1=25 C.; [0521] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00050 First phase Second phase ml/min ml/min 100 1326

[0522] Calculated based on the fluid in the circular pipeline, the combined phase Re=5539, with no static mixer. [0523] The first phase outlet flow velocity is: 23.6 m/s [0524] The second phase flow velocity is: 0.97 m/s [0525] FVR=24.4 [0526] Production quantity: 15 ml-20 ml

TABLE-US-00051 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 92 3 108 7 132 16 112 3 96.3%

Example 29: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1404 ml/min)

[0527] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0528] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm;

[0529] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0530] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0531] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0532] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0533] Combined phase length=90 mm; [0534] First phase solution temperature T.sub.1=25 C.; [0535] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00052 First phase Second phase ml/min ml/min 100 1404

[0536] Calculated based on the fluid in the circular pipeline, the combined phase Re=5841, with no static mixer. [0537] The first phase outlet flow velocity is: 23.6 m/s [0538] The second phase flow velocity is: 1.02 m/s [0539] FVR=23.1 [0540] Production quantity: 15 ml-20 ml

TABLE-US-00053 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 81 9 96 10 119 11 114 6 98.2%

Example 30: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1482 ml/min)

[0541] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0542] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0543] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0544] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0545] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0546] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0547] Combined phase length=90 mm; [0548] First phase solution temperature T.sub.1=25 C.; [0549] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00054 First phase Second phase ml/min ml/min 100 1482

[0550] Calculated based on the fluid in the circular pipeline, the combined phase Re=5236, with no static mixer. [0551] The first phase outlet flow velocity is: 23.6 m/s [0552] The second phase flow velocity is: 1.08 m/s [0553] FVR=21.9 [0554] Production quantity: 15 ml-20 ml

TABLE-US-00055 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 84 10 107 8 189 43 119 12 98.8%

Example 31: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1638 ml/min)

[0555] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0556] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0557] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0558] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0559] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0560] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0561] Combined phase length=90 mm; [0562] First phase solution temperature T.sub.1=25 C.; [0563] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00056 First phase Second phase ml/min ml/min 100 1638

[0564] Calculated based on the fluid in the circular pipeline, the combined phase Re=6750, with no static mixer. [0565] The first phase outlet flow velocity is: 23.6 m/s [0566] The second phase flow velocity is: 1.19 m/s [0567] FVR=19.8 [0568] Production quantity: 15 ml-20 ml

TABLE-US-00057 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 83 13 100 17 120 20 119 6 95.2%

Example 32: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1716 ml/min)

[0569] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0570] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0571] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0572] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0573] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0574] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0575] Combined phase length=90 mm; [0576] First phase solution temperature T.sub.1=25 C.; [0577] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00058 First phase Second phase ml/min ml/min 100 1716

[0578] Calculated based on the fluid in the circular pipeline, the combined phase Re=7053, with no static mixer. [0579] The first phase outlet flow velocity is: 23.6 m/s [0580] The second phase flow velocity is: 1.25 m/s [0581] FVR=18.9 [0582] Production quantity: 15 ml-20 ml

TABLE-US-00059 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 86 4 103 4 154 42 105 5 96.2%

Example 33: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1794 ml/min)

[0583] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0584] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0585] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0586] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0587] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0588] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0589] Combined phase length=90 mm; [0590] First phase solution temperature T.sub.1=25 C.; [0591] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00060 First phase Second phase ml/min ml/min 100 1794

[0592] Calculated based on the fluid in the circular pipeline, the combined phase Re=7356, with no static mixer. [0593] The first phase outlet flow velocity is: 23.6 m/s [0594] The second phase flow velocity is: 1.31 m/s [0595] FVR=18.1 [0596] Production quantity: 15 ml-20 ml

TABLE-US-00061 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 95 6 114 10 146 19 117 10 96.5%

Example 34: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1872 ml/min)

[0597] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0598] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0599] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0600] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0601] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0602] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0603] Combined phase length=90 mm; [0604] First phase solution temperature T.sub.1=25 C.; [0605] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00062 First phase Second phase ml/min ml/min 100 1872

