CN115400079A - Drug-loaded fatty acid nanoemulsion and preparation method and application thereof - Google Patents

Drug-loaded fatty acid nanoemulsion and preparation method and application thereof Download PDF

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Publication number
CN115400079A
CN115400079A CN202210480219.0A CN202210480219A CN115400079A CN 115400079 A CN115400079 A CN 115400079A CN 202210480219 A CN202210480219 A CN 202210480219A CN 115400079 A CN115400079 A CN 115400079A
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fatty acid
drug
phospholipid
solution
injection
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赵一麟
周媛媛
刘凤武
周旭
陈炜斌
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Taiyang Yulin Xiamen Biomedical Co ltd
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Taiyang Yulin Xiamen Biomedical Co ltd
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    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • A61K47/6455—Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
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Abstract

The invention discloses a drug-loaded fatty acid nanoemulsion, which comprises a dispersed phase and a continuous phase, wherein the dispersed phase consists of a drug-lipid complex, fatty acid/fatty acid derivatives and a phospholipid membrane; wherein the drug-loading mode is that the drug-lipid complex is uniformly dispersed in the fatty acid or the derivative thereof and then is wrapped by the phospholipid membrane; or the drug is combined on the phospholipid membrane, and the fatty acid or the derivative thereof is wrapped in the phospholipid membrane; the fatty acid has the characteristics of targeting tumor tissues and being retained in the tumor tissues for a long time, and has a therapeutic effect on tumors; the drug-lipid complex can load water-soluble drugs or difficultly soluble drugs into fatty acid; the safe nano emulsion prepared from the drug-loaded fatty acid is used for local or systemic treatment of tumors, so that the application range of the drug is expanded, and the side effects of the drug are reduced while the drug dosage is reduced.

Description

Drug-loaded fatty acid nanoemulsion and preparation method and application thereof
Technical Field
The invention relates to the field of pharmacy, in particular to a drug-loaded fatty acid nano emulsion and a preparation method and application thereof.
Background
The vegetable oil is a good carrier of antitumor drugs
Researches show that the injection of the vegetable oil into the solid tumor of the mouse can cause the necrosis and the dissolution of the solid tumor tissue, and meanwhile, the vegetable oil injected into the tumor tissue can persist for a long time and is not easy to be cleared or phagocytized. The characteristic of the vegetable oil can be used as a drug carrier, and the drug can be retained in the local part of the tumor along with the drug-loaded vegetable oil and can not flow to the whole body.
Clinical application and limitation of iodized oil
Iodized oil is also called iodized oil, ethylized oil, and comprises an organic iodine compound prepared by combining poppy seed oil and iodine, and iodized poppy seed oil fatty acid ethyl ester as an active ingredient. The iodized oil is conventionally used in primary hepatocellular carcinoma intervention, and is generally prepared by preparing iodized oil and one or two chemotherapeutic drugs into a temporary emulsion and injecting the temporary emulsion into hepatic artery through a catheter, but the temporary emulsion is very unstable and is easy to demulsify and stratify, and the iodized oil is separated out again and separated from the drugs. If the water-soluble medicine can be uniformly loaded in the iodized oil and stably exists, the emulsification operation is not needed in the operation process, the medication safety is improved, and the workload of medical personnel is reduced.
Clinically, the iodized oil embolism or the medicament-carrying iodized oil chemoembolization can only be used for treating liver cancer, but not for treating other visceral tumor, otherwise, the iodized oil embolism can be caused to the vascular terminal to cause tissue necrosis. Because the liver has two sets of blood supply systems, namely two sets of blood supply systems of hepatic artery and portal vein, and the tumor mainly supplies blood by the hepatic artery, the hepatic artery for embolizing blood supply tumor and the portal vein for supplying blood to the liver, the liver tissue necrosis can not be caused.
Uses and drawbacks of drug delivery of fatty acids or derivatives thereof
The drug-carrying capacity of the fatty acid or the derivative thereof (such as vegetable oil, the main component of which is fatty glyceride) can endow the drug with the capacity of targeting and staying in tumor tissues for a long time, so that the drug is enriched in the tumor tissues, and the systemic toxic and side effects of the drug are reduced. The water-soluble drug cannot be dissolved in fatty acid or vegetable oil and cannot be uniformly distributed in the fatty acid carrier. Small molecule targeted drugs are widely used clinically with their remarkable therapeutic effects and good tolerability, and many patients with malignant tumors have benefited from them. Most of small molecule targeted drugs are insoluble in water or oil, are oral preparations and have low bioavailability. The water-soluble drug and the insoluble drug are loaded into the fatty acid or the derivative thereof by a physical or chemical method, and the composition has the functions of synergism and attenuation for the clinical treatment of tumors.
How safe the oil drug loading becomes
Direct intravenous injection of fatty acids or vegetable oils can lead to pulmonary embolism, and arterial injection can lead to tissue necrosis due to embolism of terminal capillaries. The drug-loaded fatty acid or vegetable oil and the phospholipid are prepared into the nano emulsion together, so that the drug-loaded fatty acid or vegetable oil is changed into a water-soluble dosage form again, the targeting of the drug to the tumor can be ensured, the safety of the fatty acid or vegetable oil preparation is improved, and the drug can be injected into local parts of the tumor through veins, arteries and lymphatic vessels or through skin injection. The iodized oil nano emulsion is injected through the tail vein of the mouse, the mouse has no abnormal reaction after injection, and the state of the mouse is good within the observation period of one month.
The drug-loaded nano-emulsion has the advantages and disadvantages that the liposome is a hollow vesicle structure which is wrapped by a lipid bilayer membrane and has the size of tens of nanometers to tens of micrometers, and is widely researched and used for targeted transmission of almost all types of drugs due to the characteristics of similarity with a cell membrane, good biological safety, easy realization of targeting through various modifications and the like. The target delivery of the nano liposome drug to the tumor is mainly realized through an Enhanced Permeability and Retentivity (EPR) effect of the tumor, which is caused by abundant blood vessels, high vascular permeability and incomplete lymphatic return of tumor tissues.
The liposome is the first one to successfully enter clinical application, and is also the nanometer drug delivery system which enters the most clinical application at present, and the purposes of reducing nonspecific absorption, improving the enrichment amount of target tissues, reducing side effects and the like can be realized by loading the drugs in the liposome. However, the current liposome technology still has many defects, such as low drug loading, poor targeting effect and the like.
Disclosure of Invention
The invention aims to provide a drug-loaded fatty acid nanoemulsion aiming at the defects and shortcomings of low drug loading capacity, poor targeting effect and the like of the liposome technology.
It is yet another object of the present invention to provide clinical applications of the drug-loaded fatty acid nanoemulsion.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a drug-loaded fatty acid nanoemulsion, which comprises a dispersed phase and a continuous phase, wherein the dispersed phase consists of a drug-lipid complex, fatty acid/fatty acid derivatives and phospholipid membranes;
wherein, the fatty acid/fatty acid derivative is a targeting carrier of the drug, and the drug targets and stays in tumor tissues along with the fatty acid/fatty acid derivative and plays a role for a long time; the fatty acid/fatty acid derivative has therapeutic effect on tumor, and has synergistic effect with medicine to increase curative effect.
The coupling of the drug and the lipid increases the lipid solubility of the drug, so that the drug which is difficult to dissolve (such as small molecule targeted drug) or the water-soluble drug (such as chemotherapy drug used clinically) can be dissolved and uniformly dispersed in the fatty acid/fatty acid derivative; meanwhile, the fat solubility of the medicine is increased, so that the medicine is fixed in the fatty acid/fatty acid derivative and cannot escape; moreover, the fat solubility of the medicine is increased, so that the fatty acid/fatty acid derivative can bear more medicines, and the medicine-loading rate is improved, so that the nano-emulsion disclosed by the invention reduces the volume of the medicine, shortens the administration time, improves the feeling of a patient and improves the life quality of the patient on the premise of ensuring the treatment dosage.
The phospholipid membrane wraps the drug-loaded fatty acid/fatty acid derivative to form a water-soluble nano emulsion, so that the risk of vascular embolism caused by the fatty acid/fatty acid derivative is avoided, and the use is safer.
The dispersed phase drug loading mode in the nano emulsion is one of the following two types:
1) The drug and lipid form drug-lipid complex, and uniformly disperse in fatty acid or its derivative, then add phospholipid to prepare into nano emulsion, and the drug-lipid complex, fatty acid or its derivative are wrapped in phospholipid membrane;
2) When the lipid is phospholipid, the drug and phospholipid form drug-phospholipid complex, and fatty acid or its derivative is added to prepare into nanoemulsion, wherein the drug is bonded on phospholipid membrane, and the fatty acid or its derivative is encapsulated in phospholipid membrane.
The continuous phase in the nano-emulsion of the invention selects the common clinical injection, or the solvent of the injection, or the water solution of the auxiliary material of the injection, thus ensuring the medication safety of the nano-emulsion; comprises one or more of distilled water, 0.9% sodium chloride solution, 5% glucose solution, ringer's solution, sodium bicarbonate solution, sodium lactate solution, water-soluble contrast agent solution, water-soluble surfactant solution, acetate buffer solution, citrate buffer solution, phosphate buffer solution, tromethamine buffer solution, carbonate buffer solution, hydrochloric acid solution, sodium hydroxide solution and sodium carbonate solution.
Further, the drug may be bound to the lipid (including phospholipid) by intermolecular force or covalent bond.
Further, the intermolecular force binding is carried out by adding the drug and the lipid (including phospholipid) to the fatty acid or the derivative thereof, heating to 40-60 deg.C, and stirring for 0.5-24h;
the supercritical CO2 method is further optimized, and the reaction conditions are that the pressure is 7.38-25MPa, the temperature is 40-60 ℃, and the reaction time is 0.5-4h.
Still further, the covalent bond connection mode comprises that the drug molecules and the lipid (including phospholipid) molecules are directly connected by amido bonds or ester bonds or are connected by connecting bridges to form
Acid-sensitive hydrazone, imine, oxime, silyl ether, and maleate linkages;
a redox sensitive disulfide bond, diselenide bond, thioether bond, selenoxide bond;
enzyme-sensitive peptide bonds, galactose glycosidic bonds, glucuronide bonds, sulfate bonds, pyrophosphate bonds.
Still further, the connecting bridge may be one or more of one or more molecules, or a polymer of multiple molecules, or a block polymer; the polymer or block polymer comprises one or more of polyamino acid, polypeptide or oligopeptide, polysaccharide or oligosaccharide, polyether, polyester, modified or end-modified polyether/polyester and block polymer formed by polyether and/or polyester.
Further, the lipid includes one or more of fatty alcohols, fatty acids, fatty acid esters, fatty acid glycerides, phospholipids, steroids, fat-soluble vitamins, and derivatives thereof.
