Methods for the continuous, scalable production of ultrasound-enhanced nanoformulations

Abstract

The present invention discloses a method for continuous and scalable production of ultrasound-enhanced nano-formulations. Specifically, the present invention discloses a manufacturing system for continuous production of nano-formulations, comprising (a) a first line, (b) a second line, (f) an ultrasonic device, (c) a merged line, and (e) its (fluid) outlet, the first line and the second line are connected to the merged line, the first phase solution enters the merged line through the outlet of the first line, the second phase solution enters the merged line through the outlet of the second line, the ultrasonic device acts locally or entirely on the merged line, the first phase solution and the second phase solution turbulently mix in the merged line to form a merged phase, and flow out through the outlet of the merged line. The manufacturing system and method of the present invention can significantly improve the encapsulation rate of nano-drugs and improve the uniformity of the particle size of nanoparticles.

Description

[Technical field]

[0001] This application claims priority from Chinese patent application No. 202111522472X, filed on December 13, 2021. The entire text of the above Chinese patent application is incorporated herein by reference.

[0002] The present invention relates to the field of biomedicine technology, specifically to a manufacturing system and method for the continuous and scaled production of nano-formulations, specifically, the related manufacturing method involves the rapid mixing of a two-phase solution by the action of turbulent shear and at the same time the action of ultrasound to form a nano-formulation with stable and consistent particle size and particle size distribution, the manufacturing method has excellent stability, high reproducibility, can be scaled up step by step, and is suitable for the continuous and scaled production of nano-formulations.

[0003] The present invention belongs to the field of nanomedicine formulation technology. [Background technology]

[0004] In the process of tumor treatment, there are various treatment plans that can extend the survival time of tumor patients. Antitumor drugs used in treatment plans include chemotherapy drugs, targeted drugs, photosensitive molecules, photothermal molecules, polypeptides, proteins, siRNA, etc., among which, some drugs need to be manufactured into nano dosage forms to achieve the therapeutic effect of tumors. Common nano formulation forms include nanoparticles, nanoliposomes, polymer nanomicelles, dendrimers, etc.

[0005] Currently, large-scale manufacturing methods for nano-formulations include high-pressure homogenization, high-shear emulsification, microjet homogenization, etc., but these manufacturing methods are batch manufacturing and have disadvantages such as many process control parameters, low batch-to-batch reproducibility, and difficulty in scale-up production.

[0006] Compared with the batch manufacturing method, the continuous manufacturing method of nanoformulations can form uniform nanoparticles with adjustable size in the continuous operation process, and by monitoring the quality of the nanoformulations in real time during the production process, the nanoformulations that meet the quality standards can be collected in real time.

[0007] For example, in the case of liposome systems, continuous production can be achieved using the ethanol injection method. A microfluidic control device from Precision NanoSystems, Canada, can be used to continuously produce liposomes (Langmuir, 2012, 28, 3633), which uses laminar flow of lipid organic phase and aqueous phase to rapidly mix in a staggered static mixer and continuously produce liposomes through parameter optimization, but since the microfluidic control flow pipe is usually at the micron level, the flow of the fluid is under laminar flow conditions, the yield of a single passage is extremely small, and parallel multiple passages are required for expanded production, and the consistency of each liposome production unit needs to be controlled. A continuous blank liposome production device using the ethanol injection method disclosed in the literature (Pharm Res., 2016, 33, 404-416) and the invention patent (CN201680013882) can obtain blank liposomes with a low polydispersity coefficient by adjusting the flow rates of the ethanol phase and the aqueous phase, respectively.

[0008] For polymer / drug nanoparticle systems, they can be continuously produced by flash nanoprecipitation (FNP) (US10940118B2, CN108137819, CN108542894). Flash nanoprecipitation is based on the principle of dynamics control and utilizes fluid turbulence mixing in chemical engineering to realize the rapid production of nanoparticles, which has the characteristics of high drug loading rate, short production time (millisecond level), easy control of nanoparticle size, and easy expansion and continuous production. The principle of the preparation of drug / polymer nanoparticles by nanoprecipitation is that a carrier or stabilizer (usually an amphiphilic polymer) and a hydrophobic drug are dissolved in a good solvent that is miscible with water to form a homogeneous solution, and the solution is rapidly mixed with an antisolvent (usually water) in a fixed channel. At this time, the hydrophobic substance is in a highly supersaturated state in the mixed solvent, so that the hydrophobic substance rapidly nucleates in water, and at the same time, the hydrophobic substance interacts with a polymer (usually an amphiphilic block polymer) in the solution, and the polymer coats the core of the nucleation to form polymer nanoparticles, and the polymer plays a protective effect on the nanoparticles and prevents the formed nanoparticles from re-agglomerating, thus forming nanoparticles with good dispersibility in water (Expert Opin. Drug Deliv., 2009, 6, 865). Production equipment used in flash nanoprecipitation includes the confined impinging jet mixer (CIJM) (Physical Review Letters, 2003, 91, 118301; AIChE Journal, 2003, 49, 2264) and the multi-inlet vortex mixer (MIVM) (Mol. Pharm., 2013, 10, 4367; Angew. Chem. Int. Ed. Engl., 2021, 60, 15590).

[0009] However, when the nanoparticles of hydrophobic drugs are continuously produced by conventional flash nanoprecipitation (FNP), the reproducibility of the nanopreparation production process is low due to the significant drop in the encapsulation rate of the hydrophobic drug and the increase in the particle size distribution coefficient of the nanopreparation during the expansion production process of the nanopreparation, making it difficult to control the quality of the nanopreparation, and increasing the risk of failure during the expansion production process of the nanopreparation.In addition, in the prior art, in order to reduce the particle size, ultrasonic waves are combined with the microfluidic control technology of non-turbulent flow state to produce blank liposomes, but the blank liposomes are not related to the parameter of the encapsulation rate of the drug, so how to improve the encapsulation rate of the hydrophobic drug during the expansion production process of the nanopreparation is still an urgent problem to be solved. Summary of the Invention

[0010] The technical problem solved by the present invention overcomes the defects and shortcomings of the above-mentioned prior art, and through repeated research and testing, it has been found that by mixing two-phase solution under conditions of simultaneous turbulent shear action and ultrasonic action, it is possible to solve the problems of the decrease in drug encapsulation rate and the decrease in particle size uniformity of nano-preparations that occur in the scale-up production process of nano-preparations, thereby providing continuous, scalable and controllable production equipment for nano-preparations and a method for continuous, scalable production of ultrasound-enhanced nano-preparations, and realizing continuous, controllable scale-up production of nano-preparations.

[0011] The first objective of the present invention is to provide an equipment for continuous, scalable and controllable production of nano-formulations, which can promote the formation of nanoparticles, improve the encapsulation rate of nano-drugs, prevent the deposition of hydrophobic drug particles on the tube wall, and improve the uniformity of nanoparticle size. Applications of the equipment include, but are not limited to, the production of nano-formulations that are polymer nanomicelles, nanoliposomes, and small molecule nanoassemblies, with particle sizes ranging from 1 nm to 1000 nm.

[0012] A second object of the present invention is to provide a method for the continuous, scalable and controllable production of nanoformulations.

[0013] The present invention provides a manufacturing system for continuous production of nano-formulations, comprising: (a) a first conduit; (b) a second conduit; (f) an ultrasonic device; (c) a merging conduit; and (e) a (fluid) outlet thereof; Wherein, the first pipeline and the second pipeline are connected to a merger pipeline, the first pipeline is coaxial with the merger pipeline, the second pipeline is perpendicular to the merger pipeline, the outlet of the first pipeline is located within the merger pipeline, the first phase solution enters the merger pipeline through the outlet of the first pipeline, and the second phase solution enters the merger pipeline through the outlet of the second pipeline, the ultrasonic device acts on the merger pipeline locally or entirely, the first phase solution and the second phase solution mix in the merger pipeline to form a merged phase, and flow out through the outlet of the merger pipeline.

[0014] In some embodiments, the nanoformulation is one selected from a polymeric nanomicelle, a polymeric nanoparticle, a nanoliposome, a nanolipid particle, and a small molecule nanoassembly.

[0015] In some embodiments, the manufacturing system includes the following features:

[0016] (1) The core part of the manufacturing system includes: (a) a first pipe; (b) a second pipe; (c) a merging pipe; (d) a turbulent mixer; (e) a fluid outlet; and (f) a power-adjustable ultrasonic device. Wherein, the first and second pipelines are connected to a merge pipeline, the first phase solution enters the merge pipeline through the outlet of the first pipeline, and the second phase solution enters the merge pipeline through the outlet of the second pipeline. The first and second phase solutions merge in the merge pipeline to form a merged phase, and the power-adjustable ultrasonic device acts on the merge pipeline locally or entirely, and the mixture is thoroughly mixed by the turbulent mixer, and then collected into a suitable container through the outlet of the merged phase pipeline.

[0017] (2) The mixing process of the first phase solution and the second phase solution is carried out by the action of ultrasound.

[0018] (3) The nano-preparation is one selected from a polymer nanomicelle, a nanoliposome, or a small molecule nanoassembly.

[0019] In some embodiments, the mixing is turbulent mixing. The turbulent mixing can be achieved by increasing the number of turbulent mixing devices in the merging conduit. The turbulent mixing devices can be one or more.

[0020] In some embodiments, the first conduit outlet is a nozzle having a certain shape and aperture size, and the first phase solution passes through the first conduit and out of the nozzle into the merging conduit.

[0021] In some embodiments, the hole diameter D1(S) of the terminal nozzle of the first conduit is selected from the range of 0.03 mm to 5.0 mm, the inner diameter D2(IN) of the second conduit is selected from the range of 0.3 mm to 50.0 mm, and the inner diameter D3(IN) of the merging conduit is selected from the range of 0.3 mm to 50.0 mm.

[0022] In some embodiments, the length of the merging conduit (ie, the length of the merging phase) is in the range of 6 cm to 120 cm, for example 9 cm or 36 cm.

[0023] In some embodiments, the ratio of the length of the merging conduit to the inner diameter of the merging conduit is (16-450):1, such as 16.7:1, 30:1, or 450:1.

[0024] In some embodiments, the outer diameter D1(O) of the first pipeline is between 0.35 mm and 2 mm, for example, 0.35 mm, 1 mm, or 2 mm.

[0025] In some embodiments, the hole diameter D1(S) of the terminal nozzle of the first conduit is 0.2 mm to 0.6 mm, for example, 0.2 mm, 0.25 mm, 0.3 mm, 0.4 mm, or 0.6 mm.

[0026] In some embodiments, the outer diameter D2(O) of the second conduit is 6 mm.

[0027] In some embodiments, the second conduit has an inner diameter D2(IN) of 0.8 mm to 5.4 mm, for example, 0.8 mm, 3.0 mm, or 5.4 mm.

[0028] In some embodiments, the outer diameter D3(O) of the merging conduit is 6 mm.

[0029] In some embodiments, the inner diameter D3(IN) of the merging conduit is between 0.8 mm and 5.4 mm, for example, 0.8 mm, 3.0 mm, or 5.4 mm.

[0030] In some embodiments, the inner diameter D2(IN) of the second conduit is the same as the inner diameter D3(IN) of the merging conduit.

[0031] In some embodiments, the ratio of the hole diameter D1 (S) of the terminal nozzle of the first conduit to the inner diameter D3 (IN) of the merging conduit may be 1:(2-50), for example, 1:3.2, 1:7.5, 1:9, or 1:18.

[0032] In some embodiments, the turbulent mixing device is a device that achieves a turbulent state after mixing the first phase solution and the second phase solution, such as a static mixer. The static mixer may be one or more types selected from an SV type static mixer, an SX type static mixer, an SL type static mixer, an SH type static mixer, and an SK type static mixer, and is preferably an SK type static mixer.

[0033] In some embodiments, the materials used for the first line, the second line, the merging line, the turbulent mixer, and the fluid outlet are each one or more selected from stainless steel, polytetrafluoroethylene, polyethylene, polypropylene, latex, silica gel, or other polymeric materials.

[0034] In some embodiments, the turbulent mixing can increase the flow velocity of the fluids, which can cause the fluids in the merging phase to reach a turbulent transition state or a turbulent state. The Reynolds number in the merging phase is determined by the smoothness of the pipe wall of the circular stainless steel pipe, and for example, if the pipe wall is rough, turbulent mixing conditions (e.g., Re is 500 to 2000, which is usually considered to be laminar flow conditions) can be reached even at low Reynolds numbers.

[0035] In some embodiments, the turbulent mixing can be achieved by making the merging phase a serpentine pipe with a certain curvature to increase the mixing of the fluids by changing the flow direction of the fluids / enhancing the convection of the fluids. In this case, the Reynolds number in the merging phase calculated based on the fluids in a circular pipe can be 500-4000 in addition to being greater than 4000.

[0036] In some embodiments, the turbulent mixing can be achieved by installing a static mixer in the merging phase. The static mixer includes, but is not limited to, an SV type static mixer, an SX type static mixer, an SL type static mixer, an SH type static mixer, an SK type static mixer, etc., and the turbulent mixing member divides the fluid / changes the flow direction of the fluid / increases the convection of the fluid to increase the mixing of the fluid. In this case, the Reynolds number in the merging phase calculated based on the fluid in the circular pipe may be 500 to 4000 in addition to exceeding 4000.

[0037] In some embodiments, the flow rate Q1 of the first phase solution through the first pipeline is in the range of 1 mL / min to 1000 mL / min, the temperature T1 of the first phase solution is in the range of 0°C to 90°C, the flow rate Q2 of the second phase solution through the second pipeline is in the range of 10 mL / min to 10000 mL / min, and the temperature T2 of the second phase solution is in the range of 0°C to 90°C.

[0038] In some embodiments, the ultrasonic frequency of the adjustable power ultrasonic device is between 15 kHz and 1.0 MHz, and the ultrasonic power range is between 0.1 kW and 20 kW.

[0039] In some embodiments, the ultrasonic frequency of the adjustable power ultrasonic device is between 15 kHz and 40 kHz, and the ultrasonic power range is between 0.1 kW and 20 kW.