[0606] Calculated based on the fluid in the circular pipeline, the combined phase Re=7659, with no static mixer. [0607] The first phase outlet flow velocity is: 23.6 m/s [0608] The second phase flow velocity is: 1.36 m/s [0609] FVR=17.3 [0610] Production quantity: 15 ml-20 ml

TABLE-US-00063 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 89 6 107 5 139 17 114 5 96.3%

Example 35: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1404 ml/min)

[0611] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0612] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0613] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0614] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0615] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0616] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0617] Combined phase length=90 mm; [0618] First phase solution temperature T.sub.1=25 C.; [0619] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00064 First phase Second phase ml/min ml/min 100 1404

[0620] Calculated based on the fluid in the circular pipeline, the combined phase Re=5841, with no static mixer. [0621] The first phase outlet flow velocity is: 23.6 m/s [0622] The second phase flow velocity is: 1.02 m/s [0623] FVR=23.1 [0624] Production quantity: 60 ml

TABLE-US-00065 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 110 6 137 7 172 9 127 6 91.7%

Example 36: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.3 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1404 ml/min)

[0625] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0626] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0627] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0628] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0629] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0630] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0631] Combined phase length=90 mm; [0632] First phase solution temperature T.sub.1=25 C.; [0633] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00066 First phase Second phase ml/min ml/min 100 1404

[0634] Calculated based on the fluid in the circular pipeline, the combined phase Re=5841, with no static mixer. [0635] The first phase outlet flow velocity is: 23.6 m/s [0636] The second phase flow velocity is: 1.02 m/s [0637] FVR=23.1 [0638] Production quantity: 557 ml

TABLE-US-00067 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 92.5 0.1 114 4 186 46 129 10 89.2%

Example 37: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, First Phase 100 ml/min, Second Phase 1560 ml/min)

[0639] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0640] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0641] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0642] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0643] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0644] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0645] Combined phase length=90 mm; [0646] First phase solution temperature T.sub.1=25 C.; [0647] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00068 First phase Second phase ml/min ml/min 100 1560

[0648] Calculated based on the fluid in the circular pipeline, the combined phase Re-6477, with no static mixer. [0649] The first phase outlet flow velocity is: 5.89 m/s [0650] The second phase flow velocity is: 1.14 m/s [0651] FVR=5.2 [0652] Production quantity: 60 ml

TABLE-US-00069 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 71 5 96 20 181 16 122 5 94.2%

Example 38: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 100 ml/min, Second Phase 1560 ml/min)

[0653] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0654] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0655] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0656] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0657] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0658] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0659] Combined phase length=90 mm; [0660] First phase solution temperature T.sub.1=25 C.; [0661] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00070 First phase Second phase ml/min ml/min 100 1560

[0662] Calculated based on the fluid in the circular pipeline, the combined phase Re=6477, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0663] The first phase outlet flow velocity is: 5.89 m/s [0664] The second phase flow velocity is: 1.14 m/s [0665] FVR=5.2 [0666] Production quantity: 60 ml

TABLE-US-00071 Filtration Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 87 14 115 7 164 13 114 2 94.8%

Example 39: Preparation of SN-38/ICG Nanoparticles (D.SUB.1.(S)=0.6 mm, D.SUB.3.(IN)=5.4 mm, SK Type Static Mixer, First Phase 80 ml/min, Second Phase 1248 ml/min)

[0667] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0668] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0669] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0670] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0671] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0672] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0673] Combined phase length=90 mm; [0674] First phase solution temperature T.sub.1=25 C.; [0675] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00072 First phase Second phase ml/min ml/min 80 1248

[0676] Calculated based on the fluid in the circular pipeline, the combined phase Re=5158, with SK type static mixer, static mixer size: 5.3 mm*85 mm, with a total of 16 repeating spiral plates. [0677] The first phase outlet flow velocity is: 4.72 m/s [0678] The second phase flow velocity is: 0.91 m/s [0679] FVR=5.2 [0680] Production quantity: 425 ml

[0681] The SN-38 concentration of the preparation solution was 2.05 mg/ml, the SN-38 concentration after filtration of 0.22 m membrane was 1.89 mg/ml, the encapsulation efficiency of SN-38: 92.2%, the original solution was added 871.4 g water and purified with 0.05 m.sup.230 kDa PES ultrafiltration membrane.