The fatty alcohol comprises saturated fatty alcohol, monounsaturated fatty alcohol, polyunsaturated fatty alcohol and one or more of the fatty alcohol derivatives; the unsaturated bond in the carbon chain of the unsaturated fatty alcohol is a double bond or a triple bond; the carbon chain of the fatty alcohol can be a straight chain, a branched chain or a cyclic structure;
the fatty acid comprises saturated fatty acid, monounsaturated fatty acid, polyunsaturated fatty acid and one or more of the fatty acid derivatives; the carboxyl of the fatty acid is 1-3, and the unsaturated bond in the carbon chain of the unsaturated fatty acid is a double bond or a triple bond; the carbon chain of the fatty acid can be a straight chain, a carbon chain with a branched chain, a carbon chain with a cyclic structure, a carbon chain with hydroxyl, amino and sulfydryl;
the fatty acid ester includes an ester of a fatty acid with a fatty alcohol, an ester of a fatty acid with a compound having an alcoholic hydroxyl group and a phenolic hydroxyl group in a molecule, and also includes a thioester of a fatty acid with a compound having a mercapto group in a molecular structure;
the fatty acid glyceride is an ester formed by fatty acid and glycerol, and comprises a monoglyceride formed by one fatty acid molecule and glycerol, a diglyceride formed by two fatty acid molecules and glycerol and a triglyceride formed by three fatty acid molecules and glycerol; the fatty acids in the diglyceride and triglyceride may be the same or different.
The phospholipids comprise glycerophospholipids and sphingomyelins, wherein the glycerophospholipids comprise phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, and one or more of the above phospholipid derivatives;
the steroids include cholesterol, lanosterol, sitosterol, stigmasterol, ergosterol, bile acid, bile alcohol, and one or more of the steroid lipid derivatives;
the fat-soluble vitamins comprise vitamin A, vitamin D, vitamin E, vitamin K and one or more of the fat-soluble vitamin derivatives.
Further, the drugs include one or more of systemic chemotherapy drugs, small molecule targeted drugs, antibody and protein drugs, radionuclides, and imaging agents for tracing.
Still further, the systemic chemotherapeutic agent comprises
Drugs that interfere with nucleic acid metabolism, inhibit nucleic acid synthesis: doxifluridine, fluorouracil, mercaptopurine, thioguanine, cytarabine, fluoroguanosine, tegafur, gemcitabine, carmofur, hydroxyurea, methotrexate, ancitabine, pemetrexed, letetrexed;
drugs that disrupt DNA structure, block DNA replication: nimustine, carmustine, lomustine, semustine, cyclophosphamide, ifosfamide, narcotine, dacarbazine, procarbazine, carboplatin, cisplatin, oxaliplatin, nedaplatin, mitomycin, pellomycin, pingyangmycin, bleomycin;
topoisomerase inhibitors: irinotecan, cephalotaxine, hydroxycamptothecin, topotecan, teniposide, etoposide;
drugs that interfere with RNA transcription: actinomycin D, doxorubicin, daunorubicin, epirubicin, pirarubicin, mitoxantrone;
drugs that inhibit tubulin synthesis, block cell division: vinorelbine, paclitaxel, docetaxel, vincristine, vindesine, vinblastine;
drugs that inhibit protein synthesis: asparaginase enzyme;
anti-hormonal drugs: atamestan, aminoglutethimide, letrozole, formestane, megestrol, tamoxifen.
Still further, the small molecule targeted drug comprises:
AKT inhibitors: caspasertib (Capivasertib);
ALK inhibitors: crizotinib (Crizotinib), ceritinib (Ceritinib), oletinib (Alectinib), bugatinib (Brigatinib), loratinib (lorelatinib);
BCL-2 inhibitors: venetolara (Venetocalax);
BCR-ABL inhibitors: imatinib (Imatinib), dasatinib (Dasatinib), nilotinib (Nilotinib), ponatinib (Ponatinib);
BRAF V600E inhibitors: vemurafenib (Vemurafenib), dabrafenib (Dabrafenib), cornenfenib (Encorafenib);
BTK inhibitors: ibrutinib (Ibrutinib), acanthoib (acarabutiib), zeutiib (zanuburtinib), orbutiib (orelburtinib);
CDK4/6 inhibitors: pabociclib, ribbingillin (Ribociclib), bemacillin (Abemaciclib);
an EGFR inhibitor: gefitinib (Gefitinib), erlotinib (Erlotinib), icotinib (Icotinib), afatinib (Afatinib), dacatinib (Dacomitinib), oxitinib (osiertinib), and armertinib (almonetinib);
an FGFR inhibitor: erdatinib (Erdafitinib), pemitinib (pemitinib), inflixatitinib (Infigratinib);
EZH2 inhibitors: tasetastat (Tazemetostat);
HEG2 inhibitors: lapatinib (Lapatinib), neratinib (Neratinib), pyrroltinib (Pyrotinib), and cartitinib (tucatetinib);
HDAC inhibitors: vorinostat (Vorinostat), romidepsin (Romidepsin), belinostat (Belinostat), panobinostat (Panobinostat), cidam (Chidamide), mocetinostat;
MEK inhibitors: trametinib (Trametinib), cobinetinib (Cobimetinib), bimetinib (Binimetinib), semetinib (Selumetinib);
MET inhibitors: carbamatinib (capimatinib), tipertinib (tepotiib), voritinib (Savolitinib);
an mTOR inhibitor: sirolimus (Sirolimus), temsirolimus (Temsirolimus), everolimus (Everolimus), zotarolimus (Zotarolimus);
inhibitors of NTRK: enretinib (Entrectinib), larotinib (larotinib), and elotinib (alectiib);
PARP inhibitors: olaparib (Olaparib), nilapaparib (niaparib), talapaparib (Talazoparib), lucapaparib (rucapaparib);
PDGFR inhibitor: avancib (Avapritinib), midostaurin (midostatin), nintedanib (Nintedanib), ladostinib (Radotinib), rapitinib (riptinib);
PI3K inhibitors: arbelix (alelisib), idelalisib (Idelalisib), erbulinib (umbralisib);
proteasome (Proteasome) inhibitors: bortezomib (Bortezomib), carfilzomib (Carfilzomib), ixazoib (ixazoib);
RET inhibitors: pralistinib (Pralsetinib), selpatitinib (Selpercatinib);
ROS1 inhibitors: entrectinib (Entrectinib);
SMO inhibitors: vismodegib (Vismodegib), sonedgib (Sonidegib), glargib (Glasdegib);
Src/Ab1 dual inhibitor: bosutinib (Bosutinib);
VEGFR inhibitors: sorafenib (Sorafenib), sunitinib (Sunitinib), pazopanib (Pazopanib), regorafenib (Regorafenib), vandetanib (Vandetanib), lenvatinib (Lenvatinib), cabozantinib (Cabozantinib), axitinib (Axitinib), teratinib (Telatinib), apatinib (Apatinib), antratinib (nilotinib), furoquintinib (Fruquintinib);
and others: pomalidomide (Pomalidomide).
Still further, the antibody and protein drugs comprise
CD2 targeting drugs: dextuximab (Dinutuximab);
CD 19-targeting drugs: bornaitumomab (Blinatumomab);
CD20 targeting drugs: ibritumomab tiuxetan (Ibritumomab), rituximab (Rituximab), tositumomab (Tositumomab), obinutuzumab (Obinutuzumab), ofatumumab (Ofatumumab);
CD30 targeting drugs: present cetuximab (Brentuximab);
CD 38-targeting drugs: daratumumab (Daratumumab);
CTLA-4 targeting drugs: ipilimumab (Ipilimumab);
EGFR-targeting drugs: pertuzumab ozogamicin (Necitumumab), cetuximab (Cetuximab), panitumumab (Panitumumab);
HER2 targeting drugs: pertuzumab (Pertuzumab), trastuzumab (Trastuzumab);
nectin-4-targeted drugs: enfratuzumab (Enfortumab);
PD-1-targeted drugs: pembrolizumab (Pembrolizumab), nivolumab (Nivolumab), cimirapril mab (cemipimab), tereprimab (toripilimumab), certolizumab (Sintilimab), certolizumab (Camrelizumab), tirelizumab (tiselizumab);
PD-L1-targeted drugs: alemtuzumab (Atezolizumab), dewaluzumab (Durvalumab), avilumab (Avelumab);
drugs targeting SLAMF 7: erlotinzumab (Elotuzumab);
TROP-2-targeting drugs: certolizumab ozogamicin (Sacituzumab);
VEGF-targeting drugs: bevacizumab (Bevacizumab), cimaVax lung cancer vaccine;
VEGFR-targeting drugs: ramucirumab (Ramucirumab), sipueucel-T prostate treatment vaccine;
recombinant polypeptide and protein drugs: octreotide, aflibercept, recombinant human interleukin-2 and recombinant human endostatin.
Still further, the local anesthetic includes Procaine (Procaine), procainamide (Procainamide), chloroprocaine (Chloroprocaine), tetracaine (Tetracaine), lidocaine (Lidocaine), bupivacaine (Bupivacaine), etidocaine (etidocaine), ropivacaine (Ropivacaine), oxybuprocaine (oxybuprocaine), proparacaine (Proxymetacaine) and derivatives thereof.
Still further, the analgesic comprises non-steroidal anti-inflammatory analgesic, lappaconitine and derivatives thereof, bulleyaconitine and derivatives thereof and the like;
the nonsteroidal anti-inflammatory analgesic comprises aspirin, acetaminophen, analgin, phenylbutazone, oxyphenbutazone, indomethacin sodium, diclofenac sodium, bufexamac, naproxen sodium, naproxone, ibuprofen, ketoprofen, loxoprofen sodium, sulindac, lornoxicam, piroxicam, meloxicam, nimesulide, flurbiprofen sodium, flurbiprofen ester, celecoxib, etoricoxib, parecoxib, erexib, ketorolac tromethamine and derivatives of the above medicines.
Still further, the radionuclides include 77Br,45Ca,57Co,58Co,51Cr,131Cs,137Cs,67Cu,59Fe,67Ga,195Hg,197Hg,203Hg,123I,125I,131I,111In,177Lu,99Mo,185Os,191Os,32P,33P,203Pb,35S,113Sn,85Sr,89Sr,99Tc,132Te,201Th,48V,133Xe,87Y,90Y,91Y, 1699 Yb,65Zn.
Still further said developer for tracing comprises
Developer under X-ray: at least one of iothalamic acid, iothalamate meglumine, ioversol, iodophenyl ester, iopamidol, iohexol, iodixanol and iomeprol;
and a nuclear magnetic resonance developer: at least one of iron, gadolinium and manganese compounds.