[0040] In some embodiments, the ultrasonic frequency of the adjustable power ultrasonic device is between 15 kHz and 40 kHz, and the ultrasonic power range is between 0.1 kW and 20 kW.

[0041] In some embodiments, the ultrasonic frequency of the adjustable power ultrasonic device is between 15 kHz and 40 kHz, and the ultrasonic power range is between 100 W and 1000 W.

[0042] In some embodiments, the structure of the manufacturing system is as shown in FIG. 1 or FIG.

[0043] In some embodiments, the polymer nanomicelle is a polymer nanomicelle coated with an antitumor drug, wherein the polymer nanomicelle components are selected from amphiphilic polymers and antitumor drugs, and the amphiphilic polymers are selected from PEG-PLA, PEG-PCL, PEG-linker-PLA, and PEG-linker-PCL, wherein linker is a linker, the structure of which is C1-C 30 and PEG is a polyethylene glycol segment having a number average molecular weight of between 400 and 20,000 or a single protected polyethylene glycol segment.

[0044] In some embodiments, the nanoliposomes are blank liposomes that are not coated with a drug.

[0045] In some embodiments, the nanoliposome is an anti-tumor drug-coated liposome.

[0046] In some embodiments, the nanolipid particles are anti-tumor drug-coated lipid particles.

[0047] In some embodiments, the small molecule nanoassembly is selected from an antitumor drug / photosensitizer nanoassembly, an antitumor drug / antitumor drug nanoassembly, an antitumor drug / other drug (e.g., curcumin) nanoassembly, an antitumor drug / additive (e.g., amphiphilic polymer PEG-PLA, DSPE-PEG, or polymer PLGA) nanoassembly, a two or more drug nanoassembly (e.g., SN38 and irinotecan), or a small molecule drug / additive nanoassembly.

[0048] In some embodiments, the anti-tumor drug is abemaciclib, abiraterone, abrocitinib, acalabrutinib, afatinib, aldesleukin, alectinib, alflutinib, almonertinib, altretamine, amcenestrant, aminoglutethimide, amsacrine, anastrozole, anlotinib, apalutamide, apatinib, arzoxifene, asciminib, asparaginase, avapritinib, avitinib, axitinib, azacitidine, baricitinib, belinostat, bendamustine, bexarotene, bicalutamide, bicyclol, binimetinib, bleomycin, boanmycin, bortezomib, bosutinib, brigatinib, buserelin, busulfan, cabazitaxel, cabozantinib, calaspargase, calicheamycin, capecitabine, capmatinib, carboplatin, carfilzomib, carmustine, carmofur, cedazuidine, ceritinib, cetrorelix, chidamide, chlorambucil, cisplatin, cladribine, clofarabine, cobimetinib, colchicine, copanlisib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dacomitinib, dactinomycin, dalpiciclib, darolutamide, dasatinib, daunorubicin, decitabine, degarelix, delgociclib, denileukin, deruxtecan, docetaxel, donafenib, doxorubicin, duvelisib, enasidenib, encorafenib, ensartinib, entrectinib, enzalutamide, enzastaurin,elacestrant、epirubicin、erdafitinib、eribulin、erlotinib、estradiol、estramustine、etoposide、everolimus、exemestane、fasudil、fedatinib、filgotinib、floxuridine、fludarabine、flumatinib、fluorouracil、flutamide、fluzoparib、formestane、fostamatinib、fruquintinib、fulvestrant、gefitinib、gemcitabine、gilteritinib、giredestrant、glasdegib、goserelin、histrelin、hydroxyurea、ibrutinib、ibudilast、icaritin、icotinib、idarubicin、idelalisib、ifosfamide、imatinib、imiquimod、infigratinib、ingenol mebutate、interferon alfa-2b、irinotecan、ivosidenib、ixabepilone、ixazomib、lanreotide、lapatinib、larotrectinib、lenalidomide、lenvatinib、letrozole、leucovorin、leuprolide、lomustine、lonafarnib、lorlatinib、lurbinctedin、maytansine、mechlorethamine、medroxyprogesterone、megestrol、melphalan、melphlan flufenamide、mercaptopurine、methotrexate、methoxsalen、methylprednisolone、midostaurin、mitomycin、mitotane、mitoxantrone、mitozolomide、mobocertinib、monomethylauristatin E、monomethylauristatin F、nelarabine、nandrolone、neratinib、nearsudil、nilotinib、nilutamide、nintedanib、niraparib、octreotide、olaparib、olmutinib、omacetaxine、orelabrutinib、osimertinib、oxaliplatin、paclitaxel、pacritinib、palbociclib、pamidronate、pamiparib、panobinostat、pazopanib、peficitinib、pegaptanib、pegaspargase、peginteferon alfa-2b、pemigatinib、pemetrexed、pentetreotide、pentostatin、pexidartinib、phenoxybenzamine、pidotimod、plinabulin、plitidepsin、pomalidomide、ponatinib、porfimer、pralatrexate、pralsetinib、prednisolone、procarbazine、pyrotinib、quizartinib、radotinib、raloxifene、raltitrexed、regorafenib、ribociclib、rintatolimod、ripretinib、romidepsin、rucaparib、ruxolitinib、savolitinib、selinexor、selpercatinib、selumetinib、sonidegib、sorafenib、sotorasib、streptozocin、sunitinib、surufatinib、talazoparib、tamoxifen、tazemetostat、tegafur、temozolomide、temsirolimus、teniposide、tepotinib、teprenone、thalidomide、thioguanine、thiotepa、thyrotropin alfa、tipiracil、tipifarnib、tirabrutinib、tirbanibulin、tivozanib、trametinib、tofacitinib、topotecan、toremifene、trabectedin、tretinoin、trifluride、trilaciclib、triptorelin、tucatinib、upadacitinib、umbralisib, utidelone, uroacitide, valrubicin, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, zanubrutinib, zoledronic acid, amatoxins, anthacyclines, anthracenes, anthramycins, auristatins, bryostatins, camptothecins, carmaphycins, combretastatins, cyclosporines, cryptomycins, ecteinascidins, ellipt icenes, esperamicins, mustines, neothramycins, ozogamicins, phenoxazines, podophyllotoxins, pyrrolobenzodiazepines, sibiromycins, thailanstatins, tomamycns, tubulysins, taxanes, vinca alkaloids, 7-epipaclitaxel, 2'-acetylpaclitaxel, 10-deacetylpaclitaxel, 10-deacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-deacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, rirontaxel, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, raltotecan, gematecan, belotecan, 10-hydroxycamptothecin, 10-hydroxy-ethyl-camptothecin (SN-38), isitecan, pyran adriamycin, aclarithromycin, sirolimus, tacrolimus, progesterone, estrogen, rapamycin, precarmycin, harringtonine, or curcumin; Further, the antitumor drug is preferably camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, raltotecan, gematecan, belotecan, 10-hydroxycamptothecin, SN-38, isitecan, irinotecan, topotecan, deruxtecan, paclitaxel, docetaxel, cabazitaxel, 7-epipaclitaxel, 2'-acetylpaclitaxel, 10-deacetylpaclitaxel, 10-deacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-deacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, rirontaxel, adriamycin, epiadriamycin, daunorubicin, pyranadriamycin, aclarithromycin, etoposide, Cido, teniposide, vinblastine, vincristine, vinorelbine, vindesine, maytansine, curcumin, harringtonine, hyharringtonine, gemcitabine, capecitabine, fludarabine, cladribine, pemetrexed, bortezomib, carfilzomib, elsazomib, carmustine, fluorouracil, cytarabine, cyclosporine A, eribulin, trabectedin, The therapeutic agent is one or more selected from gefitinib, erlotinib, lapatinib, afatinib, dacomitinib, vandetanib, neratinib, osimertinib, imatinib, sorafenib, sunitinib, lapatinib, dasatinib, lymparib, niraparib, rucaparib, fluzoparib, pamiparib, veliparib, talazoparib, apatinib, palbociclib, avecilib, and ribociclib.

[0049] In some embodiments, the photosensitizer used includes a cyanine-based molecule, a porphyrin-based molecule, a porphyrin molecule precursor, a phthalocyanine-based molecule, and a chlorine-based molecule, among which the cyanine-based molecule is preferably one or more selected from indole green (IR780), new indocyanine green (IR820), indocyanine green, and indocyanine green analogs, the porphyrin-based molecule is preferably hematoporphyrin monomethyl ether, the porphyrin molecule precursor is preferably one of 5-aminovaleric acid and 5-aminovaleronate, and the phthalocyanine-based molecule is preferably one or more selected from the group consisting of 5-aminovaleric acid and 5-aminovaleronate. The phthalocyanine molecule is preferably one or more of copper phthalocyanine, cobalt phthalocyanine, aluminum phthalocyanine, nickel phthalocyanine, calcium phthalocyanine, sodium phthalocyanine, magnesium phthalocyanine, zinc phthalocyanine, indium phthalocyanine, oxytitanium phthalocyanine, magnesium phthalocyanine, manganese phthalocyanine, or a phthalocyanine derivative, and the chlorin molecule is preferably one or more of chlorin, talaporfin, verteporfin, temoporfin, rotaporfin, porfirom sodium, hemoporfin, and photochlor.

[0050] In some embodiments, the polymer nanomicelle is a PTX / PEG-PLA polymer micelle or a PTX / PEG-Phe-PLA polymer micelle.

[0051] In some embodiments, the nanoliposome is a HSPC / CHOL / DSPE-PEG blank liposome or a PTX / HSPC / CHOL / DSPE-PEG liposome.

[0052] In some embodiments, the molar ratio of HSPC / CHOL / DSPE-PEG in the nanoliposome is 56:38:5 or 89:57:4.

[0053] In some embodiments, the nanolipid particle is a Poly I nanolipid particle, for example, Poly I / ALC-0315 / DSPE-PEG2000 / HSPC / cholesterol.

[0054] In some embodiments, the polymeric nanoparticles are PEG-PLA polymeric nanoparticles, PLGA polymeric nanoparticles, or PTX / PLGA polymeric nanoparticles.

[0055] In some embodiments, the small molecule nanoassembly is an antitumor drug / photosensitizer nanoassembly, preferably SN-38 / ICG nanoparticles, PTX / ICG nanoparticles, curcumin / CPT11 nanoparticles or SN-38 / CPT11 nanoparticles.

[0056] In some embodiments, the drug loading of the antitumor drug is 10%-90%, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%.

[0057] The present invention further provides a method for producing a nano-formulation, comprising the steps of mixing a first phase solution with a second phase solution in the production system described above, and by the action of ultrasound, the resulting combined phase may be collected through its (fluid) outlet, said nano-formulation being: A. When the nano-preparation is a polymer nanomicelle, the solvent in the first phase solution is a good solvent for the antitumor drug or a pharma- ceutically acceptable salt thereof, and the solute is (1) the antitumor drug or a pharma- ceutically acceptable salt thereof, or (2) the antitumor drug or a pharma- ceutically acceptable salt thereof and a polymer; The solvent in the second phase solution is an antisolvent for the antitumor drug or a pharma- ceutically acceptable salt thereof, and the solute is (1) absent or (2) a polymer; When the solute in the first phase solution is an antitumor drug or a pharma- ceutically acceptable salt thereof and a polymer, the solute in the second phase solution is absent; When the solute in the first phase solution is an antitumor drug or a pharma- ceutically acceptable salt thereof, the solute in the second phase solution is a polymer; B. When the nano formulation is a polymer nanoparticle, the solvent of the first phase solution is a good solvent for the polymer, and the solute is (1) a polymer, or (2) a polymer and an antitumor drug; The second phase solution is water or water containing 0.5% PVA; C. When the nano-preparation is a nanoliposome, the solvent of the first phase solution is a good solvent for the lipid components, and the solute is (1) the lipid components of the liposome, or (2) the lipid components of the liposome and an antitumor drug; The second phase solution is water or a buffered aqueous solution having a certain pH value and a certain osmotic pressure, D. When the nano-formulation is a nano-lipid particle, the solvent of the first phase solution is a good solvent for the lipid component, and the solute is the lipid component of the lipid particle; The solvent of the second phase solution is a buffered aqueous solution having a certain pH value and a certain osmotic pressure, and the solute is an antitumor drug; E. When the nanoformulation is an antitumor drug / photosensitizer nanoassembly, the solvent in the first phase solution is a good solvent for the antitumor drug or a pharma- ceutically acceptable salt thereof, and the solute is (1) an antitumor drug or a pharma- ceutically acceptable salt thereof and a photosensitizer, or (2) an antitumor drug or a pharma- ceutically acceptable salt thereof; The solvent in the second phase solution is an antisolvent for the antitumor drug or a pharma- ceutically acceptable salt thereof, and the solute is (1) absent or (2) a photosensitizer; When the solutes in the first phase solution are an antitumor drug or a pharma- ceutically acceptable salt thereof and a photosensitizer, there are no solutes in the second phase solution; When the solute in the first phase solution is an anti-tumor drug or a pharma- ceutically acceptable salt thereof, the solute in the second phase solution is a photosensitizer.

[0058] In some embodiments, the temperature of the first phase solution is from 0°C to 90°C, for example, 25°C or 60°C.

[0059] In some embodiments, the temperature of the second phase solution is between 0°C and 90°C, for example, 25°C or 60°C.

[0060] In some embodiments, the fluid Reynolds number Re of the combined phase is 700 to 9500 (eg, 747, 2884, 3868, 5158, 5505, 5872, 6623, 7865 or 9176), preferably 3000 to 7000 (eg, 3868, 5158 or 6623).

[0061] In some embodiments, the flow rate ratio FVR between the first phase solution and the combined phase is 0.4 to 6, for example, 0.49, 0.64, 0.93, 1.46, 3.38, 3.4, 4.4, or 5.2.

[0062] In some embodiments, the flow rate Q1 of the first phase solution through the first line is in the range of 10 mL / min to 100 mL / min, such as 10, 11, 14, 50, 60, 80, or 100.

[0063] In some embodiments, the flow rate Q2 of the second phase solution through the second line is selected from the range of 100 mL / min to 1300 mL / min, such as 100, 193, 200, 210, 300, 936, 890, or 1248.