[0682] Ultrafiltrate was concentrated to 166.1 g, SN-38 concentration was 5.07 mg/ml; After filtration with 0.22 m membrane, the SN-38 concentration was 4.60 mg/ml, and the encapsulation efficiency of SN-38 after ultrafiltration was 90.8%.

[0683] Particle size change before and after ultrafiltration:

TABLE-US-00073 Average D10 D50 D90 diameter nm nm nm nm PDI Before 103 3 121 1 150 10 126 4 0.11 0.1 ultrafiltration After 110 4 131 5 166 10 132 2 0.19 0.08 ultrafiltration

Example 40: Preparation of SN-38/ICG Nanoparticles (SN-38:ICG=15:1-5:1, Molar Ratio)

[0684] SN-38 was dissolved in DMSO (39.2 mg/ml, 0.1 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), SN-38 in DMSO and ICG in DMSO were mixed in proportion following the table below as the first phase solution, and water as the second phase solution. [0685] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0686] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0687] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0688] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0689] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0690] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0691] Combined phase length=90 mm; [0692] First phase solution temperature T.sub.1=25 C.; [0693] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00074 First phase Second phase ml/min ml/min 100 1560

[0694] Calculated based on the fluid in the circular pipeline, the combined phase Re-6477, with no static mixer. [0695] The first phase outlet flow velocity is: 5.89 m/s [0696] The second phase flow velocity is: 1.14 m/s [0697] FVR=5.2 [0698] Production quantity: 15 ml-20 ml

TABLE-US-00075 SN-38 ICG SN38/ICG Average encapsulation encapsulation Molar D10 D50 D90 diameter C.sub.SN-38 C.sub.ICG efficiency efficiency ratio nm nm nm nm mg/ml mg/ml % % 15:1 63 127 232 139 2.08 0.23 96.1 95.6 10:1 65 128 279 117 2.06 0.39 96.6 97.4 5:1 50 108 254 94 2.06 0.80 98 98.7

Example 41: Preparation of Camptothecine/ICG Nanoparticles (Camptothecine:ICG=10:1-1:1, Molar Ratio)

[0699] Camptothecin was dissolved in DMSO (20 mg/ml, 0.057 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), camptothecin in DMSO and ICG in DMSO were mixed in proportion following the table below as the first phase solution, and water as the second phase solution. [0700] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0701] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0702] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0703] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0704] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0705] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0706] Combined phase length=90 mm; [0707] First phase solution temperature T.sub.1=25 C.; [0708] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00076 First phase Second phase ml/min ml/min 100 1560

[0709] Calculated based on the fluid in the circular pipeline, the combined phase Re=6477, with no static mixer. [0710] The first phase outlet flow velocity is: 5.89 m/s [0711] The second phase flow velocity is: 1.14 m/s [0712] FVR=5.2 [0713] Production quantity: 15 ml-20 ml

TABLE-US-00077 Average CPT encapsulation Camptothecin:ICG D10 D50 D90 diameter efficiency Molar ratio nm nm nm nm PDI % 10:1 54.82 76.95 126.4 143.9 0.22 87 5:1 21.31 28 40.41 133.9 0.25 88 2:1 27.39 37.75 58.84 119.5 0.25 88 1:1 33.3 45.59 71.03 136.7 0.27 85

Example 42: Preparation of 10-Hydroxycamptothecine/ICG Nanoparticles (10-Hydroxycamptothecine:ICG=10:1-1:1, Molar Ratio)

[0714] 10-Hydroxycamptothecin was dissolved in DMSO (36.4 mg/ml, 0.1 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), 10-Hydroxycamptothecin in DMSO and ICG in DMSO were mixed in proportion following the table below as the first phase solution, and water as the second phase solution. [0715] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0716] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0717] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0718] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0719] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0720] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0721] Combined phase length=90 mm; [0722] First phase solution temperature T.sub.1=25 C.; [0723] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00078 First phase Second phase ml/min ml/min 100 1560