Still further, the medicine comprises raw material medicines of the medicine and a clinical injection preparation containing the medicine, and the clinical injection preparation comprises injection and freeze-dried powder for injection.
Further, the fatty acid/fatty acid derivative includes any one of liquid fatty acid, liquid fatty acid monohydric alcohol ester, and liquid fatty acid glyceride, or a mixture of any two or more of the above liquid fatty acid/fatty acid derivatives, or a mixture of any one of the above liquid fatty acid/fatty acid derivatives with one or more liquid and/or non-liquid fatty acid/fatty acid derivatives added.
Still further, the fatty acid/fatty acid derivative is preferably a liquid fatty acid, a liquid fatty acid glyceride.
Still further preferably, the liquid fatty acid glyceride comprises vegetable oil, vegetable oil derivatives; the vegetable oil derivative includes organic iodine compound of vegetable oil and iodine, such as iodized oil and ethyl iodized oil.
The invention also provides a preparation method of the fatty acid nanoemulsion loaded with the medicine, wherein the preparation method is one of the following two methods:
1) Taking drug-loaded fatty acid/fatty acid derivative as an oil phase, adding phospholipid, auxiliary lipid, surfactant and water phase to mix into primary emulsion, and then uniformly dispersing to obtain the emulsion;
2) Taking fatty acid/fatty acid derivative containing medicine-phospholipid complex as oil phase, adding phospholipid, auxiliary lipid, surfactant and water phase to mix into colostrum, and uniformly dispersing to obtain the final product, wherein the medicine-phospholipid complex participates in the formation of phospholipid membrane.
Further, the preparation method of the drug-loaded fatty acid/fatty acid derivative comprises the steps of combining a drug and lipid through a covalent bond, purifying, removing a solvent, drying, and redissolving and dispersing a product in the fatty acid/fatty acid derivative to obtain a mixture; or a mixture obtained by bonding the drug and the lipid in the fatty acid/fatty acid derivative by intermolecular force or covalent bond, and filtering to remove insoluble substances.
Further preferably, the preparation method of the nano-emulsion comprises the following steps:
1) Taking fatty acid or derivatives thereof as a reaction medium, carrying out coupling reaction on the bulk drug of the drug or a clinical injection preparation containing the drug, lipid and a connecting bridge molecule added according to needs under the action of a catalyst, and filtering to remove insoluble substances to obtain drug-loaded fatty acid/fatty acid derivatives;
2) The drug-loaded fatty acid/fatty acid derivative is taken as an oil phase, phospholipid, auxiliary lipid, surfactant and water are added to be mixed into primary emulsion, and then the primary emulsion is uniformly dispersed to obtain the drug-loaded fatty acid nano emulsion.
Further, the fatty acid/fatty acid derivative containing the drug-phospholipid complex is a mixture obtained by combining a drug and a phospholipid through a covalent bond, purifying, removing a solvent and drying, and redissolving and dispersing the product in the fatty acid/fatty acid derivative; or a mixture obtained by bonding the drug and phospholipid in fatty acid/fatty acid derivative by intermolecular force or covalent bond, and filtering to remove insoluble substances.
Further preferably, the preparation method of the nano-emulsion comprises the following steps:
1) Taking fatty acid or derivatives thereof as a reaction medium, carrying out coupling reaction on the raw material medicine of the medicine or a preparation for clinical injection containing the medicine, phospholipid and a connecting bridge molecule added according to needs under the action of a catalyst, and filtering to remove insoluble substances to obtain the fatty acid/fatty acid derivatives containing the medicine-phospholipid complex;
2) Taking fatty acid/fatty acid derivative containing drug-phospholipid complex as oil phase, adding phospholipid, auxiliary lipid, surfactant and water phase, mixing to obtain colostrum, and uniformly dispersing to obtain the final product, wherein the drug-phospholipid complex participates in formation of phospholipid membrane.
Still further, the phospholipids include glycerophospholipids and sphingomyelins, wherein the glycerophospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, and one or more of the derivatives of the foregoing phospholipids.
Still further, the helper lipid comprises one or more of fatty acid monoalcohol esters, fatty acid glycerides, glycerophospholipids, sphingomyelin, steroids, fat-soluble vitamins, and derivatives of the foregoing lipids.
Still further, the surfactant includes one or more of sorbitan fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene glyceryl ether fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymer, alkyl glycoside, sucrose fatty acid ester, mannosylerythritol ester, N-fatty acyl-N-methylglucamine, and cholate.
Still further, the water phase comprises one or more of distilled water, 0.9% sodium chloride injection, 5% glucose injection, ringer's injection, sodium lactate injection, sodium bicarbonate injection, water-soluble contrast agent injection/solution, pH regulator and water-soluble surfactant solution;
the pH regulator comprises one or more of acetate buffer solution, citrate buffer solution, phosphate buffer solution, tromethamine buffer solution, carbonate buffer solution, hydrochloric acid solution, sodium hydroxide solution and sodium carbonate solution;
the water-soluble surfactant solution comprises one or more of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene glyceryl ether fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymer, alkyl glycoside, sucrose fatty acid ester, mannosylerythritol ester, N-fatty acyl-N-methylglucamine and cholate, and is dissolved or dispersed in water to form a solution;
the water-soluble contrast agent injection/solution comprises a clinical injection or a water solution of raw material medicines containing any one of iotalopram, ioflunol, iopamidol, iohexol, iodixanol and iomeprol.
Still further, the volume ratio of the oil phase to the water phase is 1; the total amount of the auxiliary lipid and the surfactant is 3-15% of the total system.
Mixing the water phase and oil phase to obtain primary emulsion at 25-60 deg.C, and stirring for 10-30min.
Further, the uniform dispersion method comprises high-speed shearing homogenization, or high-pressure filter membrane extrusion, or ultrasonic dispersion, or high-pressure slit homogenization, or supercritical method dispersion;
wherein the rotating speed of the high-speed shearing homogenizer is 3000-30000rpm/min;
conditions for high pressure membrane extrusion: the pressure is 0.1-0.5MPa, and the membrane aperture is 0.22um;
conditions of ultrasonic dispersion: the power is 140-1000W, and the ultrasonic time is 10-30min;
conditions for high pressure slit homogenization: working pressure is 10-100MPa, and 2-5 times of circulation are carried out;
conditions of the supercritical method: 7-25 MPa, and the action time is 1-4h.
The invention also provides application of the fatty acid nanoemulsion loaded with the medicine in the technical scheme, and the fatty acid nanoemulsion can be used for local injection of arteries, veins, lymphatic vessels or tumors and treatment of malignant tumors.
Compared with the prior art, the invention has the following beneficial effects:
(1) The coupling of the drug and the lipid increases the lipid solubility of the drug, so that more drugs can be dissolved or uniformly dispersed in the fatty acid/fatty acid derivative, the drug loading of the fatty acid is increased, and the drug loading of the nano-emulsion is further increased; when the dosage of the medicine is ensured, the medicine feeding volume is reduced, the medicine feeding time is shortened, the feeling of the patient is improved, and the life quality of the patient is improved.
(2) By utilizing the characteristics of the fatty acid/fatty acid derivative, the medicine can be targeted and retained in the tumor tissue along with the fatty acid/fatty acid derivative to play a role for a long time; the coupling of the drug and the lipid leads the drug to be further fixed in the fatty acid/fatty acid derivative due to the increase of lipid solubility, thus weakening the systemic side effect caused by the drug escaping from the tumor tissue and distributing to the whole body; meanwhile, the fatty acid also has a treatment effect on tumors, and the synergistic effect with the medicament enhances the treatment effect, so that the administration dosage can be properly reduced, and the side effect of the medicament is reduced.
(3) The medicine and fatty acid/fatty acid derivative in the nano emulsion are wrapped by the phospholipid membrane, so that the risk of vascular embolism is avoided, and the nano emulsion is safer to use.
(4) The invention loads water-soluble drugs or insoluble drugs into fatty acid/fatty acid derivatives, prepares safe nano-emulsion, can be used for local injection of artery, vein, lymphatic vessel and tumor, leads the drugs to directly reach the focus or directly enter the circulatory system, improves the bioavailability of the drugs, expands the application range of the drugs on one hand, reduces the dosage of the drugs on the other hand, and simultaneously lightens the side effects of the drugs.
(5) The invention provides a method for preparing a nano-emulsion by using bulk drugs or clinical preparations, which can be used for preparing the nano-emulsion on site in an operating room preparation room or a ward liquid distribution room according to a clinical treatment scheme for tumor treatment and meets the requirement of tumor individualized treatment.
Detailed Description
The present invention is further explained and illustrated by the following embodiments, which should be understood to make the technical solution of the present invention clearer and easier to understand, and not to limit the scope of the claims.
Example 1:
doxorubicin-iodized oil nano emulsion (supercritical method medicine carrying)
Preparing a water phase: distilled water 35ml, adding tromethamine 144mg and poloxamer 1882.25g, heating in water bath at 60 deg.C and stirring to dissolve, adjusting pH to 7.2-7.4 with 20% hydrochloric acid solution and/or 20% sodium hydroxide solution, adding distilled water to constant volume 40ml, and keeping the temperature at 60 deg.C for use.
Carrying out medicine loading and emulsifying: 10ml of iodized oil, 0.08g of doxorubicin hydrochloride, 0.75g of lecithin, 0.5g of glycerin monostearate and 0.53ml of tricaprylin are added into a reaction kettle; sealing the reaction kettle, starting electric heating and stirring, pumping CO2 until the pressure in the reaction kettle is 20MPa when the temperature is stabilized at 60 ℃, and maintaining the pressure for reaction for 2 hours; starting a feeding pump, injecting the prepared water phase into a reaction kettle, stirring and mixing for 30 minutes, starting ultrasound, setting the power to be 300W, and performing ultrasound for 20 minutes; slowly releasing the pressure to 0MPa after the ultrasonic treatment is finished, receiving the prepared nano emulsion from a discharge port, and storing at 4 ℃ for later use.
Example 2:
mitomycin-corn oil nanoemulsion (supercritical method for drug loading)
Preparing an aqueous phase: heating 0.9% sodium chloride injection 25ml in 40 deg.C water bath, and keeping the temperature for use.
Carrying out medicine loading and emulsification: adding 5ml of corn oil, 8mg of mitomycin, 0.825g of lecithin, 0.275g of beta-sitosterol and 80mg of polysorbate into a reaction kettle; sealing the reaction kettle, starting electric heating and stirring, pumping CO2 to the pressure level of 16MPa in the reaction kettle when the temperature is stabilized at 40 ℃, and maintaining the pressure for reaction for 1 hour; starting a feeding pump, injecting the prepared water phase into a reaction kettle, stirring and mixing for 30 minutes, starting ultrasound, setting the power to be 400W, and performing ultrasound for 20 minutes; slowly releasing the pressure to 0MPa after the ultrasonic treatment is finished, receiving the prepared nano emulsion from a discharge port, and storing at 4 ℃ for later use.