[0064] In some embodiments, the ultrasound is an ultrasonic water bath and the power of the ultrasound is 200W.

[0065] In some embodiments, the present invention further provides a method for preparing polymeric micelles, comprising: dissolving one or more of the antitumor drugs or their pharma- ceutically acceptable salts in a first phase, the solvent used in the first phase solution being a good solvent for the antitumor drugs or their pharma- ceutically acceptable salts; dissolving one or more polymers in a second phase solution, the solvent used in the second phase solution being an antisolvent for the antitumor drugs or their pharma- ceutically acceptable salts; merging the first phase solution with a flow rate Q1 and the second phase solution with a flow rate Q2 into a combined phase, and the two-phase solution is rapidly mixed under the action of turbulent shear and at the same time under the action of ultrasound, forming polymeric micelles coated with the antitumor drugs, which are stably dispersed in the mixed solvent of the first and second phases and have a certain particle size and distribution coefficient. In the mixing process of the two-phase solution, the action of ultrasound can prevent hydrophobic drug particles from depositing on the tube wall, ensuring the stability and controllability of the expanded production process of nanoformulations.

[0066] In some embodiments, the present invention further provides a preparation method for polymeric micelles, comprising: dissolving one or more of the antitumor drugs or their pharma- ceutically acceptable salts and one or more of the polymers in a first phase; the solvent used in the first phase solution is a good solvent for the antitumor drugs or their pharma- ceutically acceptable salts and the polymer; the second phase solution is an antisolvent for the antitumor drugs or their pharma- ceutically acceptable salts; and merging the first phase solution with a flow rate Q1 and the second phase solution with a flow rate Q2 into a merged phase, and the two-phase solution is rapidly mixed under the action of turbulent shear and at the same time under the action of ultrasound, forming polymeric micelles with a certain particle size and distribution coefficient, which are stably dispersed in the mixed solvent of the first phase and the second phase. In the mixing process of the two-phase solution, the action of ultrasound can prevent hydrophobic drug particles from depositing on the tube wall, ensuring the stability and controllability of the expanded production process of nanoformulations.

[0067] In some embodiments, the volumetric mass concentration range of the antitumor drug in the first phase solution is 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL, preferably 10 mg / mL to 100 mg / mL, more preferably 10 mg / mL to 20 mg / mL, for example 15 mg / mL.

[0068] In some embodiments, the volumetric mass concentration range of the polymer in the first phase solution or the second phase solution is 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL, preferably 10 mg / mL to 100 mg / mL, for example 50 mg / mL.

[0069] In some embodiments, the present invention further provides a method for the continuous production of liposomes, comprising: dissolving the lipid components of liposomes in a first phase; the solvent used for the first phase solution is a good solvent for the lipid components; the second phase solution is water, a buffer solution having a certain pH value and a certain osmotic pressure; and merging the first phase solution at a flow rate Q1 and the second phase solution at a flow rate Q2 into a merged phase, and the two-phase solution is rapidly mixed under the action of turbulent shear and at the same time under the action of ultrasonic waves, forming blank liposomes with a certain particle size and distribution coefficient, which are stably dispersed in the mixed solvent of the first phase and the second phase. In the process of mixing the two-phase solution, the action of ultrasonic waves can reduce and remove the precipitate of the merged phase on the tube wall, ensuring the stability and controllability of the expanded production process of nano formulations.

[0070] In some embodiments, the volumetric mass concentration range of the lipid component in the first phase solution is 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL, and preferably 10 mg / mL to 100 mg / mL.

[0071] In some embodiments, the lipid component is HSPC / CHOL / DSPE-PEG. 2k then the volumetric mass concentration of said HSPC in the first phase solution is 10 mg / mL.

[0072] In some embodiments, the present invention further provides a method for the continuous production of antitumor drug / photosensitizer nanoassembly, comprising: dissolving one or more of the antitumor drugs or their pharma- ceutically acceptable salts in a first phase; dissolving one or more of the photosensitizers in a second phase solution, the solvent used in the second phase solution being an antisolvent for the antitumor drug or its pharma- ceutically acceptable salts; merging the first phase solution at a flow rate Q1 and the second phase solution at a flow rate Q2 into a combined phase, and the two-phase solution is rapidly mixed under the action of turbulent shear and at the same time under the action of ultrasound, forming a composite nanoformulation of photosensitizer and antitumor drug with a certain particle size and distribution coefficient, which is stably dispersed in the mixed solvent of the first and second phases. The action of ultrasound can prevent hydrophobic drug particles from depositing on the tube wall, ensuring the stability and controllability of the scale-up production process of the nanoformulation.

[0073] In some embodiments, the present invention further provides a method for the continuous production of antitumor drug / photosensitizer nanoassembly, comprising: dissolving one or more of the antitumor drugs or their pharma- ceutically acceptable salts and one or more of the photosensitizers in a first phase, the solvent used in the first phase solution is a good solvent for the antitumor drug or its pharma- ceutically acceptable salt photosensitizer, and the second phase solution is an antisolvent for the antitumor drug or its pharma- ceutically acceptable salt, and merging the first phase solution with a flow rate Q1 and the second phase solution with a flow rate Q2 into a merged phase, and the two-phase solution is rapidly mixed under the action of turbulent shear and at the same time, under the action of ultrasound, to form a composite nano-formulation of photosensitizer and antitumor drug, which is stably dispersed in the mixed solvent of the first phase and the second phase, and has a certain particle size and distribution coefficient. The action of ultrasound can prevent hydrophobic drug particles from depositing on the tube wall, ensuring the stability and controllability of the scaled-up production process of the nano-formulation.

[0074] In some embodiments, the molar ratio of the antitumor drug or a pharma- ceutically acceptable salt thereof to the photosensitizer is (1 to 15):1, for example, 1:1, 2:1, 5:1, 6:1, 7:1, 8:1, 10:1 or 15:1, preferably 2:1.

[0075] In some embodiments, the volumetric mass concentration range of the antitumor drug in the first phase solution is 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL, and preferably 10 mg / mL to 100 mg / mL, for example, 40 mg / mL, 50 mg / mL or 100 mg / mL.

[0076] In some embodiments, the volumetric mass concentration range of the photosensitizer in the first phase solution or the second phase solution is 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL, and preferably 10 mg / mL to 100 mg / mL, for example, 40 mg / mL, 50 mg / mL, or 150 mg / mL.

[0077] In some embodiments, the solvent used in the first phase solution and the second phase solution is water, an aqueous buffer solution having a certain pH value, or an organic solvent miscible with water, further comprising one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, DMF, DMAc, HMPA, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, cyclosulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, ethylene glycol, ethylene glycol methyl ether, ethylene glycol ethyl ether, dioxane, formic acid, acetic acid, hydroxypropionic acid, ethylamine, ethylenediamine, glycerol, or pyridine.

[0078] In some embodiments, when the nanoformulation is a polymeric nanomicelle, the solvent used in the first phase solution is a nitrile-based solvent or an alcohol-based solvent, such as acetonitrile or ethanol.

[0079] In some embodiments, when the nanoformulation is a polymeric nanomicelle, the solvent used for the second phase solution is water.

[0080] In some embodiments, when the nanoformulation is a liposome, the solvent used in the first phase solution is an alcoholic solvent, such as ethanol.

[0081] In some embodiments, when the nanoformulation is a liposome, the solvent used for the second phase solution is water or an aqueous ammonium sulfate solution, preferably water or a 120 mM aqueous ammonium sulfate solution.

[0082] In some embodiments, when the nanoformulation is a polymeric nanoparticle, the solvent used in the first phase solution is an alcoholic solvent or a chlorinated alkane solvent, such as ethanol or dichloromethane.

[0083] In some embodiments, when the nanoformulation is a polymeric nanoparticle, the solvent used for the second phase solution is water or water containing 0.5% PVA.

[0084] In some embodiments, when the nanoformulation is an antitumor drug / photosensitizer nanoassembly, the solvent used in the first phase solution is a sulfoxide solvent, an alcohol solvent, such as dimethyl sulfoxide or methanol.

[0085] In some embodiments, when the nanoformulation is an antitumor drug / photosensitizer nanoassembly, the solvent used in the second phase solution is water.

[0086] In some embodiments, when the nanoformulation is a nanolipid particle, the first phase solution is an alcoholic solvent, such as ethanol.

[0087] In some embodiments, when the nanoformulation is a nanolipid particle, the second phase solution is a citrate buffer (pH 4.0).

[0088] In some embodiments, the nanoformulations produced are less than 1000 nm.

[0089] In some embodiments, the particle size of the produced nanoformulation is less than 500 nm.

[0090] In some embodiments, the particle size of the produced nanoformulation is less than 200 nm.

[0091] In some embodiments, the particle size range of the nanoformulation produced is selected from 20 nm to 200 nm.

[0092] In some embodiments, the polydispersity index of the produced nanoformulation is less than 0.3.

[0093] In some embodiments, the polydispersity index of the produced nanoformulation is less than 0.2.

[0094] In some embodiments, the polydispersity index of the produced nanoformulation is less than 0.1.

[0095] Further, the present invention provides a method for continuous production of SN-38 / indocyanine green nanoassembly, comprising the steps of: SN-38 and indocyanine green are dissolved in a first phase jointly, the solvent used for the first phase solution is a good solvent for SN-38 and indocyanine green, and the second phase solution is an antisolvent for the antitumor drug or its pharma- ceutically acceptable salt; the first phase solution at a flow rate Q1 and the second phase solution at a flow rate Q2 are combined into a combined phase, and the two-phase solution is rapidly mixed under the action of turbulent shear and ultrasonic waves at the same time, to form SN-38 / indocyanine green nanoassemblies with a certain particle size and distribution coefficient, which are stably dispersed in the mixed solvent of the first phase and the second phase; the solvent used for the first phase solution and the second phase solution is water, a buffer aqueous solution having a certain pH value, or water and and an organic solvent to be mixed, the organic solvent being one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, DMF, DMAc, HMPA, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, cyclosulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, ethylene glycol, ethylene glycol methyl ether, ethylene glycol ethyl ether, dioxane, formic acid, acetic acid, hydroxypropionic acid, ethylamine, ethylenediamine, glycerol, and pyridine.

[0096] In some embodiments, the encapsulation rate of SN-38 / ICG nanoparticles SN-38 produced on a scale of 15 mL to 20 mL under conditions without ultrasound is 98.4%, and the particle size of the nanoparticles is 98±4 nm.

[0097] In some embodiments, the encapsulation rate of SN-38 / ICG nanoparticles produced at a 1.0 L scale without ultrasound dropped to 92.4%, the SN-38 drug obviously deposited in the outlet duct, and the particle size of the nanoparticles was 111±6 nm.

[0098] In some embodiments, the encapsulation rate of SN-38 / ICG nanoparticles SN-38 produced at a 1.0 L scale under ultrasonic conditions was close to that produced in small batches, at 97.5%, with an average particle size of 109±10 nm.

[0099] In some embodiments, the encapsulation rate of SN-38 / ICG nanoparticles SN-38 produced on a scale of 15 mL to 20 mL without ultrasonication is 98.8%, and the particle size of the nanoparticles is 109±5 nm.

[0100] In some embodiments, the encapsulation rate of SN-38 / ICG nanoparticles SN-38 produced at a 425 mL scale without ultrasound dropped to 92.2%, the SN-38 drug obviously deposited in the outlet duct, and the particle size of the nanoparticles was 126±4 nm.

[0101] In some embodiments, the encapsulation rate of SN-38 / ICG nanoparticles SN-38 produced at a 425 mL scale under ultrasonic conditions was close to that produced in small batches, at 97.0%, and the average particle size was 113±4 nm.

[0102] In some embodiments, the encapsulation rate of PTX / ICG nanoparticles produced at a scale of 20 mL without ultrasound is 98.2%, and the particle size of the nanoparticles is 75±3 nm.

[0103] In some embodiments, the encapsulation rate of PTX / ICG nanoparticles produced at a 400 mL scale without ultrasound drops to 93.4%, and the particle size of the nanoparticles is 81±5 nm.

[0104] In some embodiments, the encapsulation rate of PTX / ICG nanoparticles produced at a 400 mL scale under ultrasonic conditions was close to that produced in small batches, at 98.7%, and the average particle size was 72±2 nm.

[0105] In some embodiments, HSPC / CHOL / DSPE-PEG blank liposomes are prepared under conditions without ultrasound, and the resulting blank liposomes exhibit a multi-peak distribution.

[0106] In some embodiments, HSPC / CHOL / DSPE-PEG blank liposomes are prepared under ultrasonic conditions, and the resulting blank liposomes exhibit a single-peak distribution, with a particle size of 131.7±2.9 nm, indicating that ultrasonic waves can promote the formation of blank liposomes.

[0107] In some embodiments, HSPC / CHOL / DSPE-PEG blank liposomes are prepared under ultrasonic conditions, and the resulting blank liposomes exhibit a single-peak distribution, with a particle size of 115.3±1.6 nm, indicating that ultrasonic waves can promote the formation of blank liposomes.

[0108] In some embodiments, HSPC / CHOL / DSPE-PEG / paclitaxel liposomes are prepared under ultrasonic conditions, and the resulting paclitaxel liposomes show a single-peak distribution, with a particle size of 81.1±1.7 nm, indicating that ultrasound can promote the formation of paclitaxel liposomes.

[0109] In some embodiments, the PTX / PEG-PLA polymer micelles produced under non-ultrasonic conditions have a lot of white floccules in the solution, a broad particle size distribution, and low overlap.

[0110] In some embodiments, the PTX / PEG-PLA polymeric micelles prepared under ultrasonic conditions had a uniform particle size distribution and an average particle size of 25.6±1.0 nm, indicating that ultrasound can promote the formation of drug-loaded polymeric micelles.

[0111] In some embodiments, the PTX / PEG-Phe-PLA polymeric micelles produced under non-ultrasonic conditions have a lot of white floccules in the solution, a broad particle size distribution, and low overlap.

[0112] In some embodiments, the PTX / PEG-Phe-PLA polymeric micelles prepared under ultrasonic conditions had a uniform particle size distribution, with an average particle size of 23.4±0.8 nm, indicating that ultrasound can promote the formation of drug-loaded polymeric micelles.