[0724] Calculated based on the fluid in the circular pipeline, the combined phase Re-6477, with no static mixer. [0725] The first phase outlet flow velocity is: 5.89 m/s [0726] The second phase flow velocity is: 1.14 m/s [0727] FVR=5.2 [0728] Production quantity: 15 ml-20 ml

TABLE-US-00079 10-Hydroxycamptoth ICG 10- Average encapsulation encapsulation Hydroxycamptothecin:ICG D10 D50 D90 diameter efficiency efficiency Molar ratio nm nm nm nm PDI % % 10:1 23.46 32.57 51.99 103 0.29 97 100 5:1 27.52 37.7 59.34 120.4 0.25 93 95 2:1 19.86 26.44 44.53 190.3 0.34 93 98 1:1 74.56 104.6 189.4 226.3 0.25 85 97

Example 43: Preparation of Exatecan/ICG Nanoparticles (Exatecan:ICG=1:1-10:1, Molar Ratio)

[0729] Exatecan (free base, Mw=435.4) was dissolved in DMSO (43.5 mg/ml, 0.1 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), Exatecan in DMSO and ICG in DMSO were mixed in proportion following the table below as the first phase solution, and water as the second phase solution. [0730] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0731] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0732] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0733] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0734] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0735] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0736] Combined phase length=90 mm; [0737] First phase solution temperature T.sub.1=25 C.; [0738] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00080 First phase Second phase ml/min ml/min 100 1560

[0739] Calculated based on the fluid in the circular pipeline, the combined phase Re-6477, with no static mixer. [0740] The first phase outlet flow velocity is: 5.89 m/s [0741] The second phase flow velocity is: 1.14 m/s [0742] FVR=5.2 [0743] Production quantity: 15 ml-20 ml

TABLE-US-00081 Exatecan ICG Average encapsulation encapsulation Exatecan:ICG D10 D50 D90 diameter efficiency efficiency Molar ratio nm nm nm nm PDI % % 10:1 45 95 254 87 0.3 75 74 5:1 39 82 258 76 0.32 102 94 2:1 47 101 489 320 0.51 101 96 1:1 100 95 Note: Exatecan:ICG = 1:1 gave a transparent solution.

Example 44: Preparation of Dxd/ICG Nanoparticles (Dxd:ICG=10:1-1:1, Molar Ratio)

[0744] Dxd (Mw=493.5) was dissolved in DMSO (49.4 mg/ml, 0.1 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), Dxd in DMSO and ICG in DMSO were mixed in proportion following the table below as the first phase solution, and water as the second phase solution. [0745] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0746] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0747] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0748] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0749] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0750] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0751] Combined phase length=90 mm; [0752] First phase solution temperature T.sub.1=25 C.; [0753] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00082 First phase Second phase ml/min ml/min 100 1560

[0754] Calculated based on the fluid in the circular pipeline, the combined phase Re=6477, with no static mixer. [0755] The first phase outlet flow velocity is: 5.89 m/s [0756] The second phase flow velocity is: 1.14 m/s [0757] FVR=5.2 [0758] Production quantity: 15 ml-20 ml

TABLE-US-00083 Dxd ICG Average encapsulation encapsulation Dxd:ICG D10 D50 D90 diameter efficiency efficiency Molar ratio nm nm nm nm PDI % % 10:1 104 130 165 119 0.38 94 99 5:1 120 154 202 123 0.24 91 96 2:1 104 96 1:1 103 95 Note: Dxd:ICG = 2:1-1:1 gave a transparent solution.

Example 45: Preparation of Sorafenib/ICG Nanoparticles (Sorafenib:ICG=1:1-8:1,Molar Ratio)

[0759] Sorafenib was dissolved in DMSO (46.5 mg/ml, 0.1 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), Sorafenib in DMSO and ICG in DMSO were mixed in proportion following the table below as the first phase solution, and water as the second phase solution. [0760] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0761] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0762] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0763] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0764] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0765] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0766] Combined phase length=90 mm; [0767] First phase solution temperature T.sub.1=25 C.; [0768] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00084 First phase Second phase ml/min ml/min 40 400 [0769] Production quantity: 15 ml-20 ml [0770] After centrifugation, Sorafenib:ICG=1:1 gave a transparent solution, and the precipitate gradually increases when the amount of sorafenib is increased.