Example 3:
oxicetinib-eicosapentaenoic acid (EPA) nanoemulsion (drug loaded by supercritical method)
Preparing an aqueous phase: 35ml of 0.9% sodium chloride injection is added with 2.25g of poloxamer 188, heated in water bath at 60 ℃ and stirred to be dissolved, the pH value is adjusted to 6.9-7.1 by 10% sodium carbonate solution, the 0.9% sodium chloride injection is added to be constant volume to 40ml, and the mixture is kept warm at 60 ℃ for standby.
Carrying out medicine loading and emulsification: 10ml of EPA, 0.08g of ocitinib mesylate, 0.75g of lecithin, 0.5g of glycerin monostearate and 0.53ml of tricaprylin are added into a reaction kettle; sealing the reaction kettle, starting electric heating and stirring, pumping CO2 until the pressure in the reaction kettle is 10MPa when the temperature is stabilized at 60 ℃, and maintaining the pressure for reaction for 4 hours; starting a feeding pump, injecting the prepared water phase into a reaction kettle, stirring and mixing for 30 minutes, starting ultrasound, setting the power to be 300W, and performing ultrasound for 20 minutes; slowly releasing the pressure to 0MPa after the ultrasonic treatment is finished, receiving the prepared nano emulsion from a discharge port, and storing at 4 ℃ for later use.
Example 4:
lunvatinib-docosahexaenoic acid (DHA) nanoemulsion (supercritical method drug loading)
Preparing an aqueous phase: 45ml of phosphate buffer (pH 7.2-7.4) was heated to 40 ℃ with stirring, and the mixture was kept warm for use.
Carrying out medicine loading and emulsification: 5ml of DHA, 12mg of electrovatinib mesylate, 0.8g of lecithin, 0.27g of beta-sitosterol and 25mg of Tween-80 are added into a reaction kettle; sealing the reaction kettle, starting electric heating and stirring, pumping CO2 until the pressure in the reaction kettle is 16MPa when the temperature is stabilized at 40 ℃, and maintaining the pressure for reaction for 3 hours; starting a feeding pump, injecting the prepared water phase into a reaction kettle, stirring and mixing for 30 minutes, starting ultrasound, setting the power to be 500W, and performing ultrasound for 30 minutes; slowly releasing the pressure to 0MPa after the ultrasonic treatment, receiving the prepared nano emulsion from a discharge port, and storing at 4 ℃ for later use.
Example 5:
raltitrexed-linoleic acid nanoemulsion (supercritical method drug loading)
Preparing an aqueous phase: heating 16ml ioversol injection to 40 deg.C, and keeping the temperature for use.
Carrying out medicine loading and emulsification: 4ml of linoleic acid, 4mg of triptolide, 0.66g of lecithin, 0.22g of beta-sitosterol and 40mg of Tween-80 40mg are added into a reaction kettle; sealing the reaction kettle, starting electric heating and stirring, pumping CO2 until the pressure in the reaction kettle is 12MPa when the temperature is stabilized at 40 ℃, and maintaining the pressure for reaction for 2.5 hours; starting a charging pump, injecting the prepared water phase into a reaction kettle, stirring and mixing for 30 minutes, starting ultrasound, setting the power to be 600W, and performing ultrasound for 20 minutes; slowly releasing the pressure to 0MPa after the ultrasonic treatment is finished, receiving the prepared nano emulsion from a discharge port, and storing at 4 ℃ for later use.
Example 6:
regorafenib-oleic acid nanoemulsion (supercritical method for drug loading)
Preparing a water phase: heating 40ml of iodixanol injection to 40 ℃, and preserving heat for later use.
Carrying out medicine loading and emulsification: adding 10ml of oleic acid, 160mg of regorafenib, 1.65g of lecithin, 0.55g of beta-sitosterol and 0.1g of Tween-80 into a reaction kettle; sealing the reaction kettle, starting electric heating and stirring, pumping CO2 until the pressure in the reaction kettle is 20MPa when the temperature is stabilized at 40 ℃, and maintaining the pressure for reaction for 2 hours; starting a feeding pump, injecting the prepared water phase into a reaction kettle, stirring and mixing for 30 minutes, starting ultrasound, setting the power to be 600W, and performing ultrasound for 20 minutes; slowly releasing the pressure to 0MPa after the ultrasonic treatment is finished, receiving the prepared nano emulsion from a discharge port, and storing at 4 ℃ for later use.
Example 7:
oxaliplatin-iodized oil nanoemulsion (fatty acid coupling method drug loading)
Oxaliplatin-oleic acid coupling: oleoyl chloride 1.8ml was dissolved in 5ml of diethyl ether for further use. Dissolving 1g of oxaliplatin in 20ml of DMF, adding 0.8ml of triethylamine, slowly dropwise adding oleoyl chloride diethyl ether solution while stirring, stirring and reacting for 16h at room temperature after dropwise adding, adding water with the volume of 2 times of that of the reaction solution for quenching, adding diethyl ether to extract a product, washing an organic phase with 5% hydrochloric acid, water and a saturated sodium chloride solution in sequence, dehydrating with anhydrous sodium sulfate, and drying in vacuum to obtain a coupling product for later use.
Preparing a nano emulsion: heating 40ml of 5% glucose injection to 40 ℃, and preserving heat for later use; adding oxaliplatin-oleic acid conjugate 117mg, lecithin 1.65g, beta-sitosterol 0.55g and Tween-80.1 g into 10ml of iodized oil, heating in a water bath at 40 ℃, and stirring until the mixture is completely dissolved; slowly adding isothermal water phase under stirring, adjusting pH to 6.5-7.0 with 20% hydrochloric acid solution and/or 10% sodium carbonate solution, stirring and mixing for 20min, setting ultrasonic power at 300W, and ultrasonic treating for 20min to obtain white nanometer emulsion, and storing at 4 deg.C.
Example 8:
taxol-linolenic acid nanoemulsion (fatty acid coupling method for drug loading)
Paclitaxel-lauric acid coupling: dissolving 1.75g of paclitaxel in 10ml of acetonitrile for later use; 0.83g of lauric acid is dissolved in 30ml of acetonitrile, 1.2ml of triethylamine and 0.8g of p-toluenesulfonyl chloride are added, heating reflux reaction is carried out for 40min, then paclitaxel solution is added, reflux reaction is carried out for 10min, insoluble substances are removed by filtration after the reaction is finished, filtrate is subject to rotary evaporation to remove the acetonitrile, residues are dissolved by 40ml of dichloromethane, 5 percent sodium bicarbonate solution is used successively, water is used for cleaning, anhydrous sodium sulfate is used for dehydration, and the solvent is removed in vacuum to obtain a coupling product;
preparing a nano emulsion: 35ml of 0.9 percent sodium chloride injection is added with 2.25g of poloxamer 188, heated in water bath at 60 ℃, stirred and dissolved, added with 0.9 percent sodium chloride injection to be constant volume to 40ml, and kept warm at 60 ℃ for standby; adding 10ml of linolenic acid, 0.3g of coupling product, 0.75g of lecithin, 0.5g of glyceryl monostearate and 0.53ml of tricaprylin, heating in a water bath at 60 ℃, stirring until the coupling product is completely dissolved, adding an isothermal water phase, adjusting the pH to 6.5-7.0 by using a 20% hydrochloric acid solution and/or a 20% sodium hydroxide solution, and stirring for 20min to form primary emulsion; the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, the pressure is 500bar, and the obtained nano emulsion is stored for standby at 4 ℃.
Example 9:
gemcitabine-soybean oil nanoemulsion (coupling fatty acid method for drug loading)
Gemcitabine coupling palmitic acid: and dissolving 9g of palmitic acid in 50ml of DMF, adding PyBOP 20g, NMM 7.5ml and gemcitabine hydrochloride 5g, stirring the mixture at room temperature for reaction for 24 hours, adding water into the reaction liquid for quenching, extracting the aqueous solution by using dichloromethane, separating the organic phase, washing the organic phase by using 5% hydrochloric acid, water and a saturated sodium chloride solution in sequence, dehydrating by using anhydrous sodium sulfate, and drying in vacuum to obtain a coupling product for later use.
Preparing a nano emulsion: adding 4.5g of poloxamer into 130ml of 0.9% sodium chloride injection, heating in a water bath at 60 ℃, stirring for dissolving, adding 0.9% sodium chloride injection to fix the volume to 140ml, and keeping the temperature at 60 ℃ for later use; adding coupling product 0.3g, lecithin 1.5g, glyceryl monostearate 1g and glyceryl tricaprylate 1.1ml into soybean oil for injection 20ml, heating in water bath at 60 deg.C, stirring to dissolve completely, adding isothermal water phase, adjusting pH to 6.5-7.0 with 20% hydrochloric acid solution and/or 20% sodium hydroxide solution, and stirring for 20min to obtain primary emulsion; the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, the pressure is 500bar for three times, and the obtained nano emulsion is stored for standby at 4 ℃.
Example 10:
sunitinib-docosahexaenoic acid (DHA) nanoemulsion (fatty acid coupling method drug-loading)
0.5g of sunitinib malate is dissolved in 10ml of DMF, 0.7ml of DHA is added, the mixture is placed in an ice bath, 0.55ml of DPPA and 0.35ml of triethylamine are added under stirring, the mixture is stirred for 2 hours under the ice bath, then the mixture is stirred at room temperature for reaction for 12 hours, dichloromethane is added after the reaction is finished, 10% citric acid, water, a saturated sodium bicarbonate solution, water and a saturated sodium chloride solution are sequentially used for washing, anhydrous sodium sulfate is used for dehydration, and vacuum drying is carried out to obtain a coupling product.
Preparing a nano emulsion: 30ml of 0.9% sodium chloride injection, 188.9 g of poloxamer, heating in water bath at 60 ℃, stirring until the poloxamer is completely dissolved, adding the 0.9% sodium chloride injection to the constant volume of 36ml, and keeping the temperature for later use;
DHA 4ml, coupling product 0.125g, lecithin 0.3g, glyceryl monostearate 0.2g, glyceryl tricaprylate 0.21ml, heating in water bath at 60 ℃ and stirring to dissolve completely, adding isothermal water phase, adjusting pH to 6.5-7.0 with 20% hydrochloric acid solution and/or 20% sodium hydroxide solution, and stirring for 20min to form primary emulsion; the obtained colostrum passes through 0.22 micrometer filter membrane (Millex-GP 33mm PES 0.22um Sterile), and is repeated three times, and the last filtrate is collected to obtain nanoemulsion, and stored at 4 deg.C for use.