[0113] Compared with the prior art, the present invention has the following beneficial effects: the manufacturing system and manufacturing method of the present invention can significantly improve the encapsulation rate of nano-drugs and improve the uniformity of the particle size of nanoparticles. In addition, the encapsulation rate is improved, which reduces drug deposition. It is advantageous for continuous manufacturing production. [Brief description of the drawings]

[0114] [Figure 1] FIG. 1 is a schematic diagram of a nano-formulation manufacturing apparatus that does not include a static mixer. [Diagram 2] FIG. 1 is a schematic diagram of a nanoformulation manufacturing apparatus equipped with an SK static mixer in the mixing phase. [Diagram 3] FIG. 13 is a particle size distribution diagram of SN-38 / ICG nanoparticles produced with and without ultrasound under low turbulence conditions in Example 4. [Figure 4] FIG. 11 is a particle size distribution diagram of SN-38 / ICG nanoparticles in Example 5. As can be seen from the diagram, when SN-38 / ICG is produced in small amounts (10 mL to 25 mL), the nanoparticles obtained using a manufacturing device without ultrasound exhibit a single peak distribution, and the average particle size is 98±4 nm. [Diagram 5] FIG. 11 is a particle size distribution diagram of SN-38 / ICG nanoparticles in Example 6. As can be seen from the diagram, when SN-38 / ICG is produced in large quantities (1.0 L), the nanoparticles obtained using a production device without ultrasound exhibit a double-peak distribution, with an average particle size of 111±6 nm. [Figure 6] FIG. 11 is a particle size distribution diagram of SN-38 / ICG nanoparticles in Example 7. As can be seen from the diagram, when SN-38 / ICG is produced in a large amount (1.0 L), the nanoparticles obtained by the action of ultrasound exhibit a single peak distribution, with an average particle size of 109±10 nm. [Figure 7]FIG. 2 shows the particle size distribution of HSPC / CHOL / DSPE-PEG blank liposomes in Example 20 and Example 21. As can be seen from the figure, when HSPC / CHOL / DSPE-PEG blank liposomes are prepared by the action of no ultrasound, the resulting blank liposomes exhibit a multi-peak distribution. [Figure 8] Figure 2 shows the particle size distribution of HSPC / CHOL / DSPE-PEG blank liposomes in Example 22 and Example 23. As can be seen from the figure, when HSPC / CHOL / DSPE-PEG blank liposomes are prepared by the action of ultrasound, the obtained blank liposomes show a single peak distribution, and the particle sizes are 131.7±2.9nm and 115.3±1.6nm, respectively. [Figure 9] FIG. 2 shows the particle size distribution of PTX / HSPC / CHOL / DSPE-PEG liposomes in Example 24. As can be seen from the figure, when PTX / HSPC / CHOL / DSPE-PEG liposomes are prepared by the action of ultrasound, the resulting paclitaxel liposomes exhibit a single-peak distribution, and the particle size is 81.1±1.7 nm. [Figure 10] FIG. 27 shows the particle size distribution of PTX / PEG-PLA nanomicelles in Example 27. As can be seen from the figure, when PTX / PEG-PLA nanomicelles are prepared by the action of ultrasound, the obtained nanomicelles show a single peak distribution, and the particle size is 45.1±1.1 nm. [Figure 11] FIG. 3 is a particle size distribution diagram of the PEG-PLA nanoparticles in Example 30. As can be seen from the diagram, when the PEG-PLA nanoparticles are produced by the action of no ultrasound, the obtained nanoparticles exhibit a multi-peak distribution, with a particle size of 69.5±7.3 nm and a PI of 0.520. [Figure 12] FIG. 3 is a particle size distribution diagram of the PEG-PLA nanoparticles in Example 31. As can be seen from the diagram, when the PEG-PLA nanoparticles are produced by the action of ultrasound, the obtained nanoparticles exhibit a single peak distribution, with a particle size of 25.0±0.1 nm and a PI of 0.152. [Figure 13]FIG. 3 is a particle size distribution diagram of PLGA nanoparticles in Example 32. As can be seen from the diagram, when PLGA nanoparticles are prepared by the action of ultrasound, the obtained nanoparticles exhibit a single peak distribution, with a particle size of 218.5±2.1 nm and a PI of 0.063. [Figure 14] 1 is a particle size distribution diagram of PTX / PLGA nanoparticles in Example 33. As can be seen from the diagram, when PTX / PLGA nanoparticles are produced by the action of ultrasound, the obtained nanoparticles exhibit a single peak distribution, with a particle size of 225.9±1.2 nm and a PI of 0.027. [Figure 15] FIG. 3 is a particle size distribution diagram of Poly I nanolipid particles in Example 34. As can be seen from the diagram, when Poly I nanolipid particles are produced by synergistic action without ultrasound, the obtained nanoparticles exhibit a multi-peak distribution, with a particle size of 89.6 nm and a PI of 0.414. [Figure 16] FIG. 3 is a particle size distribution diagram of PolyI nanolipid particles in Example 35. As can be seen from the diagram, when PolyI nanolipid particles are produced by the synergistic action of ultrasound, the obtained nanoparticles exhibit a single-peak distribution, with a particle size of 85.7 nm and a PI of 0.214. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0115] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the described examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions or product instructions.

[0116] The endpoints of any ranges and any values ​​disclosed herein are not limited to the exact ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. Numerical ranges between the individual range endpoints, between the individual range endpoints and any single point value, and between any single point value can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed herein.

[0117] Unless otherwise specified, "with ultrasound" in the present invention means that the two phases are simultaneously subjected to ultrasonic action in the turbulent mixing process.

[0118] The abbreviations used in this invention are as shown in the table below.

[0119] [Table 1] TIFF2025501493000003.tif98169

[0120] A turbulent mixing section in this application is a circular conduit of constant diameter and length that achieves turbulent flow conditions by one or more of several methods:

[0121] 1) Increase in flow rate: To achieve sufficient mixing, turbulence must be reached, Re>4000 Flow rate Q=πd 2 / 4*υ Re = ρυd / μ = 4ρQ / (πdμ) > 4000 When d=0.25mm Q>πμd=2.8L / h When d=4mm Q>45L / h In the case of d=40mm Q>450L / h In this, Re is the Reynolds number, Q is the flow rate, d is the pipe diameter, υ is the flow velocity of the fluid in the pipe, μ is the fluid viscosity, and 20℃ μ 水 =10 -3 Pa·s It should be noted that when preparing composite nanoparticles of some photosensitizers and antitumor drugs, the Re can be set within the range of 500-4000 to obtain nano-preparations with a certain particle size and particle size distribution.

[0122] 2) Change in pipe shape: Increasing the degree of pipeline tortuosity forces the fluid flow direction to change, enhancing fluid mixing.

[0123] 3) Add a static mixer in the pipeline: Static mixers include, but are not limited to, SV type static mixers, SX type static mixers, SL type static mixers, SH type static mixers, SK type static mixers, etc., and the turbulent mixing elements divide the fluid / change the flow direction of the fluid / increase the convection of the fluid to increase the mixing of the fluid.

[0124] The SV type static mixer unit is a cylindrical body made by assembling corrugated plates with a certain degree of discipline.

[0125] The SX type static mixer unit is a multiple X-shaped unit with cross bars arranged according to a certain discipline.

[0126] The SL type static mixer unit is an X-shaped unit with intersecting cross bars arranged according to a certain discipline.

[0127] The SK type static mixer unit is made by welding a spiral sheet with a single channel twisted left and right.

[0128] The SH type static mixer unit is configured with a double channel with a fluid redistribution chamber located between the units.

[0129] Example 1: Measurement of drug concentration Instrument: Agilent 1260 high performance liquid chromatograph Column: Waters XBridge C18 4.6*150mm, 3.5μm Mobile phase: 10 mmol / L sodium dihydrogen phosphate solution (phosphoric acid adjusted to pH 4.0) was used as phase A, and acetonitrile was used as phase B. Gradient elution was performed according to the following table:

[0130] [Table 2]

[0131] Chromatography parameters: flow rate: 1 mL / min, column temperature: 35°C, detection wavelength: 264 nm, injection volume: 10 μL Calculation method: Peak area external standard method Example 2: Measurement of nanoparticle size Dynamic light scattering method: The nanoparticle concentration was set to 10 μg / mL to 100 μg / mL, and the particle size and distribution of the nanoparticles were measured using a nanoparticle sizer (laser light source 633 nm). Each sample was measured three times, and the average particle size and variance of the nanoparticles were calculated.

[0132] Example 3: Measurement of drug encapsulation rate 1 mL of the nanoparticle solution was taken and filtered through a 0.22 μm nylon needle filter, and the hydrophobic drug concentration was determined by HPLC.

[0133]

number

[0134] Example 4: Production of SN-38 / ICG nanoparticles (SK static mixer, first phase 11 mL / min, second phase 193 mL / min, total production volume 20 mL) Phase 1 solution: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0135] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.6 mm. The inner diameter of the second pipe D2(IN)=5.4 mm, Inner diameter of the merged pipe D3(IN) = 5.4 mm, Outer diameter D1(O) of the end of the first pipe = 2 mm, Outer diameter of second pipe D2(O)=6mm, Outer diameter of merged pipe D3(O) = 6mm, Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0136] [Table 3]

[0137] According to the calculation according to the fluid in the circular pipe, the merged phase Re=747, the merged phase is added with an SK type static mixer, the size of the static mixer is 5.3mm*85mm, a total of 16 segments of overlapping spiral sheets. First phase outlet velocity: 0.648m / s Flow velocity of the combined phase: 0.148m / s FVR=4.4 Production amount: 20mL

[0138] [Table 4]

[0139] Comparing (1) and (2) above, it was found that due to the synergistic effect of ultrasound, the encapsulation rate of SN-38 increased from 53.5% to 94.8%, the particle size changed from a multi-peak distribution to a single-peak distribution (Figure 3), and the average particle size significantly decreased.

[0140] Example 5: Production of SN-38 / ICG nanoparticles (first phase 60 mL / min, second phase 936 mL / min, no ultrasound, total production volume 20 mL) Phase 1 solution: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0141] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.6 mm. The inner diameter of the second pipe D2(IN)=5.4 mm, Inner diameter of the merged pipe D3(IN) = 5.4 mm, Outer diameter D1(O) of the end of the first pipe = 2 mm, Outer diameter of second pipe D2(O)=6mm, Outer diameter of merged pipe D3(O) = 6mm, Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0142] [Table 5]

[0143] Calculations according to the flow in a circular pipe showed that the merged phase Re=3868 and no static mixer was added to the merged phase.

[0144] First phase outlet velocity: 3.54m / s 2nd phase flow velocity: 0.68m / s FVR=5.2 Production amount: 20mL

[0145] [Table 6]

[0146] Example 6: Production of SN-38 / ICG nanoparticles (first phase 60 mL / min, second phase 936 mL / min, with ultrasound, total production volume 1.0 L) Phase 1 solution: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0147] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.6 mm. The inner diameter of the second pipe D2(IN)=5.4 mm, Inner diameter of the merged pipe D3(IN) = 5.4 mm, Outer diameter D1(O) of the end of the first pipe = 2 mm, Outer diameter of second pipe D2(O)=6mm, Outer diameter of merged pipe D3(O) = 6mm, Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0148] [Table 7]

[0149] Calculations according to the flow in a circular pipe showed that the merged phase Re=3868 and no static mixer was added to the merged phase.

[0150] First phase outlet velocity: 3.54m / s 2nd phase flow velocity: 0.68m / s FVR=5.2 Production quantity: 1.0L

[0151] [Table 8]

[0152] Comparing Examples 5 and 6, it was found that in the expanded nanoparticle production process (expanding from 20 mL to 1000 mL) without simultaneous ultrasonic action, the encapsulation rate dropped significantly, the ratio of D90 to D10 increased significantly, and the particle size showed a multi-peak distribution (Figure 5).

[0153] Example 7: Production of SN-38 / ICG nanoparticles (first phase 60 mL / min, second phase 936 mL / min, with ultrasound, total production volume 1.0 L) Phase 1 solution: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0154] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.6 mm. The inner diameter of the second pipe D2(IN)=5.4 mm, Inner diameter of the merged pipe D3(IN) = 5.4 mm, Outer diameter D1(O) of the end of the first pipe = 2 mm, Outer diameter of second pipe D2(O)=6mm, Outer diameter of merged pipe D3(O) = 6mm, Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0155] [Table 9]

[0156] Calculations according to the flow in a circular pipe showed that the merged phase Re=3868 and no static mixer was added to the merged phase.

[0157] First phase outlet velocity: 3.54m / s 2nd phase flow velocity: 0.68m / s FVR=5.2 Production quantity: 1.0L

[0158] [Table 10]

[0159] Comparing Examples 7 and 6, it was found that in the nanoparticle expansion manufacturing process, under the condition of simultaneous application of ultrasonic action, the encapsulation rate was significantly improved (97.5% vs. 92.4%), the ratio of D90 to D10 was reduced (1.63 vs. 2.39), and the particle size showed a single peak distribution (Figure 6). Under the condition of simultaneous application of ultrasonic action, the effect of expanding nanoparticle production is similar to the test result under small-scale production conditions (Example 5).

[0160] Example 8: Preparation of SN-38 / ICG nanoparticles (SK static mixer, 1st phase 80 mL / min, 2nd phase 1248 mL / min, no ultrasound, total production volume 20 mL) Phase 1 solution: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0161] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.6 mm. The inner diameter of the second pipe D2(IN)=5.4 mm, Inner diameter of the merged pipe D3(IN) = 5.4 mm, Outer diameter D1(O) of the end of the first pipe = 2 mm, Outer diameter of second pipe D2(O)=6mm, Outer diameter of merged pipe D3(O) = 6mm, Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0162] [Table 11]

[0163] According to the calculation according to the fluid in the circular pipe, the merged phase Re=5158, the SK type static mixer is added to the merged phase, the size of the static mixer is 5.3mm*85mm, and the total number of overlapping spiral sheets is 16 segments.