TABLE-US-00085 Sorafenib/ICG Average diameter Encapsulation efficiency Molar ratio nm PDI % 1:1 Not detected / 99.4 4:1 Not detected / 99.2 5:1 Not detected / 99.8 6:1 76.7 0.098 98.2 8:1 76.5 0.097 96.7 Conclusion: When Sorafenib:ICG = 6:1 and 8:1, the particle size can be detected, indicating that sorafenib and ICG can self-assemble into nanoparticles.

Example 46: Preparation of PTX/ICG Nanoparticles (PTX:ICG-1:1-10:1, Molar Ratio)

[0771] PTX was dissolved in MeOH (42.7 mg/ml, 0.05 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), PTX in MeOH and ICG in DMSO were mixed in proportion following the table below as the first phase solution, and water as the second phase solution. [0772] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0773] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0774] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0775] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0776] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0777] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0778] Combined phase length=90 mm; [0779] First phase solution temperature T.sub.1=25 C.; [0780] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00086 First phase Second phase ml/min ml/min 40 400 [0781] Production quantity: 15 ml-20 ml

TABLE-US-00087 PTX ICG PTX:ICG Average encapsulation encapsulation Molar D10 D50 D90 diameter efficiency efficiency ratio nm nm nm nm PDI % % 10:1 49.24 66.96 102.9 116.6 0.13 96 100 5:1 50.23 67.99 103.7 113.9 0.1 93 94 2:1 0.55 0.68 0.9 6.25 0.56 98 98 1:1 0.56 0.68 0.87 6.09 0.51 98 100

Example 47: Preparation of Curcumin/ICG Nanoparticles (Curcumin:ICG=2:1-8:1, Molar Ratio)

[0782] Curcumin was dissolved in DMSO (36.8 mg/ml, 0.1 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), Curcumin in DMSO and ICG in DMSO were mixed in proportion following the table below as the first phase solution, and water as the second phase solution. [0783] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.3 mm; [0784] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0785] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0786] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0787] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0788] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0789] Combined phase length=90 mm; [0790] First phase solution temperature T.sub.1=25 C.; [0791] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00088 First phase Second phase ml/min ml/min 40 400 [0792] Production quantity: 15 ml-20 ml

[0793] After centrifugation, the solution with a volume ratio of 2:1 and 4:1 was clear, and no precipitate was found. The precipitation gradually increased from 5:1.

TABLE-US-00089 Average Encapsulation Curcumin/ICG diameter efficiency Molar ratio nm PDI % 2:1 Not detected / 99.5 4:1 Not detected / 97.6 5:1 110 0.16 96.5 6:1 155 0.20 94.4 7:1 131 0.15 93.6 8:1 141 0.08 88.3 Note: when Curcumin:ICG = 2:1-4:1, the particle size is too small and cannot be detected. The particle size gradually increases as the proportion of curcumin increases.

Example 48: Preparation of SN-38/Ce6 Nanoparticles (SN-38/Ce6=2:1, Molar Ratio)

[0794] Ce6 was dissolved in DMSO (59.7 mg/ml, 0.1 M), SN-38 was dissolved in DMSO (39.2 mg/ml, 0.1 M), SN-38 in DMSO and Ce6 in DMSO were mixed in 2:1 volume ratio as the first phase solution, and water as the second phase solution. [0795] Spray hole diameter at the end of first pipeline D.sub.1(S)=0.6 mm; [0796] Inner diameter of the second pipeline D.sub.2(IN)=5.4 mm; [0797] Inner diameter of the combined pipeline D.sub.3(IN)=5.4 mm; [0798] Outer diameter at the end of first pipeline D.sub.1(O)=2 mm; [0799] Outer diameter of the second pipeline D.sub.2(O)=6 mm; [0800] Outer diameter of the combined pipeline D.sub.3(O)=6 mm; [0801] Combined phase length=90 mm; [0802] First phase solution temperature T.sub.1=25 C.; [0803] Second phase solution temperature T.sub.2=25 C.;