Example 11:
crizotinib-olive oil nanoemulsion (fatty acid coupling method drug loading)
Dissolving 1.6g of heptadecanoic acid in 40ml of DMF, adding 1.4g of CDI in 7 times with equal amount, adding the mixture at an interval of 5min each time, continuously stirring for 10min after all the materials are added, adding 1.25g of crizotinib once, stirring for reaction for 3h at room temperature, adding diethyl ether, stirring for 10min, filtering, diluting the filtrate with diethyl ether, washing twice with 5% citric acid solution successively, washing once with saturated sodium chloride solution, dehydrating with anhydrous sodium sulfate, and drying in vacuum to obtain the coupling product.
Preparing a nano emulsion: 35ml of 0.9% sodium chloride injection and 2.25g of poloxamer 188 are heated in water bath at 60 ℃ and stirred until the components are completely dissolved, the 0.9% sodium chloride injection is added to be constant volume to 40ml, and the mixture is kept warm for standby; adding 10ml of olive oil, 0.53g of coupling product, 0.75g of lecithin, 0.5g of glycerin monostearate and 0.53ml of tricaprylin, heating in a water bath at 60 ℃, stirring until the coupling product is completely dissolved, adding an isothermal water phase, adjusting the pH value to 6.5-7.0 by using a 20% hydrochloric acid solution and/or a 20% sodium hydroxide solution, and stirring for 20min to form primary emulsion; setting ultrasonic power 300W, ultrasonic treating for 20min, and storing the obtained nano emulsion at 4 ℃ for later use.
Example 12:
olaparib-eicosapentaenoic acid (EPA) nanoemulsion (fatty acid coupling method drug loading)
2.25ml of EPA, 5.5g of PyBOP and 1.43g of HOBT are added into 10ml of DMF, the mixture is stirred to be dissolved and mixed evenly, 3g of olaparib and 1.2ml of DIPEA are added, the mixture is stirred and reacted for 4 hours at room temperature, after the reaction is finished, dichloromethane and saturated sodium bicarbonate solution are added, an organic phase is separated, the mixture is washed twice by saturated sodium chloride solution, anhydrous sodium sulfate is used for dehydration, and vacuum drying is carried out to obtain the coupling product.
Preparing a nano emulsion: 80ml of 0.9% sodium chloride injection, heating in a water bath at 60 ℃, and keeping the temperature for later use; 20ml of cottonseed oil for injection, 1.017g of coupling product, 3.3g of lecithin and 1.1g of beta-sitosterol are added, the mixture is heated in a water bath at 60 ℃ and stirred until the coupling product is completely dissolved, an isothermal water phase and a 20% hydrochloric acid solution and/or a 20% sodium hydroxide solution are added to adjust the pH value to be 6.5-7.0, and the mixture is stirred for 20min to form primary emulsion; setting the ultrasonic power of 500W, carrying out ultrasonic treatment for 20 minutes, and storing the obtained nano emulsion at 4 ℃ for later use.
Example 13:
afatinib-decenoic acid nanoemulsion (drug loading cholesterol coupling method)
Dissolving 500mg of cholesteryl chloroformate in 10ml of dichloromethane for later use; adding 400mg of afatinib maleate and 0.3ml of NMM into 20ml of dichloromethane, stirring for dissolving, and slowly dropwise adding a cholesteryl chloroformate solution; stirring for 16h at room temperature after the dropwise addition is finished, adding 2.5 times of water for quenching after the reaction is finished, extracting the product by using dichloromethane, washing an organic phase by using 5% hydrochloric acid, water and a saturated sodium chloride solution in sequence, dehydrating by using anhydrous sodium sulfate, and drying in vacuum to obtain a coupling product.
Preparing a nano emulsion: 80ml of 0.9 percent sodium chloride injection, heating in a water bath at 50 ℃, and keeping the temperature for later use; decenoic acid 20ml, coupling product 0.75g, lecithin 1.7g and cholesterol 0.15g are added, the mixture is heated in a water bath at 50 ℃ and stirred to be completely dissolved, isothermal water phase is added, pH value is adjusted to 6.5-7.0 by 20% hydrochloric acid solution and/or 20% sodium hydroxide solution, and stirring is carried out for 20min to form primary emulsion; setting the ultrasonic power at 400W, performing ultrasonic treatment for 20 minutes, and storing the obtained nano emulsion at 4 ℃ for later use.
Example 14:
sondegji-nonanoic acid nanoemulsion (vitamin E coupling method drug loading)
Adding 2g of Sonedgil diphosphonate, 1.6g of vitamin E succinate and 0.45ml of triethylamine into 30ml of DMF, stirring to dissolve, then adding 1.1g of HBTU, and stirring at room temperature to react for 2h; and after the reaction is finished, adding a saturated sodium chloride solution, adding dichloromethane to extract a product, washing an organic phase with 5% hydrochloric acid, 5% sodium bicarbonate solution and water in sequence, dehydrating with anhydrous sodium sulfate, and drying in vacuum to obtain a coupling product.
Preparing a nano emulsion: 30ml of 0.9% sodium chloride injection and 2.25g of poloxamer 188 are heated in water bath at 60 ℃ and stirred until the components are completely dissolved, the 0.9% sodium chloride injection is added to be constant volume to 40ml, and the mixture is kept warm for standby; 10ml of pelargonic acid, 0.293g of coupling product, 0.6g of lecithin, 0.5g of glycerin monostearate and 0.53ml of tricaprylin are added, the mixture is heated in a water bath at 60 ℃ and stirred until the coupling product is completely dissolved, an isothermal water phase is added, a 20% hydrochloric acid solution and/or a 20% sodium hydroxide solution are/is added to adjust the pH value to be 6.5-7.0, and the mixture is stirred for 20min to form primary emulsion; setting ultrasonic power 500W, ultrasonic treating for 20min, and storing the obtained nano emulsion at 4 ℃ for later use.
Example 15:
sorafenib-iodized oil nanoemulsion (drug loading by phospholipid complex method)
Adding soybean lecithin 5.8g, sorafenib tosylate 1.6g, HOBT 1.2g and EDCI 1.7g into DMF 20ml, stirring at room temperature for reaction for 4h, adding water for quenching after the reaction is finished, extracting the product by dichloromethane, washing an organic phase by using 5% hydrochloric acid, water and a saturated sodium chloride solution in sequence, dehydrating by using anhydrous sodium sulfate, and drying in vacuum to obtain the product.
Preparing a nano emulsion: 40ml of 0.9% sodium chloride injection, heating in water bath at 50 deg.C, and keeping the temperature; adding coupling product 0.84g, lecithin 1.05g and cholesterol 0.5g into iodized oil 10ml, heating in water bath at 50 ℃, stirring until the coupling product is completely dissolved, adding isothermal water phase, adjusting pH value to 6.5-7.0 by 20% hydrochloric acid solution and/or 20% sodium hydroxide solution, and stirring for 20min to form primary emulsion; setting the ultrasonic power at 400W, performing ultrasonic treatment for 20 minutes, and storing the obtained nano emulsion at 4 ℃ for later use.
Example 16:
doxorubicin-sunflower seed oil nanoemulsion (phospholipid complex method for drug loading)
Dissolving 1g of doxorubicin hydrochloride in 20ml of dichloromethane, adding 3g of diaxol phosphatidylcholine, adding 0.45g of DMAP and 1.5g of DCC, stirring and reacting at room temperature for 6 hours, diluting the reaction solution with diethyl ether, washing with 5% hydrochloric acid, water and a saturated sodium chloride solution in sequence, dehydrating with anhydrous sodium sulfate, and drying in vacuum to obtain the drug phospholipid coupling product.
Preparing a nano emulsion: 90ml of 0.9% sodium chloride injection, heating in a water bath at 50 ℃, and keeping the temperature for later use; adding coupling product 70mg, lecithin 1.65g and cholesterol 0.55g into sunflower seed oil 10ml for injection, heating in water bath at 50 deg.C, stirring to dissolve completely, adding isothermal water phase, adjusting pH to 6.5-7.0 with 20% hydrochloric acid solution and/or 20% sodium hydroxide solution, and stirring for 20min to obtain primary emulsion; setting the ultrasonic power at 400W, performing ultrasonic treatment for 20 minutes, and storing the obtained nano emulsion at 4 ℃ for later use.
Example 17:
pemetrexed-undecylenic acid nanoemulsion (phospholipid complex method for drug loading)
Adding 8.5ml of phosphatidylethanolamine, 2.2ml of isobutyl chloroformate and 2g of sodium carbonate into 20ml of DMF, and stirring at room temperature for reaction for 30min; dissolving 3.8g of pemetrexed disodium in 10ml of DMF, slowly dripping the solution into the reaction solution in the previous step while stirring, and stirring and reacting for 12 hours at room temperature; after the reaction is finished, water is added for quenching, dichloromethane is used for extracting a product, an organic phase is washed twice by a saturated sodium chloride solution, anhydrous sodium sulfate is used for dehydration, and vacuum drying is carried out to obtain a coupling product.
Preparing a nano emulsion: 40ml of 0.9% sodium chloride injection, heating in water bath at 50 deg.C, and keeping the temperature; 10ml of undecylenic acid, 1.55g of coupling product, 0.5g of lecithin and 0.5g of cholesterol are added, the mixture is heated in a water bath at 50 ℃ and stirred until the coupling product is completely dissolved, an isothermal water phase is added, a 20% hydrochloric acid solution and/or a 20% sodium hydroxide solution are/is added to adjust the pH value to be 6.5-7.0, and the mixture is stirred for 20min to form primary emulsion; setting the ultrasonic power at 400W, performing ultrasonic treatment for 20 minutes, and storing the obtained nano emulsion at 4 ℃ for later use.
Example 18:
erlotinib-dodecenoic acid nanoemulsion (phospholipid complex method for drug loading)
Adding dimyristoyl phosphatidylcholine 3g, nsCl 0.78g and triethylamine 2ml into 20ml of DMF, stirring and reacting for 40min at 50 ℃, adding erlotinib hydrochloride DMF solution (1.5 g is dissolved in 15ml of DMF), continuing to react for 4h at 50 ℃, adding water to quench after the reaction is finished, extracting a product by using dichloromethane, washing an organic phase by using 5% hydrochloric acid, water and saturated sodium chloride solution in sequence, dehydrating by using anhydrous sodium sulfate, and drying in vacuum to obtain a coupling product.