[0164] First phase outlet velocity: 4.72m / s 2nd phase flow velocity: 0.91m / s FVR=5.2 Production amount: 20mL

[0165] [Table 12]

[0166] Example 9: Preparation of SN-38 / ICG nanoparticles (SK static mixer, 1st phase 80 mL / min, 2nd phase 1248 mL / min, no ultrasound, total production volume 425 mL) Phase 1 solution: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0167] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.6 mm. The inner diameter of the second pipe D2(IN)=5.4 mm, Inner diameter of the merged pipe D3(IN) = 5.4 mm, Outer diameter D1(O) of the end of the first pipe = 2 mm, Outer diameter of second pipe D2(O)=6mm, Outer diameter of merged pipe D3(O) = 6mm, Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0168] [Table 13]

[0169] According to the calculation according to the fluid in the circular pipe, the merged phase Re=5158, the SK type static mixer is added to the merged phase, the size of the static mixer is 5.3mm*85mm, and the total number of overlapping spiral sheets is 16 segments.

[0170] First phase outlet velocity: 4.72m / s 2nd phase flow velocity: 0.91m / s FVR=5.2 Production amount: 425mL

[0171] [Table 14]

[0172] Comparing Examples 8 and 9, it was found that in the expanded nanoparticle production process (expanded from 20 mL to 425 mL) without simultaneous ultrasonic action, the encapsulation rate dropped significantly and the ratio of D90 to D10 increased.

[0173] Example 10: Production of SN-38 / ICG nanoparticles (SK static mixer, 1st phase 80 mL / min, 2nd phase 1248 mL / min, with ultrasound, total production volume 425 mL) Phase 1 solution: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0174] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.6 mm. The inner diameter of the second pipe D2(IN)=5.4 mm, Inner diameter of the merged pipe D3(IN) = 5.4 mm, Outer diameter D1(O) of the end of the first pipe = 2 mm, Outer diameter of second pipe D2(O)=6mm, Outer diameter of merged pipe D3(O) = 6mm, Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0175] [Table 15]

[0176] According to the calculation according to the fluid in the circular pipe, the merged phase Re=5158, the SK type static mixer is added to the merged phase, the size of the static mixer is 5.3mm*85mm, and the total number of overlapping spiral sheets is 16 segments.

[0177] First phase outlet velocity: 4.72m / s 2nd phase flow velocity: 0.91m / s FVR=5.2 Production amount: 425mL

[0178] [Table 16]

[0179] Comparing Example 10 and Example 9, it was found that in the nanoparticle expansion manufacturing process, under the condition of simultaneous application of ultrasonic action, the encapsulation rate was significantly improved (97.0% vs. 92.2%), the ratio of D90 to D10 was reduced (1.52 vs. 1.94), and the particle size showed a single peak distribution. Under the condition of simultaneous application of ultrasonic action, the effect of expanding nanoparticle production is similar to the test result under small-scale production conditions (Example 8).

[0180] Example 11: Production of PTX / ICG nanoparticles (first phase 60 mL / min, second phase 890 mL / min, no ultrasound, total production volume 20 mL) Phase 1 solution: PTX and ICG were co-dissolved in methanol, with a PTX concentration of 100 mg / mL and an ICG concentration of 50 mg / mL, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0181] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0182] [Table 17]

[0183] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0184] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 20mL

[0185] [Table 18]

[0186] Example 12: Production of PTX / ICG nanoparticles (first phase 60 mL / min, second phase 890 mL / min, no ultrasound, total production volume 400 mL) Phase 1 solution: PTX and ICG were co-dissolved in methanol, with a PTX concentration of 100 mg / mL and an ICG concentration of 50 mg / mL, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0187] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0188] [Table 19]

[0189] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0190] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 400mL

[0191] [Table 20]

[0192] Comparing Examples 11 and 12, it was found that in the expanded nanoparticle manufacturing process (expanding from 20 mL to 400 mL) without simultaneous ultrasonic action, the encapsulation rate dropped significantly and the ratio of D90 to D10 increased.

[0193] Example 13: Production of PTX / ICG nanoparticles (first phase 60 mL / min, second phase 890 mL / min, with ultrasound, total production volume 400 mL) Phase 1 solution: PTX and ICG were co-dissolved in methanol, with a PTX concentration of 100 mg / mL and an ICG concentration of 50 mg / mL, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0194] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0195] [Table 21]

[0196] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0197] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 400mL

[0198] [Table 22]

[0199] Comparing Examples 13 and 12, it was found that in the nanoparticle expansion manufacturing process, under the condition of simultaneous application of ultrasonic action, the encapsulation rate was significantly improved (98.7% vs. 93.4%), the ratio of D90 to D10 was reduced (1.27 vs. 1.59), and the particle size showed a single peak distribution. Under the condition of simultaneous application of ultrasonic action, the effect of expanding nanoparticle production is similar to the test result under small-scale production conditions (Example 11).

[0200] Example 14: Preparation of curcumin / CPT11 nanoparticles (first phase 60 mL / min, second phase 890 mL / min, no ultrasound, total production volume 20 mL) Phase 1 solution: Curcumin and CPT11 were co-dissolved in DMSO, with a curcumin concentration of 50 mg / mL and a CPT11 concentration of 150 mg / mL, and filtered through a 0.22 μm nylon filter membrane.

[0201] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0202] [Table 23]

[0203] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0204] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 20mL

[0205] [Table 24]

[0206] Example 15: Preparation of curcumin / CPT11 nanoparticles (first phase 60 mL / min, second phase 890 mL / min, no ultrasound, total production volume 400 mL) Phase 1 solution: Curcumin and CPT11 were co-dissolved in DMSO, with a curcumin concentration of 50 mg / mL and a CPT11 concentration of 150 mg / mL, and filtered through a 0.22 μm nylon filter membrane.

[0207] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0208] [Table 25]

[0209] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0210] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 400mL

[0211] [Table 26]

[0212] Comparing Examples 15 and 14, it was found that in the expanded nanoparticle manufacturing process (expanding from 20 mL to 400 mL) without simultaneous ultrasonic action, the encapsulation rate dropped significantly and the ratio of D90 to D10 increased.

[0213] Example 16: Preparation of curcumin / CPT11 nanoparticles (first phase 60 mL / min, second phase 890 mL / min, with ultrasound, total production volume 400 mL) Phase 1 solution: Curcumin and CPT11 were co-dissolved in DMSO, with a curcumin concentration of 50 mg / mL and a CPT11 concentration of 150 mg / mL, and filtered through a 0.22 μm nylon filter membrane.

[0214] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0215] [Table 27]

[0216] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0217] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 400mL

[0218] [Table 28]

[0219] Comparing Examples 16 and 15, it was found that in the nanoparticle expansion manufacturing process, under the condition of simultaneous application of ultrasonic action, the encapsulation rate was significantly improved (98.2% vs. 93.6%), the ratio of D90 to D10 was reduced (1.40 vs. 1.80), and the particle size showed a single peak distribution. Under the condition of simultaneous application of ultrasonic action, the effect of expanding nanoparticle production is similar to the test result under small-scale production conditions (Example 14).

[0220] Example 17: Production of SN-38 / CPT11 nanoparticles (first phase 60 mL / min, second phase 890 mL / min, no ultrasound, total production volume 20 mL) Phase 1 solution: SN-38 and CPT11 were co-dissolved in DMSO, with an SN-38 concentration of 40 mg / mL and a CPT11 concentration of 40 mg / mL, and the solution was filtered through a 0.22 μm nylon filter membrane.

[0221] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0222] [Table 29]

[0223] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0224] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 20mL

[0225] [Table 30]

[0226] Example 18: Production of SN-38 / CPT11 nanoparticles (first phase 60 mL / min, second phase 890 mL / min, no ultrasound, total production volume 400 mL) Phase 1 solution: SN-38 and CPT11 were co-dissolved in DMSO, with an SN-38 concentration of 40 mg / mL and a CPT11 concentration of 40 mg / mL, and the solution was filtered through a 0.22 μm nylon filter membrane.

[0227] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0228] [Table 31]

[0229] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0230] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 400mL

[0231] [Table 32]

[0232] Comparing Examples 17 and 18, it was found that in the expanded nanoparticle manufacturing process (expanding from 20 mL to 400 mL) without simultaneous ultrasonic action, the encapsulation rate dropped significantly and the ratio of D90 to D10 increased.

[0233] Example 19: Production of SN-38 / CPT11 nanoparticles (first phase 60 mL / min, second phase 890 mL / min, with ultrasound, total production volume 400 mL) Phase 1 solution: SN-38 and CPT11 were co-dissolved in DMSO, with an SN-38 concentration of 40 mg / mL and a CPT11 concentration of 40 mg / mL, and the solution was filtered through a 0.22 μm nylon filter membrane.

[0234] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.4 mm. The inner diameter of the second pipe D2(IN)=3.0 mm, Inner diameter of the merged pipe D3(IN) = 3.0 mm, The outer diameter D1(O) of the end of the first pipe is 1.0 mm. Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0235] [Table 33]

[0236] Calculated according to the flow in a circular pipe, the combined phase Re=6623.

[0237] First phase outlet velocity: 7.58m / s 2nd phase flow velocity: 2.24m / s FVR=3.38 Production amount: 400mL

[0238] [Table 34]

[0239] Comparing Examples 19 and 18, it was found that in the nanoparticle expansion manufacturing process, under the condition of simultaneous application of ultrasonic action, the encapsulation rate was significantly improved (98.1% vs. 90.2%), the ratio of D90 to D10 was reduced (1.16 vs. 2.02), and the particle size showed a single peak distribution. Under the condition of simultaneous application of ultrasonic action, the effect of expanding nanoparticle production is similar to the test result under small-scale production conditions (Example 17).

[0240] Example 20: Preparation of HSPC / CHOL / DSPE-PEG blank liposomes (first phase 10 mL / min, second phase 100 mL / min, no ultrasound, total preparation volume 50 mL) Phase 1 solution: HSPC, CHOL, DSPE-PEG 2k were dissolved in ethanol and filtered through a 0.22 μm nylon filter membrane. 2k = 56:38:5 (molar ratio), and the HSPC concentration is 10 mg / mL.

[0241] Phase 2 solution: 120 mM ammonium sulfate in water.

[0242] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0243] [Table 35]

[0244] Calculated according to the flow in a circular pipe, the combined phase Re=2884.

[0245] First phase outlet velocity: 3.4m / s Flow velocity of the merging phase: 3.65m / s FVR=0.93 Production amount: 50mL

[0246] [Table 36]

[0247] The blank liposomes produced without ultrasonication showed a multi-peak particle size distribution (FIG. 7), and the blank liposomes had a relatively large particle size distribution and variance.

[0248] Example 21: Preparation of HSPC / CHOL / DSPE-PEG blank liposomes (first phase 10 mL / min, second phase 200 mL / min, no ultrasound, total preparation volume 50 mL) Phase 1 solution: HSPC, CHOL, DSPE-PEG 2k were dissolved in ethanol and filtered through a 0.22 μm nylon filter membrane. 2k = 56:38:5 (molar ratio), and the HSPC concentration is 10 mg / mL.

[0249] Phase 2 solution: 120 mM ammonium sulfate in water.

[0250] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0251] [Table 37]

[0252] Calculated according to the flow in a circular pipe, the combined phase Re=5505.

[0253] First phase outlet velocity: 3.40m / s Flow velocity of the merged phase: 6.96m / s FVR=0.49 Production amount: 50mL

[0254] [Table 38]

[0255] The blank liposomes produced without ultrasonic action exhibited a multi-peak particle size distribution (FIG. 7), and the blank liposomes had a relatively large particle size distribution and variance.

[0256] Example 22: Preparation of HSPC / CHOL / DSPE-PEG blank liposomes (first phase 10 mL / min, second phase 100 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: HSPC, CHOL, DSPE-PEG 2k were dissolved in ethanol and filtered through a 0.22 μm nylon filter membrane. 2k = 56:38:5 (molar ratio), and the HSPC concentration is 10 mg / mL.

[0257] Phase 2 solution: 120 mM ammonium sulfate in water.

[0258] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0259] [Table 39]

[0260] Calculated according to the flow in a circular pipe, the combined phase Re=2884.

[0261] First phase outlet velocity: 3.4m / s Flow velocity of the combined phase: 3.65m / s FVR=0.93 Production amount: 50mL

[0262] [Table 40]

[0263] Comparing Examples 22 and 20, it was found that the blank liposomes produced under conditions in which ultrasonic action was simultaneously applied exhibited a single peak in the particle size distribution (FIG. 8).

[0264] Example 23: Preparation of HSPC / CHOL / DSPE-PEG blank liposomes (first phase 10 mL / min, second phase 200 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: HSPC, CHOL, DSPE-PEG 2k were dissolved in ethanol and filtered through a 0.22 μm nylon filter membrane. 2k = 56:38:5 (molar ratio), and the HSPC concentration is 10 mg / mL.

[0265] Phase 2 solution: 120 mM ammonium sulfate in water.

[0266] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0267] [Table 41]

[0268] Calculated according to the flow in a circular pipe, the combined phase Re=5505.

[0269] First phase outlet velocity: 3.40m / s Flow velocity of the merged phase: 6.96m / s FVR=0.49 Production amount: 50mL

[0270] [Table 42]

[0271] Comparing Examples 23 and 22, it was found that under the condition of simultaneous application of ultrasonic action, the flow rate of the second phase increased, the average particle size of blank liposomes decreased, and the particle size distribution exhibited a single peak (Figure 8).

[0272] Example 24: Preparation of PTX / HSPC / CHOL / DSPE-PEG liposomes (first phase 10 mL / min, second phase 200 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: PTX, HSPC, CHOL, DSPE-PEG 2k were dissolved in ethanol and filtered through a 0.22 μm nylon filter membrane. 2k = 9:89:57:4 (molar ratio), and the HSPC concentration is 10 mg / mL.

[0273] Second phase solution: water.

[0274] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0275] [Table 43]

[0276] Calculated according to the flow in a circular pipe, the combined phase Re=5505.