TABLE-US-00090 First phase Second phase ml/min ml/min 30 468

[0804] Calculated based on the fluid in the circular pipeline, the combined phase Re=1934, with no static mixer. [0805] The first phase outlet flow velocity is: 1.77 m/s [0806] The second phase flow velocity is: 0.34 m/s [0807] FVR=5.2 [0808] Production quantity: 15 ml-20 ml

TABLE-US-00091 Centrifugal Average encapsulation D10 D50 D90 diameter efficiency nm nm nm nm (SN-38) 215 258 332 258 93%

Comparative Example 1: Preparation of PTX/ICG Nanoparticles by Thin-film Hydration Method

[0809] 15.72 mg paclitaxel and 36.42 mg ICG were added to a 50 ml eggplant flask and dissolved in 5 ml methanol. The paclitaxel content was 30 wt. %. The methanol was removed in vacuo. Adding 7.860 ml of deionized water pre-warmed at 60 C. and rotating hydration at 60 C. did not yield uniform PTX/ICG nanoparticles.

[0810] The published literature shows that mPEG.sub.2k-PLA.sub.2k and PTX can form PTX/mPEG-PLA micelles at 20 nm by thin-film hydration method with a drug load of 30 wt. % and an encapsulation efficiency of >90%.

[0811] Therefore, the properties of polymers and photosensitizers are fundamentally different and cannot be simply replaced.

Comparative Example 2: Preparation of SN-38/ICG Nanoparticles (SN-38:ICG=10:1-5:1, Molar Ratio) by Nanoprecipitation Method in Intermittent Small Batches

[0812] SN-38 was dissolved in DMSO (39.2 mg/ml, 0.1 M), ICG was dissolved in DMSO (77.5 mg/ml, 0.1 M), SN-38 in DMSO and ICG in DMSO were filtered with 0.22 m membrane and mixed in proportion following the table below in 1.5 ml EP tube.

[0813] Water was pre-added to 8 ml vials according to the following table, placed in a 120 W ultrasonic bath, SN-38 and ICG DMSO mixture was quickly added to the water with a pipette, and continued to sonicate for 30 s to determine the particle size distribution and encapsulation efficiency.

TABLE-US-00092 Added Added Theoretical Theoretical SN-38 ICG SN-38:ICG SN-38:ICG SN-38 ICG DMSO DMSO (Molar (Mass added added solution solution H.sub.2O ratio) ratio) (mg) (mg) (l) (l) (l) 10:1 5.06 2 0.39 50 4.9 3945 5:1 2.53 2 0.79 50 9.9 3940 2:1 1.01 2 1.97 50 24.7 3925 1:1 0.51 2 3.95 50 49.4 3901

TABLE-US-00093 SN-38 ICG SN-38/ICG Average encapsulation encapsulation (Molar D10 D50 D90 diameter C.sub.SN-38 C.sub.ICG efficiency efficiency ratio) (nm) (nm) (nm) (nm) (mg/ml) (mg/ml) PDI (%) (%) 10:1 36.72 49.18 74.07 207.60 0.47 0.097 0.30 72.3 89.7 5:1 60.31 86.47 160.00 225.70 0.45 0.167 0.21 53.3 83.8 2:1 43.99 61.48 127.60 336.90 0.46 0.44 0.36 36.9 97.7 1:1 80.00 117.10 232.90 341.50 0.48 0.91 0.36 27.1 97.8 2:1 34.72 48.48 78.82 166.40 0.48 0.91 0.23 76.1 97.7 ultrasonic probe Note: The 2:1 ultrasonic probe refers to SN-38:ICG = 2:1 (molar ratio) samples continue to be sonicated with a 300 W probe sonicator for 30 s, sonicated for 1 s and stopped for 1 s.

[0814] When the molar ratio of SN-38 to ICG was 10:1-1:1, the encapsulation efficiency of SN-38 decreased from 72.3% to 27.1%, and the encapsulation efficiency of SN-38 was only increased to 76.1% from 36.9% with 300 W probe sonicator (SN-38:ICG=2:1).

[0815] Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only illustrations, and that various changes or modifications may be made to these embodiments without deviating from the principle and substance of the present invention. Therefore, the scope of protection of the present invention is limited by the attached claims.