Preparing a nano emulsion: 30ml of 0.9% sodium chloride injection and 188.25g of poloxamer, heating in a water bath at 60 ℃, stirring until the components are completely dissolved, adding the 0.9% sodium chloride injection to fix the volume to 40ml, and keeping the temperature for later use; 10ml of dodecenoic acid, 0.37g of coupling product, 0.52g of lecithin, 0.5g of glyceryl monostearate and 0.53ml of tricaprylin are added, the mixture is heated in a water bath at 60 ℃ and stirred until the components are completely dissolved, an isothermal water phase is added, a 20% hydrochloric acid solution and/or a 20% sodium hydroxide solution are/is added to adjust the pH value to be 6.5-7.0, and the mixture is stirred for 20min to form primary emulsion; setting the ultrasonic power at 400W, performing ultrasonic treatment for 20 minutes, and storing the obtained nano emulsion at 4 ℃ for later use.
Example 19:
celecoxib-ethyl oleate nanoemulsion (taking celecoxib coupled behenic acid as an example)
Dissolving celecoxib 400mg in 10ml DMF, adding 388mg behenic acid, placing in an ice bath, adding 0.24ml DPPA and 0.16ml triethylamine under stirring, stirring for 2h in the ice bath, then stirring at room temperature for reaction for 12h, adding dichloromethane after the reaction is finished, washing with 10% citric acid, water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution successively, dehydrating with anhydrous sodium sulfate, and drying in vacuum to obtain a coupling product.
Preparing a nano emulsion: sodium chloride injection 16ml with concentration of 0.9%, heating in water bath at 50 deg.C, and keeping the temperature for use; refining 4ml of ethyl oleate, adding 0.39g of coupling product, 0.3g of lecithin, 0.3g of cholesterol and 0.02g of Tween 80, heating in a water bath at 50 ℃, stirring until the coupling product is completely dissolved, adding an isothermal water phase, adjusting the pH value to 6.5-7.0 by using a 20% hydrochloric acid solution and/or a 20% sodium hydroxide solution, and stirring for 20min to form primary emulsion; the colostrum is filtered through 0.22 micron filter membrane (Millex-GP 33mm PES 0.22um Sterile), repeated for three times, the third filtrate is collected to be the nano emulsion, and the nano emulsion is stored at 4 ℃ for standby.
Example 20:
the iodized oil nanoemulsion loaded with chemotherapeutic drugs is clinically prepared for interventional operation (for example, gemcitabine is coupled with linoleic acid)
Iodine oil medicine carrying: adding gemcitabine hydrochloride 1g (gemcitabine hydrochloride for injection, 200 mg/bottle 5 bottle), linoleic acid 1.5ml, EDCI 1g, heating in a water bath at 60 ℃ and stirring for reacting for 4h; and (5) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded iodized oil.
Preparing a water phase: 30ml of 0.9 percent sodium chloride injection, 2.25g of poloxamer 188 and 750mg of soybean lecithin are added, the mixture is heated in water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the 0.9 percent sodium chloride injection is added to be constant volume to 40ml, and the mixture is kept at 60 ℃ for standby.
Oil phase preparation and colostrum preparation: loading iodine oil in water bath at 60 deg.C, adding 0.5g glyceryl monostearate and 0.53ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain colostrum.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 300W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 21:
the clinical preparation of the chemotherapy drug-loaded docosahexaenoic acid (DHA) nanoemulsion is used for interventional surgery (taking the example of the Nedaplatin coupled DHA)
Iodine oil drug loading: DHA 10ml, adding Nedaplatin 0.1g (Nedaplatin for injection, 50 mg/bottle 2 bottles), EDCI 0.2g, heating in water bath at 60 ℃ and stirring, reacting for 4h; and (5) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded iodized oil.
Preparing a water phase: 30ml of 0.9% sodium chloride injection, 2.25g of poloxamer and 750mg of soybean phospholipid are added, the mixture is heated in water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the 0.9% sodium chloride injection is added to be constant volume to 40ml, and the mixture is kept warm at 60 ℃ for standby.
Oil phase preparation and colostrum preparation: loading iodine oil in water bath at 60 deg.C, adding 0.5g glyceryl monostearate and 0.53ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain colostrum.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 300W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 22:
the oleic acid nanoemulsion loaded with chemotherapeutic drugs is prepared clinically for interventional operation (taking docetaxel coupled oleic acid as an example)
Iodine oil medicine carrying: oleic acid 5ml (10 ml/0.5 pieces), docetaxel 80mg (docetaxel injection, 2.0 ml; and (5) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded iodized oil.
Preparing a water phase: 15ml of 0.9% sodium chloride injection, 1.13g of poloxamer and 375mg of soybean phospholipid are added, the mixture is heated in water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the 0.9% sodium chloride injection is added to be constant volume to be 20ml, and the mixture is kept at 60 ℃ for standby.
Oil phase preparation and colostrum preparation: loading iodine oil into water bath at 60 deg.C, adding 0.25g glyceryl monostearate and 0.27ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain primary emulsion.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 300W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 23:
the eicosapentaenoic acid (EPA) nanoemulsion loaded with the chemotherapeutics is clinically prepared for interventional operation (taking vinorelbine coupled EPA as an example)
Drug coupling: 0.1ml of EPA, adding EDCI 60mg and sulfo-NSH 20mg, shaking and dissolving at room temperature for later use; 3ml of vinorelbine tartrate injection (1ml.
Preparing a water phase: adding 15ml of 0.9% sodium chloride injection, adding 188.13g of poloxamer and 375mg of soybean phospholipid, heating in water bath at 60 ℃, stirring, adding 0.9% sodium chloride injection to a constant volume of 17ml after completely dissolving, adding the drug fatty acid conjugate solution, stirring and mixing uniformly, and keeping the temperature at 60 ℃ for later use.
Oil phase preparation and colostrum preparation: placing 5ml of EPA in water bath at 60 ℃, adding 0.25g of glyceryl monostearate and 0.27ml of tricaprylin under stirring, adding an isothermal water phase after the glyceryl monostearate is melted, adjusting the pH value to 6.5-7.0 by using 10% sodium carbonate, and continuously stirring for 30min to obtain primary emulsion.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 300W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 24:
the iodized oil nanoemulsion loaded with chemotherapeutic drugs is clinically prepared for interventional operation (taking epirubicin coupled soybean phospholipid as an example)
Iodine oil drug loading: adding epirubicin hydrochloride 30mg (epirubicin hydrochloride for injection, 10 mg/bottle 3 bottles), soybean phospholipid (for injection) 300mg, EDCI 80mg, heating in water bath at 60 ℃ and stirring for reaction for 4h; and (5) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded iodized oil.
Preparing a water phase: 30ml of 0.9 percent sodium chloride injection, 2.25g of poloxamer and 450mg of soybean phospholipid are added, the mixture is heated in water bath at 60 ℃ and stirred, after complete dissolution, the 0.9 percent sodium chloride injection is added to be constant volume to 40ml, and the mixture is kept warm at 60 ℃ for standby.
Oil phase preparation and colostrum preparation: loading iodine oil in water bath at 60 deg.C, adding 0.5g glyceryl monostearate and 0.53ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain colostrum.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 300W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 25:
the palmitoleic acid nanoemulsion loaded with chemotherapeutic drugs is clinically prepared for interventional operation (taking Raltitrexed coupling polyene phosphatidyl choline as an example)
Drug coupling and aqueous phase preparation: 15ml (5ml, 232.5mg,3 pieces) of polyene phosphatidyl choline injection, 4mg of raltitrexed (raltitrexed for injection, 2 mg/bottle 2 bottles), 10mg of EDCI, 10mg of Sulfo-NSH, reacting for 2 hours under stirring at room temperature, performing suction filtration by using a G1 sand core filter funnel after the reaction is finished, and adding 0.9% sodium chloride injection into the filtrate to fix the volume to 40ml for later use.
Oil phase preparation and colostrum preparation: placing palmitoleic acid 5ml in 40 deg.C water bath, adding vitamin E injection 5ml (1ml.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 500W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 26:
the clinical preparation of the chemotherapy drug loaded decatetraenoic acid nanoemulsion is used for interventional surgery (taking 5-fluorouracil coupled polyene phosphatidyl choline as an example)
Drug coupling and aqueous phase preparation: 15ml (5 ml, 232.5mg,3 pieces) of polyene phosphatidyl choline injection, 4mg of raltitrexed (raltitrexed for injection, 2 mg/bottle 2 bottles), 10mg of EDCI, 10mg of Sulfo-NSH are added, the mixture is stirred at room temperature and reacts for 2 hours, after the reaction is finished, the mixture is filtered by a G1 sand core filter funnel, and 0.9% sodium chloride injection is added into the filtrate to be constant volume to 40ml for standby.
Oil phase preparation and colostrum preparation: placing 5ml of decatetraenoic acid in 40 deg.C water bath, adding 5ml of vitamin E injection (1ml.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 500W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 27:
the linoleic acid nanoemulsion loaded with the chemotherapeutic drug is clinically prepared for interventional operation (taking nedaplatin coupled linoleic acid as an example)
Linoleic acid drug loading: refining 10ml of linoleic acid, adding 0.1g of nedaplatin (nedaplatin for injection, 50 mg/bottle 2 bottles), 0.2g of EDCI, heating in water bath at 60 ℃, stirring, and reacting for 4 hours; and (4) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded linoleic acid.
Preparing a water phase: 30ml of iodixanol injection is added with 188.25g of poloxamer and 750mg of soybean phospholipid, the mixture is heated in water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the iodixanol injection is added to fix the volume to 40ml, and the mixture is kept warm at 60 ℃ for standby.
Oil phase preparation and colostrum preparation: loading linoleic acid into water bath at 60 deg.C, adding 0.5g glyceryl monostearate and 0.53ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain colostrum.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 300W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 28:
the ibuprofen linoleic acid ethyl ester loaded nano emulsion is prepared and loaded clinically for interventional operation (taking ibuprofen coupled lauryl alcohol as an example)
And (3) carrying out medicine loading by using ethyl linoleate: adding 1.6g of ibuprofen, 1.45g of lauryl alcohol and 1.5g of EDCI into 10ml of ethyl linoleate, heating in a water bath at 60 ℃, stirring and reacting for 4 hours; and (4) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded linoleic acid ethyl ester.
Preparing a water phase: 30ml of 0.9% sodium chloride injection, 2.25g of poloxamer and 750mg of soybean phospholipid are added, the mixture is heated in water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the 0.9% sodium chloride injection is added to be constant volume to 40ml, and the mixture is kept warm at 60 ℃ for standby.