[0277] First phase outlet velocity: 3.40m / s Flow velocity of the merged phase: 6.96m / s FVR=0.49 Production amount: 50mL

[0278] [Table 44]

[0279] Under the condition of simultaneous application of ultrasonic action, PTX liposomes with relatively small particle size can be produced, and the particle size distribution shows a single peak (Figure 9).

[0280] Example 25: Preparation of PTX / PEG-PLA polymeric micelles (first phase 14 mL / min, second phase 210 mL / min, no ultrasound, total production volume 50 mL) Phase 1 solution: PTX and PEG-PLA were co-dissolved in acetonitrile, and the solution was filtered through a 0.22 μm nylon filter membrane (PEG-PLA (50 mg / mL), PTX (15 mg / mL)).

[0281] Second phase solution: water.

[0282] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0283] [Table 45]

[0284] Calculated according to the flow in a circular pipe, the combined phase Re=5872.

[0285] First phase outlet velocity: 4.75m / s Flow velocity of the merging phase: 7.43m / s FVR=0.64 Production volume 50mL The solution obtained without ultrasonication had a relatively large amount of white flocculent precipitate, and the particle size could not be detected.

[0286] Example 26: Preparation of PTX / PEG-PLA polymeric micelles (first phase 14 mL / min, second phase 210 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: PTX and PEG-PLA were co-dissolved in acetonitrile, and the solution was filtered through a 0.22 μm nylon filter membrane (PEG-PLA (50 mg / mL), PTX (15 mg / mL)).

[0287] Second phase solution: water.

[0288] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0289] [Table 46]

[0290] Calculated according to the flow in a circular pipe, the combined phase Re=5872.

[0291] First phase outlet velocity: 4.75m / s Flow velocity of the merging phase: 7.43m / s FVR=0.64 Production volume 50mL

[0292] [Table 47]

[0293] From the table, it can be seen that when polymer nanomicelles are produced by the combined action of shear force and ultrasound, the results of three parallel tests have good reproducibility and stability.

[0294] Comparing Examples 26 and 25, it was found that stable polymer nanomicelles could be produced by simultaneously applying ultrasonic action under production conditions that originally did not allow the formation of polymer nanomicelles.

[0295] Example 27: Preparation of PTX / PEG-PLA polymer micelles (first phase 50 mL / min, second phase 300 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: PTX and PEG-PLA were co-dissolved in ethanol, and the resulting solution (PEG-PLA (50 mg / mL), PTX (15 mg / mL)) was filtered through a 0.22 μm nylon filter membrane.

[0296] Second phase solution: water.

[0297] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0298] [Table 48]

[0299] Calculated according to the flow in a circular pipe, the combined phase Re=9176.

[0300] First phase outlet velocity: 17.0m / s Flow velocity of the merging phase: 11.6m / s FVR=1.46 Production volume 50mL

[0301] [Table 49]

[0302] Comparing Examples 26 and 27, it was found that by the combined action of shear force and ultrasound, polymer nanomicelles with relatively small particle size could be similarly prepared using different organic solvents and different flow rates of the organic phase, and the prepared polymer nanomicelles had good stability (Figure 10).

[0303] Example 28: Preparation of PTX / PEG-Phe-PLA polymeric micelles (first phase 14 mL / min, second phase 210 mL / min, no ultrasound, total production volume 50 mL) Phase 1 solution: PTX and PEG-Phe-PLA were co-dissolved in acetonitrile, and the resulting solution (PEG-Phe-PLA (50 mg / mL), PTX (15 mg / mL)) was filtered through a 0.22 μm nylon filter membrane.

[0304] Second phase solution: water.

[0305] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0306] [Table 50]

[0307] Calculated according to the flow in a circular pipe, the combined phase Re=5872.

[0308] First phase outlet velocity: 4.75m / s Flow velocity of the merging phase: 7.43m / s FVR=0.64 Production volume 50mL The solution obtained without ultrasonication had a relatively large amount of white flocculent precipitate, and the particle size could not be detected.

[0309] Example 29: Preparation of PTX / PEG-Phe-PLA polymeric micelles (first phase 14 mL / min, second phase 210 mL / min, with ultrasound, total production volume 50 mL) PTX and PEG-Phe-PLA were co-dissolved in acetonitrile, and the PEG-Phe-PLA (50 mg / mL) and PTX (15 mg / mL) were filtered through a 0.22 μm nylon filter membrane.

[0310] Second phase solution: water.

[0311] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0312] [Table 51]

[0313] Calculated according to the flow in a circular pipe, the combined phase Re=5872.

[0314] First phase outlet velocity: 4.75m / s Flow velocity of the merging phase: 7.43m / s FVR=0.64 Production volume 50mL

[0315] [Table 52]

[0316] From the table, it can be seen that when polymer nanomicelles are produced by the combined action of shear force and ultrasound, the results of three parallel tests have good reproducibility and stability.

[0317] Comparing Examples 29 and 28, it was found that stable polymer nanomicelles could be produced by simultaneously applying ultrasonic action under production conditions that originally did not allow the formation of polymer nanomicelles.

[0318] Example 30: Preparation of PEG-PLA polymer nanoparticles (first phase 50 mL / min, second phase 300 mL / min, no ultrasound, total production volume 50 mL) Phase 1 solution: PEG-PLA was dissolved in ethanol, and the PEG-PLA (50 mg / mL) was filtered through a 0.22 μm nylon filter membrane.

[0319] Second phase solution: water.

[0320] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, The temperature of the first phase solution t1 = 60°C, The temperature of the second phase solution t2 = 60°C, Combine two phases into a 200W ultrasonic bath

[0321] [Table 53]

[0322] Calculated according to the flow in a circular pipe, the combined phase Re=9176.

[0323] First phase outlet velocity: 17.0m / s Flow velocity of the merging phase: 11.6m / s FVR=1.46 Production volume 50mL

[0324] [Table 54]

[0325] Example 31: Production of PEG-PLA polymer nanoparticles (first phase 50 mL / min, second phase 300 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: PEG-PLA was dissolved in ethanol, and the PEG-PLA (50 mg / mL) was filtered through a 0.22 μm nylon filter membrane.

[0326] Second phase solution: water.

[0327] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, The temperature of the first phase solution t1 = 60°C, The temperature of the second phase solution t2 = 60°C, Combine two phases into a 200W ultrasonic bath

[0328] [Table 55]

[0329] Calculated according to the flow in a circular pipe, the combined phase Re=9176.

[0330] First phase outlet velocity: 17.0m / s Merged phase velocity: 11.6m / s FVR=1.46 Production volume 50mL

[0331] [Table 56]

[0332] Comparing Example 30 (Fig. 11) and Example 31 (Fig. 12), it can be seen that the nanoparticles obtained without ultrasonic action have a relatively large particle size, a multi-peak distribution, a wide multi-distribution index, and a non-uniform particle size, while the nanoparticles produced by the joint action of shear force and ultrasonic action have a relatively small particle size, a single-peak distribution, a narrow multi-distribution index, and a more uniform particle size. This shows that the synergistic effect of ultrasonic action plays an important role in the production process of nanoparticles with small particle size and narrow distribution.

[0333] Example 32: Production of PLGA polymer nanoparticles (first phase 50 mL / min, second phase 300 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: PLGA was dissolved in ethanol and filtered through a 0.22 μm nylon filter membrane.

[0334] Second phase solution: water.

[0335] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, The temperature of the first phase solution t1 = 60°C, The temperature of the second phase solution t2 = 60°C, Combine two phases into a 200W ultrasonic bath

[0336] [Table 57]

[0337] Calculated according to the flow in a circular pipe, the combined phase Re=9176.

[0338] First phase outlet velocity: 17.0m / s Merged phase velocity: 11.6m / s FVR=1.46 Production volume 50mL

[0339] [Table 58]

[0340] From the table, it can be seen that the combined action of shear force and ultrasound can produce PLGA polymer nanoparticles, the particles having a narrow size distribution and exhibiting a single peak distribution (Figure 13).

[0341] Example 33: Production of PTX / PLGA polymer nanoparticles (first phase 50 mL / min, second phase 300 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: PTX and PLGA were dissolved in ethanol and filtered through a 0.22 μm nylon filter membrane.

[0342] Second phase solution: water.

[0343] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0344] [Table 59]

[0345] Calculated according to the flow in a circular pipe, the combined phase Re=9176.

[0346] First phase outlet velocity: 17.0m / s Flow velocity of the merging phase: 11.6m / s FVR=1.46 Production volume 50mL

[0347] [Table 60]

[0348] From the table, it can be seen that the combined action of shear force and ultrasound can produce PTX / PLGA polymer nanoparticles, and the particles have a narrow size distribution and exhibit a single-peak distribution (Figure 14).

[0349] Example 34: Production of Poly I nanolipid particles (first phase 100 mL / min, second phase 200 mL / min, no ultrasound, total production volume 50 mL) Phase 1 solution: 32.31 mg of ALC-0315 (CAS: 2036272-55-4), 4.08 mg of DSPE-PEG2000 (CAS: 147867-65-0), 7.08 mg of HSPC (CAS: 92128-87-5), and 14.01 mg of cholesterol were dissolved in ethanol and filtered through a 0.22 μm nylon membrane.

[0350] Phase 2 solution: 5.71 mg of Poly I (CAS: 30918-54-8) was dissolved in 3 mM citrate buffer (pH 4.0).

[0351] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0352] [Table 61]

[0353] Calculated according to the flow in a circular pipe, the combined phase Re=7865.

[0354] First phase outlet velocity: 34.0m / s Flow velocity of the merging phase: 9.94m / s FVR=3.4 Production volume 50mL

[0355] [Table 62]

[0356] PolyI nanolipid particles prepared by synergy without ultrasound showed multi-peak distribution (FIG. 15) and low encapsulation efficiency.

[0357] Example 35: Production of Poly I nanolipid particles (first phase 100 mL / min, second phase 200 mL / min, with ultrasound, total production volume 50 mL) Phase 1 solution: 32.31 mg of ALC-0315, 4.08 mg of DSPE-PEG2000, 7.08 mg of HSPC, and 14.01 mg of cholesterol were dissolved in ethanol and filtered through a 0.22 μm nylon filter membrane.

[0358] Phase 2 solution: 5.71 mg of Poly I was dissolved in 3 mM citrate buffer (pH 4.0).

[0359] The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.25 mm. The inner diameter of the second pipe D2(IN)=0.8 mm, Inner diameter of the merged pipe D3(IN) = 0.8 mm, The outer diameter D1(O) of the end of the first pipe is 0.35 mm. Length of merger phase = 360 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C; Combine two phases into a 200W ultrasonic bath

[0360] [Table 63]

[0361] Calculated according to the flow in a circular pipe, the combined phase Re=7865.

[0362] First phase outlet velocity: 34.0m / s Flow velocity of the merging phase: 9.94m / s FVR=3.4 Production volume 50mL

[0363] [Table 64]

[0364] From the table, it can be seen that the PolyI nanolipid particles produced by the combined action of shear force and ultrasound exhibited a single peak distribution (FIG. 16), narrow particle size distribution, and high encapsulation rate.

[0365] Comparative Example 1: Preparation of SN-38 / ICG nanoparticles (ultrasonic application after mixing) Phase 1 solution: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0366] Second phase solution: water The hole diameter D1(S) of the terminal nozzle of the first pipe is 0.6 mm. The inner diameter of the second pipe D2(IN)=5.4 mm, Inner diameter of the merged pipe D3(IN) = 5.4 mm, Outer diameter D1(O) of the end of the first pipe = 2 mm, Outer diameter of second pipe D2(O)=6mm, Outer diameter of merged pipe D3(O) = 6mm, Length of merger phase = 90 mm, Temperature of the first phase solution t1 = 25°C; The temperature of the second phase solution t2 = 25°C;

[0367] [Table 65]

[0368] According to the calculation according to the fluid in the circular pipe, the merged phase Re=747, the merged phase is added with an SK type static mixer, the size of the static mixer is 5.3mm*85mm, a total of 16 segments of overlapping spiral sheets. First phase outlet velocity: 0.648m / s Flow velocity of the combined phase: 0.148m / s FVR=4.4 Production quantity: 20mL.

[0369] First, the mixture was mixed according to the above conditions, and the resulting mixture was subjected to ultrasonic treatment for 10 minutes (ultrasonic power: 200 W, ultrasonic temperature: 25° C.).

[0370] [Table 66]

[0371] Compared with Example 4(2), the particle size of the nanoparticles was slightly reduced, but the encapsulation rate could not be improved.

[0372] Comparative Example 2: Preparation of SN-38 / ICG nanoparticles (by ultrasonic action only) Solution A: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0373] 45 mL of water was added to the flask, and then 5 mL of solution A was added by ultrasonic action (ultrasonic power 200 W), and ultrasonic treatment was continued for 10 min at 25 °C. The resulting mixture had a relatively large amount of flocculent precipitates, and the particle size could not be detected, and nanoparticles could not be formed.

[0374] Comparative Example 3: Production of SN-38 / ICG nanoparticles (first ultrasonic treatment, then mixing with a mixer) Solution A: ICG and SN-38 were dissolved in DMSO, the SN-38 content was 3.394 wt.%, the ICG content was 3.397 wt.%, and the molar ratio of SN-38 to ICG was 2:1, and the solution was filtered through a 0.22 μm nylon membrane filter.

[0375] 45 mL of water was added to the flask, and 5 mL of solution A was added by ultrasonic action (ultrasonic power 200 W), and ultrasonic treatment was continued for 10 minutes at 25°C. The resulting mixture (containing a relatively large amount of flocculent precipitate) was passed through a mixer under the conditions of Example 4 (2). The resulting mixture was a suspension, and nanoparticles could not be formed, the particle size could not be detected, and the pipe was clogged.

[0376] Although specific embodiments of the present invention have been described above, it should be understood by those skilled in the art that these are merely illustrative and can be modified or altered without departing from the principles and substance of the present invention. Therefore, the scope of protection of the present invention is limited to the scope of the appended claims.