Oil phase preparation and colostrum preparation: loading linoleic acid ethyl ester into water bath at 60 deg.C, adding 0.5g glyceryl monostearate and 0.53ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain colostrum.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 300W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 29:
the iodized oil nanoemulsion loaded with small molecular targeted drugs is clinically prepared for interventional operation (taking the ranvatinib coupled lauric acid as an example)
Iodine oil medicine carrying: 5ml of iodized oil injection (10 ml/branch x 0.5 branch), 12mg of methylsulfonic acid lunvatinib, 15mg of lauric acid, 15mg of EDCI, heating in water bath at 60 ℃, stirring and reacting for 4 hours; and (5) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded iodized oil.
Preparing a water phase: 10ml of 0.9% sodium chloride injection is added with 1.13g of poloxamer, heated in water bath at 60 ℃ and stirred, after being completely dissolved, 10ml of polyene phosphatidyl choline injection (5ml.
Preparing an oil phase and preparing primary emulsion: loading iodine oil into water bath at 60 deg.C, adding 0.25g glyceryl monostearate and 0.27ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain primary emulsion.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 300W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 30:
linolenic acid nanoemulsion loaded with VEGF antibody medicine is clinically prepared for interventional operation (taking bevacizumab coupling linolenic acid as an example)
Drug coupling and aqueous phase preparation: linolenic acid 0.1ml, EDCI 70mg, sulfo-NSH 80mg are added, and shaking dissolution is carried out at room temperature; 12ml (100mg.
Oil phase preparation and colostrum preparation: placing 5ml of linolenic acid in a water bath at 40 ℃, adding 0.25g of glyceryl monostearate and 0.27ml of tricaprylin under stirring, adding an isothermal water phase after the glyceryl monostearate is dissolved, adjusting the pH value to 6.5-7.0 by using 10% sodium carbonate, and continuously stirring for 30min to obtain primary emulsion.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 500W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 31:
the linoleic acid nanoemulsion targeting PD-1 antibody drug is clinically prepared for interventional operation (taking nivolumab coupling linoleic acid as an example)
Drug coupling and aqueous phase preparation: 0.1ml of linoleic acid, EDCI 60mg and sulfo-NSH 66mg are added, and the mixture is shaken and dissolved at room temperature; 16ml of the nauzumab injection (40mg.
Preparing an oil phase and preparing primary emulsion: placing linoleic acid 5ml in water bath at 40 deg.C, adding glyceryl monostearate 0.25g and glyceryl tricaprylate 0.27ml under stirring, dissolving glyceryl monostearate, adding isothermal water phase, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain primary emulsion.
Ultrasonic emulsification: subjecting the primary emulsion to ultrasonic treatment, setting ultrasonic power at 500W, and working for 30min to obtain nanometer emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 32:
the chemotherapy drug-carrying docosahexaenoic acid (DHA) nanoemulsion is clinically prepared for intravenous injection (taking vincristine coupled DHA as an example)
Carrying out DHA medicine loading: 5ml of DHA, adding 2mg of vincristine sulfate (vincristine sulfate for injection, 1 mg/bottle, 2 bottles), heating in EDCI 10mg of water bath at 60 ℃, stirring, and reacting for 4h; and (5) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the medicine-carrying DHA.
Preparing a water phase: 40ml of 0.9 percent sodium chloride injection, 1.13g of poloxamer and 375mg of soybean phospholipid are added, the mixture is heated in water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the 0.9 percent sodium chloride injection is added to be constant volume to 45ml, and the mixture is kept warm at 60 ℃ for standby.
Preparing an oil phase and preparing primary emulsion: putting the DHA-carrying medicine in a water bath at 60 ℃, adding 0.25g of glyceryl monostearate and 0.27ml of glyceryl tricaprylate under stirring, adding an isothermal water phase after the glyceryl monostearate is melted, adjusting the pH value to 6.5-7.0 by using 10% sodium carbonate, and continuously stirring for 30min to obtain colostrum.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is circulated for three times at 800bar, so that the nano emulsion is prepared. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 33:
the soybean oil nanoemulsion carrying the chemotherapeutic drug is clinically prepared for intravenous injection (taking nimustine hydrochloride coupled with myristic acid as an example)
Carrying out soybean oil medicine loading: adding 0.5g of myristic acid, 150mg of nimustine hydrochloride (nimustine hydrochloride for injection, 25 mg/bottle, 6 bottles) and 0.45g of EDCI into 10ml of soybean oil for injection, heating in a water bath at 60 ℃, stirring, and reacting for 4 hours; and (5) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded soybean oil.
Preparing a water phase: 80ml of 0.9% sodium chloride injection, 2.25g of poloxamer 188 and 750mg of soybean lecithin are added, the mixture is heated in water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the 0.9% sodium chloride injection is added to be constant volume to 90ml, and the mixture is kept warm at 60 ℃ for standby.
Oil phase preparation and colostrum preparation: loading soybean oil into water bath at 60 deg.C, adding 0.5g glyceryl monostearate and 0.53ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain primary emulsion.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is circulated for three times at 800bar, so that the nano emulsion is prepared. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 34:
the octanoic acid nanoemulsion loaded with chemotherapeutic drugs is clinically prepared for intravenous injection (taking mitoxantrone coupled polyene phosphatidylcholine as an example)
Drug coupling and aqueous phase preparation: 5ml of polyene phosphatidyl choline injection (5ml, 232.5mg and 1 branch), adding EDCI 70mg, shaking and dissolving at room temperature for later use; 10ml (5 mg, 5ml, using 2 bottles) of mitoxantrone hydrochloride injection, slowly dripping the pretreated polyene phosphatidyl choline injection into the injection under room temperature stirring, stirring the injection at room temperature after dripping is finished to react for 2 hours, performing suction filtration by using a G1 sand core filter funnel after the reaction is finished, adding 15ml of polyene phosphatidyl choline injection into the filtrate, and then adding 0.9% sodium chloride injection to fix the volume to 85ml for later use.
Oil phase preparation and colostrum preparation: placing 10ml of octanoic acid in 40 deg.C water bath, adding 5ml of vitamin E injection (1ml.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is 800bar for three times, so as to prepare the nano emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 35
Clinical preparation of methyl palmitoleate nanoemulsion loaded with analgesic for intravenous injection (taking flurbiprofen coupled tetradecanol as an example)
Palm methyl oleate drug loading: adding 10ml of methyl palmitoleate, adding 176mg of tetradecanol, 200mg of flurbiprofen, 160mg of EDCI, heating in water bath at 60 ℃, stirring, and reacting for 4 hours; and (4) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded methyl palmitate.
Preparing a water phase: 80ml of 0.9% sodium chloride injection, 2.25g of poloxamer 188 and 750mg of soybean lecithin are added, the mixture is heated in water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the 0.9% sodium chloride injection is added to be constant volume to 90ml, and the mixture is kept warm at 60 ℃ for standby.
Oil phase preparation and colostrum preparation: putting the drug-loaded methyl palmitate in a water bath at 60 ℃, adding 0.5g of glyceryl monostearate and 0.53ml of glyceryl tricaprylate under stirring, adding an isothermal water phase after the glyceryl monostearate is melted, adjusting the pH value to 6.5-7.0 by using 10% sodium carbonate, and continuously stirring for 30min to obtain primary emulsion.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is circulated for three times at 800bar, so that the nano emulsion is prepared. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 36:
the camellia oil nanoemulsion loaded with small molecule targeted drugs is clinically prepared for intravenous injection (taking the coupling lauric acid of vemurafenib as an example)
Carrying out drug loading on camellia oil: 20ml of camellia oil for injection, 0.96g of vemurafenib, 0.79g of lauric acid and 0.76g of EDCI, heating in a water bath at 50 ℃, stirring and reacting for 4 hours; and (5) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded camellia oil.
Preparing a water phase: 160ml of 0.9% sodium chloride injection, 4.5g of poloxamer and 1.5g of soybean phospholipid are added, the mixture is heated in a water bath at 60 ℃ and stirred, after the mixture is completely dissolved, the 0.9% sodium chloride injection is added to be constant volume to 180ml, and the mixture is kept warm at 50 ℃ for standby.
Oil phase preparation and colostrum preparation: placing the camellia oil carrying the medicine in a water bath at 50 ℃, adding 1g of glyceryl monostearate and 1.1ml of glyceryl tricaprylate under stirring, adding an isothermal water phase after the glyceryl monostearate is melted, adjusting the pH to 6.5-7.0 by using 10% sodium carbonate, and continuously stirring for 30min to obtain primary emulsion.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is 800bar for three times, so as to prepare the nano emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 37:
the linolenic acid nanoemulsion loaded with small molecular targeted drugs is clinically prepared for intravenous injection (taking the tassitat coupling linolenic acid as an example)
Linolenic acid carrying medicine: 20ml of refined linolenic acid, 0.8g of tasstat hydrobromide, 0.5g of EDCI, heating in a water bath at 50 ℃ and stirring for reacting for 4 hours; and (4) carrying out suction filtration by using a G1 sand core funnel, and collecting filtrate to obtain the drug-loaded linolenic acid.
Preparing a water phase: 160ml of 0.9% sodium chloride injection, 4.5g of poloxamer and 1.5g of soybean phospholipid are added, the mixture is heated in a water bath at 60 ℃ and stirred, the 0.9% sodium chloride injection is added after the mixture is completely dissolved, the volume is adjusted to 180ml, and the mixture is kept at 50 ℃ for standby.
Oil phase preparation and colostrum preparation: loading linolenic acid into 50 deg.C water bath, adding 1g glyceryl monostearate and 1.1ml glyceryl tricaprylate under stirring, adding isothermal water phase after glyceryl monostearate melts, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain colostrum.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is 800bar for three times, so as to prepare the nano emulsion. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 38:
clinically, an antibody drug of docosahexaenoic acid (DHA) nano-emulsion targeting HER2 is prepared for intravenous injection (taking trastuzumab coupling DHA as an example)
Drug coupling and aqueous phase preparation: 0.12ml of DHA, adding EDCI 70mg and sulfo-NSH 75mg, shaking and dissolving at room temperature for later use; taking a trastuzumab 1 bottle for injection (containing 440mg of trastuzumab), adding 20mL of water for injection to dissolve, transferring the mixture into a beaker, slowly dropwise adding activated DHA while stirring, stirring at room temperature for reaction for 2h after the dropwise addition is finished, performing suction filtration by using a G1 sand core filter funnel after the reaction is finished, adding 40mL (5ml, 232.5mg,4 pieces) of polyene phosphatidylcholine injection into the filtrate, heating and stirring in a 40 ℃ water bath, adding 0.9% sodium chloride injection after the complete dissolution to fix the volume to 90ml, and performing heat preservation in a 40 ℃ water bath for later use.