Claims

1. 1. A manufacturing system for continuous production of nano-formulations, comprising: (a) a first conduit; (b) a second conduit; (f) an ultrasonic device; (c) a merging conduit; and (e) a (fluid) outlet thereof, The first and second pipelines are connected to a merging pipeline, the first pipeline is coaxial with the merging pipeline, the second pipeline is perpendicular to the merging pipeline, the outlet of the first pipeline is located within the merging pipeline, the first phase solution enters the merging pipeline through the outlet of the first pipeline, and the second phase solution enters the merging pipeline through the outlet of the second pipeline, the ultrasonic device acts on the merging pipeline locally or entirely, the first phase solution and the second phase solution mix in the merging pipeline to form a merged phase, and then flow out through the outlet of the merging pipeline. Manufacturing system.

2. (1) The core part of the manufacturing system includes: (a) a first pipeline, (b) a second pipeline, (c) a merging pipeline, (d) a turbulent mixer, (e) a fluid outlet, and (f) a power-adjustable ultrasonic device, wherein the first pipeline and the second pipeline are connected to the merging pipeline, the first phase solution enters the merging pipeline through the first pipeline outlet, and the second phase solution enters the merging pipeline through the second pipeline outlet, and the first phase solution and the second phase solution merge in the merging pipeline to form a merged phase, and the power-adjustable ultrasonic device acts on the merger pipeline locally or entirely, and after being thoroughly mixed by the turbulent mixer, the mixed phase is collected into a suitable container through the outlet of the merged phase pipeline; (2) The mixing process of the first phase solution and the second phase solution is carried out by the action of ultrasound; (3) The nano-preparation is a polymer nanomicelle, nanoliposome, or small molecule nanoassembly; The manufacturing system according to claim 1 .

3. (1) the nanoformulation is selected from one or more of polymer nanomicelles, polymer nanoparticles, nanoliposomes, nanolipid particles, and small molecule nanoassemblies; (2) The outlet of the first conduit is a nozzle having a certain shape and a certain hole diameter, and the first phase solution passes through the first conduit and enters the merging conduit from the nozzle. The manufacturing system according to claim 1 .

4. (1) The length of the merging pipe is selected from the range of 6 cm to 120 cm, for example, 9 cm or 36 cm; (2) the ratio of the length of the merging conduit to the inner diameter of the merging conduit is (16 to 450):1, for example, 16.7:1, 30:1, or 450:1; (3) Outer diameter D of the first pipeline １ (O) is 0.35 mm to 2 mm, for example, 0.35 mm, 1 mm, or 2 mm; (4) The diameter D of the terminal nozzle of the first pipe １ (S) is in the range of 0.03 mm to 5.0 mm, preferably 0.2 mm to 0.6 mm, for example, 0.2 mm, 0.25 mm, 0.3 mm, 0.4 mm, or 0.6 mm; (5) Outer diameter D of the second pipeline ２ (O) is 6 mm, (6) Inner diameter D of the second pipeline ２ (IN) is in the range of 0.3 mm to 50.0 mm, preferably 0.8 mm to 5.4 mm, for example 0.8 mm, 3.0 mm, or 5.4 mm; (7) Outer diameter D of the merger pipe ３ (O) is 6 mm, (8) Inner diameter D of the merger pipe ３ (IN) is in the range of 0.3 mm to 50.0 mm, preferably 0.8 mm to 5.4 mm, for example 0.8 mm, 3.0 mm, or 5.4 mm; (9) Inner diameter D of the second pipeline ２ (IN) is the inner diameter D of the merging pipe ３ (IN) is the same as (10) The diameter D of the terminal nozzle of the first pipe １ (S) and the inner diameter D of the merged pipe ３ (IN) may be 1:(2-50), for example 1:3.2, 1:7.5, 1:9 or 1:18; (11) The mixing is turbulent mixing that can be achieved by increasing one or more turbulent mixing devices in the merging pipe; (12) The ultrasonic device satisfies one or more of the following conditions: the ultrasonic device is an adjustable power ultrasonic device. The manufacturing system according to claim 1 .

5. (1) The materials used for the first pipe, the second pipe, the merging pipe, the turbulent mixer, and the fluid outlet are each one or more selected from stainless steel, polytetrafluoroethylene, polyethylene, polypropylene, latex, silica gel, or other polymer materials; (2) The methods for realizing turbulence using the turbulent mixer include (a) increasing the combined phase flow rate, (b) changing the degree of pipeline tortuosity, and (c) increasing the number of baffles or irregular shapes such as static mixers in the pipeline. The range of fluid Reynolds number Re in the merging phase calculated in a circular pipe is selected from 500 to 100,000, (3) The turbulent mixing device is a device such as a static mixer that achieves a turbulent state after mixing the first-phase solution and the second-phase solution, and the static mixer may be one or more types selected from an SV-type static mixer, an SX-type static mixer, an SL-type static mixer, an SH-type static mixer, and an SK-type static mixer, and is preferably an SK-type static mixer; (4) the flow rate Q of the first phase solution through the first line １ is selected from the range of 1 mL / min to 1000 mL / min, and the temperature T １ The range is selected from 0°C to 90°C, and the flow rate Q of the second phase solution through the second pipeline is ２ The range of the second phase solution is selected from 10 mL / min to 10,000 mL / min, and the temperature T ２ The range is selected from 0°C to 90°C, (5) The ultrasonic frequency of the power-adjustable ultrasonic device is 15 kHz to 1.0 MHz, preferably 15 kHz to 40 kHz, more preferably 19 kHz to 40 kHz, and the ultrasonic power is adjustable within a range of 0.1 kW to 20 kW, preferably 100 W to 1000 W. The manufacturing system according to claim 4 .

6. (1) The components of the polymer nanomicelle are selected from an amphiphilic polymer and an antitumor drug, and the amphiphilic polymer is selected from PEG-PLA, PEG-PCL, PEG-linker-PLA, or PEG-linker-PCL; Among them, linker is a linker, and its structure is C １ ~C ３０ wherein PEG is a polyethylene glycol segment or a monoprotected polyethylene glycol segment having a number average molecular weight between 400 and 20,000; (2) The nanoliposome is a blank liposome not coated with a drug or a liposome coated with an antitumor drug; (3) The nanolipid particles are lipid particles coated with an antitumor drug; (4) The small molecule nanoassembly satisfies one or more of the following conditions: it is selected from antitumor drug / photosensitizer nanoassemblies, antitumor drug / antitumor drug nanoassemblies, antitumor drug / other drug (e.g., curcumin) nanoassemblies, antitumor drug / additive (e.g., amphiphilic polymer PEG-PLA, DSPE-PEG, or polymer PLGA) nanoassemblies, two or more types of drug nanoassemblies (e.g., SN38 and irinotecan), or small molecule drug / additive nanoassemblies; The manufacturing system according to claim 1 .

7. (1) The anti-tumor drug is abemaciclib, abiraterone, abrocitinib, acalabrutinib, afatinib, aldesleukin, alectinib, alflutamide, almonertinib, altretamine, amcenestrant, aminoglutethimide, amsacrine, anastrozole, anlotinib, apalutamide, apatinib, arzoxifene, asiminib, asparaginase, avapritinib, avitinib, axitinib, azacitidine, baricitinib, belinostat, bendamustine, bexarotene, bicalutamide, bicyclol, binimetinib, bleomycin, boanmycin, bortezomib, bosutinib, brigatinib, buserelin, busulfan, cabazitaxel, cabozantinib, calaspargase, calicheamycin, capecitabine, capmatinib, carboplatin, carfilzomib, carmustine, carmofur, cedazuidine, ceritinib, cetrorelix, chidamide, chlorambucil, cisplatin, cladribine, clofarabine, cobimetinib, colchicine, copanlisib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dacomitinib, dactinomycin, dalpicilib, darolutamide, dasatinib, daunorubicin, decitabine, degarelix, delgociclid, denileukin, deruxtecan, docetaxel, donafenib, doxorubicin, duvelisib, enasidenib, encorafenib, ensartinib, entrectinib, enzalutamide, enzastaurin, elacestrant,epirubicin、erdafitinib、eribulin、erlotinib、estradiol、estramustine、etoposide、everolimus、exemestane、fasudil、fedatinib、filgotinib、floxuridine、fludarabine、flumatinib、fluorouracil、flutamide、fluzoparib、formestane、fostamatinib、fruquintinib、fulvestrant、gefitinib、gemcitabine、gilteritinib、giredestrant、glasdegib、goserelin、histrelin、hydroxyurea、ibrutinib、ibudilast、icaritin、icotinib、idarubicin、idelalisib、ifosfamide、imatinib、imiquimod、infigratinib、ingenol mebutate、interferon alfa-2b、irinotecan、ivosidenib、ixabepilone、ixazomib、lanreotide、lapatinib、larotrectinib、lenalidomide、lenvatinib、letrozole、leucovorin、leuprolide、lomustine、lonafarnib、lorlatinib、lurbinctedin、maytansine、mechlorethamine、medroxyprogesterone、megestrol、melphalan、melphlan flufenamide、mercaptopurine、methotrexate、methoxsalen、methylprednisolone、midostaurin、mitomycin、mitotane、mitoxantrone、mitozolomide、mobocertinib、monomethylauristatin E、monomethylauristatin F、 nelarabine、nandrolone、neratinib、nearsudil、nilotinib、nilutamide、nintedanib、niraparib、octreotide、olaparib、olmutinib、omacetaxine、orelabrutinib、osimertinib、oxaliplatin、paclitaxel、pacritinib、palbociclib、pamidronate、pamiparib、panobinostat、pazopanib、peficitinib、pegaptanib、pegaspargase、peginteferon alfa-2b、pemigatinib、pemetrexed、pentetreotide、pentostatin、pexidartinib、phenoxybenzamine、pidotimod、plinabulin、plitidepsin、pomalidomide、ponatinib、porfimer、pralatrexate、pralsetinib、prednisolone、procarbazine、pyrotinib、quizartinib、radotinib、raloxifene、raltitrexed、regorafenib、ribociclib、rintatolimod、ripretinib、romidepsin、rucaparib、ruxolitinib、savolitinib、selinexor、selpercatinib、selumetinib、sonidegib、sorafenib、sotorasib、streptozocin、sunitinib、surufatinib、talazoparib、tamoxifen、tazemetostat、tegafur、temozolomide、temsirolimus、teniposide、tepotinib、teprenone、thalidomide、thioguanine、thiotepa、thyrotropin alfa、tipiracil、tipifarnib、tirabrutinib、tirbanibulin、tivozanib、trametinib、tofacitinib、topotecan、toremifene、trabectedin、tretinoin、trifluride、trilaciclib、triptorelin、tucatinib、upadacitinib、umbralisib、utidelone, uroacitide, valrubicin, vandetanib, vemurafenib, venetoclax, vinblastine, vincri stine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, zanubrutinib, zoledronic acid, amatoxins, anthacyclines, anthracenes, anthramycins, auristatins, bryostatins, campto thecins, carmaphycins, combretastatins, cyclosporines, cryptomycins, ecteinascidins, ellipt icenes, esperamicins, mustines, neothramycins, ozogamicins, phenoxazines, podophyllotoxins, pyrrolobenzodiazepines, sibiromycins, thailanstatins, tomamycins, tubulysins, taxanes, vinca one or more selected from the group consisting of alkaloids, 7-epipaclitaxel, 2'-acetylpaclitaxel, 10-deacetylpaclitaxel, 10-deacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-deacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, lirontaxel, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, raltotecan, gematecan, belotecan, 10-hydroxycamptothecin, 10-hydroxy-ethyl-camptothecin (SN-38), isitecan, pyran adriamycin, acralithromycin, sirolimus, tacrolimus, progesterone, estrogen, rapamycin, precarmycin, harringtonine, and curcumin; Preferably, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, raltotecan, gematecan, belotecan, 10-hydroxycamptothecin, SN-38, isitecan, irinotecan, topotecan, deruxtecan, paclitaxel, docetaxel, cabazitaxel, 7-epipaclitaxel, 2'-acetylpaclitaxel, 10-deacetylpaclitaxel, 10-deacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-deacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, rirontaxel, adriamycin, epiadriamycin, daunorubicin, pyranadriamycin, acralithromycin, etoposide, tenimycin, Poside, vinblastine, vincristine, vinorelbine, vindesine, maytansine, curcumin, harringtonine, hyharringtonine, gemcitabine, capecitabine, fludarabine, cladribine, pemetrexed, bortezomib, carfilzomib, elsazomib, carmustine, fluorouracil, cytarabine, cyclosporine A, eribulin, trabectedin, geffi one or more selected from the group consisting of tinib, erlotinib, lapatinib, afatinib, dacomitinib, vandetanib, neratinib, osimertinib, imatinib, sorafenib, sunitinib, lapatinib, dasatinib, linparib, niraparib, rucaparib, fluzoparib, pamiparib, veliparib, talazoparib, apatinib, palbociclib, abecilib, and ribociclib; (2) The photosensitizer includes a cyanine molecule, a porphyrin molecule, a porphyrin molecule precursor, a phthalocyanine molecule, or a chlorin molecule; The cyanine-based molecule is preferably one or more selected from IR780, IR820, indocyanine green, and indocyanine green analogs; the porphyrin-based molecule is preferably hematoporphyrin monomethyl ether; the porphyrin molecule precursor is preferably one selected from 5-aminovaleric acid and 5-aminovaleronate; and the phthalocyanine-based molecule is preferably copper phthalocyanine, cobalt phthalocyanine, aluminum phthalocyanine, nickel phthalocyanine, calcium phthalocyanine, or the like. the phthalocyanine molecule is one or more selected from phthalocyanine, sodium phthalocyanine, magnesium phthalocyanine, zinc phthalocyanine, indium phthalocyanine, oxytitanium phthalocyanine, magnesium phthalocyanine, manganese phthalocyanine, and phthalocyanine derivatives, and the chlorin molecule is preferably one or more selected from chlorin, talaporfin, verteporfin, temoporfin, rotaporfin, porfirom sodium, hemoporfin, and photochlor; The manufacturing system according to claim 6 .

8. (1) The polymer nanomicelle is a PTX / PEG-PLA polymer micelle or a PTX / PEG-Phe-PLA polymer micelle; (2) The nanoliposome is a HSPC / CHOL / DSPE-PEG blank liposome or a PTX / HSPC / CHOL / DSPE-PEG liposome, in which the molar ratio of HSPC / CHOL / DSPE-PEG is preferably 56:38:5 or 89:57:4; (3) the nanolipid particle is a Poly I nanolipid particle, e.g., Poly I / ALC-0315 / DSPE-PEG2000 / HSPC / cholesterol; (4) The polymer nanoparticles are PEG-PLA polymer nanoparticles, PLGA polymer nanoparticles, or PTX / PLGA polymer nanoparticles; (5) The manufacturing system of claim 3, characterized in that the small molecule nanoassembly satisfies one or more of the following conditions: the small molecule nanoassembly is an antitumor drug / photosensitizer nanoassembly, preferably SN-38 / ICG nanoparticles, PTX / ICG nanoparticles, curcumin / CPT11 nanoparticles, or SN-38 / CPT11 nanoparticles.

9. 2. A method for producing a nano-preparation in a production system according to claim 1, comprising the steps of: mixing a first phase solution and a second phase solution; and subjecting the resulting combined phase to the action of ultrasound; and collecting the nano-preparation through an outlet thereof; A. When the nano-preparation is a polymer nanomicelle, the solvent in the first phase solution is a good solvent for the antitumor drug or a pharmaceutically acceptable salt thereof, and the solute is (1) the antitumor drug or a pharmaceutically acceptable salt thereof, or (2) the antitumor drug or a pharmaceutically acceptable salt thereof and a polymer; the solvent in the second phase solution is an antisolvent for the antitumor drug or a pharmaceutically acceptable salt thereof, and the solute is (1) absent or (2) a polymer; When the solute in the first phase solution is an antitumor drug or a pharmaceutically acceptable salt thereof and a polymer, the solute in the second phase solution is absent; When the solute in the first phase solution is an antitumor drug or a pharmaceutically acceptable salt thereof, the solute in the second phase solution is a polymer; B. When the nano-preparation is a polymer nanoparticle, the solvent of the first phase solution is a good solvent for the polymer, and the solute is (1) the polymer, or (2) the polymer and the anti-tumor drug; the second phase solution is water or water containing 0.5% PVA; C. When the nano-preparation is a nanoliposome, the solvent of the first phase solution is a good solvent for the lipid component, and the solute is (1) the lipid component of the liposome, or (2) the lipid component of the liposome and the antitumor drug; the second phase solution is water or a buffered aqueous solution having a certain pH value and a certain osmotic pressure; D. When the nano-preparation is a nano-lipid particle, the solvent of the first phase solution is a good solvent for the lipid component, and the solute is the lipid component of the lipid particle; the solvent of the second phase solution is a buffered aqueous solution having a certain pH value and a certain osmotic pressure, and the solute is an antitumor drug; E. When the nanoformulation is an antitumor drug / photosensitizer nanoassembly, the solvent in the first phase solution is a good solvent for the antitumor drug or a pharmaceutically acceptable salt thereof, and the solute is (1) the antitumor drug or a pharmaceutically acceptable salt thereof and a photosensitizer, or (2) the antitumor drug or a pharmaceutically acceptable salt thereof; The solvent in the second phase solution is an antisolvent for the antitumor drug or a pharmaceutically acceptable salt thereof, and the solute is (1) absent or (2) a photosensitizer; When the solutes in the first phase solution are an antitumor drug or a pharmaceutically acceptable salt thereof and a photosensitizer, the solutes in the second phase solution are absent; When the solute in the first phase solution is an anti-tumor drug or a pharmaceutically acceptable salt thereof, the solute in the second phase solution is a photosensitizer. Manufacturing method.

10. a. (1) A system according to any one of claims 1 to 5, (2) The amphiphilic polymer according to claim 6. (3) The antitumor drug according to claim 7. (4) one or more of the antitumor drugs or pharmaceutically acceptable salts thereof are dissolved in a first phase, and the solvent used for the first phase solution is a good solvent for the antitumor drug or pharmaceutically acceptable salt thereof; (5) One or more amphiphilic polymers are dissolved in a second phase solution, and the solvent used in the second phase solution is an antisolvent for the antitumor drug or a pharmaceutically acceptable salt thereof; (6) The flow rate Q １ of the first phase solution and the flow rate Q ２ a first phase solution and a second phase solution of the first phase solution are combined into a combined phase, and the two-phase solution is rapidly mixed by the action of turbulent shear and ultrasonic waves at the same time, to form polymer nanomicelles coated with an antitumor drug, which are stably dispersed in a mixed solvent of the first phase and the second phase and have a constant particle size and distribution coefficient; b. (1) A system according to any one of claims 1 to 5, (2) The amphiphilic polymer according to claim 6. (3) The antitumor drug according to claim 7. (4) one or more kinds of the antitumor drugs or pharmaceutically acceptable salts thereof, and one or more kinds of the amphiphilic polymers are dissolved in a first phase, and the solvent used for the first phase solution is a good solvent for the antitumor drugs or pharmaceutically acceptable salts thereof; (5) The second phase solution is an antisolvent for the antitumor drug or a pharmaceutically acceptable salt thereof; (6) The flow rate Q １ of the first phase solution and the flow rate Q ２ a first phase solution and a second phase solution of the first phase solution are combined into a combined phase, and the two-phase solution is rapidly mixed by the action of turbulent shear and ultrasonic waves, thereby forming polymer nanomicelles having a constant particle size and distribution coefficient that are stably dispersed in the mixed solvent of the first phase and the second phase; c. (1) A system according to any one of claims 1 to 6, (3) The lipid components of the liposome are dissolved in a first phase, and the solvent used for the first phase solution is a good solvent for the lipid components; (4) The second phase solution is selected from water, a buffered aqueous solution having a certain pH value and a certain osmotic pressure; (5) The flow rate Q １ of the first phase solution and the flow rate Q ２ a first phase solution and a second phase solution of the first phase solution are combined into a combined phase, and the two-phase solution is rapidly mixed by the action of turbulent shear and ultrasonic waves to form blank nanoliposomes having a uniform particle size and distribution coefficient, which are stably dispersed in a mixed solvent of the first phase and the second phase; d. (1) A system according to any one of claims 1 to 6, (2) The antitumor drug and photosensitizer according to claim 7, (3) dissolving one or more of the antitumor drugs or pharmaceutically acceptable salts thereof in the first phase; (4) one or more of the photosensitizers are dissolved in a second phase solution, and the solvent used in the second phase solution is an antisolvent for the antitumor drug or a pharmaceutically acceptable salt thereof; (5) The flow rate Q １ of the first phase solution and the flow rate Q ２ and merging the first and second phase solutions into a combined phase, and rapidly mixing the two-phase solutions under the action of turbulent shear and ultrasonic waves to form a composite nano-preparation of the photosensitizer and the anti-tumor drug stably dispersed in the mixed solvent of the first and second phases, with a consistent particle size and distribution coefficient. e. (1) A system according to any one of claims 1 to 6, (2) The antitumor drug and photosensitizer according to claim 7, (3) One or more types of the antitumor drug or a pharmaceutically acceptable salt thereof and one or more types of the photosensitizer are dissolved in a first phase, and the solvent used for the first phase solution is a good solvent for the antitumor drug or a pharmaceutically acceptable salt thereof and the photosensitizer; (4) The second phase solution is an antisolvent for the antitumor drug or a pharmaceutically acceptable salt thereof; (5) The flow rate Q １ of the first phase solution and the flow rate Q ２ and a second phase solution of the first phase into a combined phase, and the two-phase solution is rapidly mixed by the action of turbulent shear and at the same time by the action of ultrasound, to form a composite nano-formulation of the photosensitizer and the anti-tumor drug stably dispersed in the mixed solvent of the first and second phases, with a consistent particle size and distribution coefficient. The manufacturing method according to claim 9 .

11. (1) the temperature of the first phase solution is 0°C to 90°C, for example, 25°C or 60°C; (2) the temperature of the second phase solution is 0°C to 90°C, for example, 25°C or 60°C; (3) The fluid Reynolds number Re of the combined phase is 700 to 9500 (e.g., 747, 2884, 3868, 5158, 5505, 5872, 6623, 7865, or 9176), preferably 3000 to 7000 (e.g., 3868, 5158, or 6623); (4) The flow rate ratio FVR of the first phase solution to the combined phase is 0.4 to 6, for example, 0.49, 0.64, 0.93, 1.46, 3.38, 3.4, 4.4, or 5.2; (5) The ultrasonic wave is an ultrasonic water bath, and the ultrasonic power is 200 W; (6) The solvents used for the first phase solution and the second phase solution are each selected from water, a buffered aqueous solution having a certain pH value, or a water-miscible organic solvent, and the organic solvent is one or more selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, DMF, DMAc, HMPA, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, cyclosulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, ethylene glycol, ethylene glycol methyl ether, ethylene glycol ethyl ether, dioxane, formic acid, acetic acid, hydroxypropionic acid, ethylamine, ethylenediamine, glycerol, and pyridine; (7) the flow rate Q of the first phase solution through the first line １ is in the range of 10 mL / min to 100 mL / min, for example 10, 11, 14, 50, 60, 80, or 100; (8) the flow rate Q of the second phase solution through the second line ２ is selected from the range of 100 mL / min to 1300 mL / min, for example, 100, 193, 200, 210, 300, 936, 890, or 1248; The manufacturing method according to claim 9 .

12. (1) When the nano-preparation is a polymer nanomicelle, the volumetric mass concentration range of the antitumor drug in the first phase solution may be 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, or 200 mg / mL, preferably 10 mg / mL to 100 mg / mL, more preferably 10 mg / mL to 20 mg / mL, for example, 15 mg / mL; (2) When the nano-preparation is a polymer nanomicelle, the volumetric mass concentration range of the polymer in the first phase solution or the second phase solution may be 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, or 200 mg / mL, and preferably 10 mg / mL to 100 mg / mL, for example, 50 mg / mL; (3) When the nano-preparation is a nanoliposome, the volumetric mass concentration range of the lipid component in the first phase solution is 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, or 200 mg / mL, and preferably 10 mg / mL to 100 mg / mL; (4) When the nano-preparation is an antitumor drug / photosensitizer nanoassembly, the molar ratio of the antitumor drug or a pharmaceutically acceptable salt thereof to the photosensitizer is (1-15):1, for example, 1:1, 2:1, 5:1, 6:1, 7:1, 8:1, 10:1 or 15:1, preferably 2:1; (5) When the nanoformulation is an antitumor drug / photosensitizer nanoassembly, the volumetric mass concentration range of the antitumor drug in the first phase solution is 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL, preferably 10 mg / mL to 100 mg / mL, for example, 40 mg / mL, 50 mg / mL, or 100 mg / mL; (6) When the nanoformulation is an antitumor drug / photosensitizer nanoassembly, the volumetric mass concentration range of the photosensitizer in the first or second phase solution is 0.1 mg / mL to 200 mg / mL, for example, 0.1 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, or 200 mg / mL, and preferably 10 mg / mL to 100 mg / mL, for example, 40 mg / mL, 50 mg / mL, or 150 mg / mL; The manufacturing method according to claim 9 .

13. (1) When the nano-preparation is a polymer nanomicelle, the solvent used for the first phase solution is a nitrile-based solvent or an alcohol-based solvent, such as acetonitrile or ethanol; (2) When the nano-preparation is a polymer nanomicelle, the solvent used for the second phase solution is water; (3) When the nano-preparation is a liposome, the solvent used in the first phase solution is an alcohol-based solvent, such as ethanol; (4) When the nano-preparation is a liposome, the solvent used for the second phase solution is water or an aqueous ammonium sulfate solution, preferably water or a 120 mM aqueous ammonium sulfate solution; (5) When the nano-preparation is a polymer nanoparticle, the solvent used for the first phase solution is an alcohol-based solvent or a chlorinated alkane-based solvent, such as ethanol or dichloromethane; (6) When the nano-preparation is a polymer nanoparticle, the solvent used for the second phase solution is water or water containing 0.5% PVA; (7) When the nano-formulation is an antitumor drug / photosensitizer nanoassembly, the solvent used for the first phase solution is a sulfoxide solvent or an alcohol solvent, such as dimethyl sulfoxide or methanol; (8) When the nanoformulation is an antitumor drug / photosensitizer nanoassembly, the solvent used in the second phase solution is water; (9) When the nano-preparation is a nano-lipid particle, the first phase solution is an alcohol-based solvent, for example, ethanol; (10) When the nano-preparation is a nano-lipid particle, the second phase solution is a citrate buffer solution (pH 4.0). The manufacturing method according to claim 9 .

14. The nanoparticles of the nanopreparation have a particle size of less than 1000 nm, preferably less than 500 nm, more preferably less than 200 nm, for example, selected from 20 nm to 200 nm; The manufacturing method according to claim 9 .

15. The polydispersity index of the nanoparticles of the nanoformulation is less than 0.4; The manufacturing method according to claim 9 .

16. A manufacturing method for continuous production of SN-38 / indocyanine green nanoassembly, comprising: (1) A system according to any one of claims 1 to 5, (2) SN-38 and ICG are dissolved together in the first phase, and the solvent used for the first phase solution is a good solvent for SN-38 and ICG; (4) The second phase solution is an antisolvent for the antitumor drug or a pharmaceutically acceptable salt thereof; (5) The flow rate Q １ of the first phase solution and the flow rate Q ２ and the second phase solution of the first phase into a combined phase, and the two-phase solution is rapidly mixed by the action of turbulent shear and at the same time by the action of ultrasound to form SN-38 / indocyanine green nanoassemblies having a consistent particle size and distribution coefficient and stably dispersed in the mixed solvent of the first and second phases. Manufacturing method.

17. The solvents used for the first phase solution and the second phase solution are each selected from water, a buffered aqueous solution having a certain pH value, or a water-miscible organic solvent, and the organic solvent is one or more selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, DMF, DMAc, HMPA, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, cyclosulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, ethylene glycol, ethylene glycol methyl ether, ethylene glycol ethyl ether, dioxane, formic acid, acetic acid, hydroxypropionic acid, ethylamine, ethylenediamine, glycerol, and pyridine. The method of claim 16.

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