Oil phase preparation and colostrum preparation: putting 10ml of DHA into a water bath at 40 ℃, adding 0.5g of glyceryl monostearate and 0.53ml of glyceryl tricaprylate under stirring, adding an isothermal water phase after the glyceryl monostearate is dissolved, adjusting the pH value to 6.5-7.0 by using 10% sodium carbonate, and continuously stirring for 30min to obtain primary emulsion.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is circulated for three times at 800bar, so that the nano emulsion is prepared. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 39:
the antibody drug of CTLA-4 targeted oleic acid nanoemulsion is clinically prepared for intravenous injection (taking ipilimumab coupled oleic acid as an example)
Drug coupling and aqueous phase preparation: 0.1ml of oleic acid, EDCI 60mg and sulfo-NSH 66mg are added, and shaking dissolution is carried out at room temperature for standby; 30ml of ipilimumab injection (50mg, 10ml,3 bottles), slowly dropwise adding activated DHA while stirring, stirring at room temperature for reacting for 2 hours after dropwise adding, performing suction filtration by using a G1 sand core filter funnel after the reaction is finished, adding 40ml of polyene phosphatidyl choline injection (5ml, 232.5mg,4 pieces) into filtrate, heating and stirring in water bath at 40 ℃ by 188.25g of poloxamer, adding 0.9% sodium chloride injection after complete dissolution, fixing the volume to 90ml, and performing heat preservation in water bath at 40 ℃ for later use.
Preparing an oil phase and preparing primary emulsion: placing 10ml of oleic acid in 40 deg.C water bath, adding 0.5g of glyceryl monostearate and 0.53ml of glyceryl tricaprylate under stirring, adding isothermal water phase when glyceryl monostearate is dissolved, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain primary emulsion.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is circulated for three times at 800bar, so that the nano emulsion is prepared. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 40:
clinically, the linoleic acid nanoemulsion targeting PD-1 antibody drug is prepared for intravenous injection (pembrolizumab coupled with linoleic acid is taken as an example)
Drug coupling and aqueous phase preparation: 0.1ml of linoleic acid, adding EDCI 65mg and sulfo-NSH 70mg, shaking and dissolving at room temperature for later use; 8ml of pembrolizumab injection (100mg, 4ml,2 bottles), slowly dropwise adding activated linoleic acid under stirring, stirring at room temperature for reacting for 2 hours after dropwise adding, performing suction filtration by using a G1 sand core filter funnel after the reaction is finished, adding 20ml of polyene phosphatidyl choline injection (5ml, 232.5mg,2 pieces) into filtrate, heating and stirring in water bath at 40 ℃ by 188.13g of poloxamer, adding 0.9% sodium chloride injection after complete dissolution to fix the volume to 95ml, and performing heat preservation in water bath at 40 ℃ for later use.
Oil phase preparation and colostrum preparation: placing linoleic acid 5ml in water bath at 40 deg.C, adding glyceryl monostearate 0.25g and glyceryl tricaprylate 0.27ml under stirring, adding isothermal water phase when glyceryl monostearate is dissolved, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain colostrum.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is circulated for three times at 800bar, so that the nano emulsion is prepared. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
Example 41:
clinically prepared antibody drug eicosapentaenoic acid (EPA) nano-emulsion targeting PDL-1 for intravenous injection (taking atelizumab coupled with EPA as an example)
Drug coupling and aqueous phase preparation: 0.3ml of EPA, 0.18g of EDCI and 0.21g of sulfo-NSH are added, and the mixture is shaken and dissolved at room temperature for standby; 20ml of alemtuzumab injection (1200mg, 20ml,1 bottle), slowly dripping activated EPA under stirring, stirring at room temperature for reacting for 2 hours after dripping, performing suction filtration by using a G1 sand core filter funnel after reaction, adding 4.5g of poloxamer 188 into filtrate, heating in a water bath at 40 ℃, stirring, completely dissolving, adding 0.9% sodium chloride injection to fix the volume to 180ml, and keeping the temperature in the water bath at 40 ℃ for later use.
Preparing an oil phase and preparing primary emulsion: placing 20ml EPA in 40 deg.C water bath, adding 1g glyceryl monostearate and 1.1ml glyceryl tricaprylate under stirring, adding isothermal water phase when glyceryl monostearate is dissolved, adjusting pH to 6.5-7.0 with 10% sodium carbonate, and stirring for 30min to obtain primary emulsion.
High-pressure homogenizing and emulsifying: the obtained primary emulsion is further emulsified under high pressure by an APV 1000 high-pressure homogenizer, and the pressure is circulated for three times at 800bar, so that the nano emulsion is prepared. Refrigerating at 4 deg.C for use. Sterilized by filtration through a 0.22 μm filter before use.
In summary, after reading the document of the present invention, those skilled in the art can make various other corresponding changes according to the technical scheme and technical concept of the present invention without creative mental labor, and different application scenarios all belong to the protection scope of the present invention.

Claims (12)

1. A drug-loaded fatty acid nanoemulsion comprising a dispersed phase and a continuous phase; the dispersed phase comprises a dispersed phase and a continuous phase, wherein the dispersed phase consists of a medicament-lipid compound, fatty acid/fatty acid derivative and a phospholipid membrane;
the drug loading mode of the dispersed phase is one of the following two types:
1) The drug and the lipid form a drug-lipid complex which is uniformly dispersed in the fatty acid or the derivative thereof, and the drug-lipid complex, the fatty acid or the derivative thereof are wrapped in the phospholipid membrane;
2) When the lipid selected is a phospholipid, the drug forms a drug-phospholipid complex with the phospholipid, the drug is bound to the phospholipid membrane, and the fatty acid or derivative thereof is encapsulated in the phospholipid membrane.
The continuous phase comprises one or more of distilled water, 0.9% sodium chloride solution, 5% glucose solution, ringer's solution, sodium bicarbonate solution, sodium lactate solution, water-soluble contrast agent solution, water-soluble surfactant solution, acetate buffer solution, citrate buffer solution, phosphate buffer solution, tromethamine buffer solution, carbonate buffer solution, hydrochloric acid solution, sodium hydroxide solution and sodium carbonate solution.
2. The drug-loaded fatty acid nanoemulsion of claim 1, wherein the drug is bound to lipids (including phospholipids) through intermolecular forces or covalent bonds.
3. The drug-loaded fatty acid nanoemulsion of claim 2, wherein the covalent bond linkage comprises a direct amide bond or ester bond linkage of the drug molecule to a lipid (including phospholipid) molecule, or a linkage bridge linkage, forming a hydrazone bond, imine bond, oxime bond, silicon ether bond, maleate diester bond, disulfide bond, diselenide bond, thioether bond, selenoether bond, peptide bond, galactoside bond, glucuronide bond, sulfate bond, pyrophosphate bond.
4. The drug-loaded fatty acid nanoemulsion of claim 3, wherein the connecting bridge is one or more of a molecule or a polymer of molecules or a block polymer; the polymer or block polymer comprises one or more of polyamino acid, polypeptide or oligopeptide, polysaccharide or oligosaccharide, polyether, polyester, modified or end-modified polyether/polyester and block polymer formed by polyether and/or polyester.
5. The drug-loaded fatty acid nanoemulsion of claim 1, wherein the lipid comprises one or more of fatty alcohols, fatty acids, fatty acid esters, fatty acid glycerides, phospholipids, steroids, liposoluble vitamins, and derivatives of the foregoing lipids;
preferably, the drug comprises one or more of systemic chemotherapeutic drugs, small molecule targeted drugs, antibodies and protein drugs, local anesthetics, analgesics, radionuclides, and imaging agents for tracking;
further preferably, the medicine comprises raw material medicines of the medicine and a clinical injection preparation containing the medicine, and the clinical injection preparation comprises injection and freeze-dried powder for injection;
preferably, the fatty acid/fatty acid derivative is any one of liquid fatty acid, liquid fatty acid monohydric alcohol ester and liquid fatty acid glyceride, or a mixture of any two or more of the liquid fatty acid/fatty acid derivatives, or a mixture of any one of the liquid fatty acid/fatty acid derivatives and one or more liquid and/or non-liquid fatty acid/fatty acid derivatives;
further preferably, the fatty acid/fatty acid derivative is preferably a liquid fatty acid, a liquid fatty acid glyceride;
further preferably, the liquid fatty acid glyceride comprises a vegetable oil, a vegetable oil derivative; the vegetable oil derivative includes organic iodine compound of vegetable oil and iodine, such as iodized oil and ethyl iodized oil.
6. A method of preparing the drug-loaded fatty acid nanoemulsion of any one of claims 1-5, characterized in that the method of preparation is one of the two following:
1) Taking drug-loaded fatty acid/fatty acid derivative as an oil phase, adding phospholipid, auxiliary lipid, surfactant and water phase to mix into primary emulsion, and then uniformly dispersing to obtain the emulsion;
2) Taking fatty acid/fatty acid derivative containing drug-phospholipid complex as oil phase, adding phospholipid, auxiliary lipid, surfactant and water phase, mixing to obtain colostrum, and uniformly dispersing to obtain the final product, wherein the drug-phospholipid complex participates in formation of phospholipid membrane.
7. The method of claim 6, wherein the drug-loaded fatty acid/fatty acid derivative is prepared by combining a drug with a lipid via a covalent bond, purifying, removing the solvent, and drying to obtain a product, redissolving the product in a mixture of the drug and the lipid dispersed in the fatty acid/fatty acid derivative; or a mixture obtained by bonding the drug and the lipid in the fatty acid/fatty acid derivative by intermolecular force or covalent bond, and filtering to remove insoluble substances.
8. The method of claim 6, comprising the steps of:
1) Taking fatty acid or derivatives thereof as a reaction medium, carrying out coupling reaction on the bulk drug of the medicament or a preparation for clinical injection containing the medicament, lipid and connecting bridge molecules added according to needs under the action of a catalyst, and filtering to remove insoluble substances to obtain medicament-carrying fatty acid/fatty acid derivatives;
2) Taking the drug-loaded fatty acid/fatty acid derivative as an oil phase, adding phospholipid, auxiliary lipid, a surfactant and a water phase to mix into primary emulsion, and then uniformly dispersing to obtain the drug-loaded fatty acid nano emulsion.
9. The method according to claim 6, wherein the fatty acid/fatty acid derivative comprising the drug-phospholipid complex is a mixture obtained by re-dissolving and dispersing a product obtained by covalently bonding a drug and a phospholipid, purifying, removing a solvent, and drying in a fatty acid/fatty acid derivative; or a mixture obtained by bonding the drug and phospholipid in fatty acid/fatty acid derivative by intermolecular force or covalent bond, and filtering to remove insoluble substances.
10. The method of claim 6, comprising the steps of:
1) Taking fatty acid or derivatives thereof as a reaction medium, carrying out coupling reaction on the raw material medicine of the medicine or a clinical injection preparation containing the medicine, phospholipid and a connecting bridge molecule added according to needs under the action of a catalyst, and filtering to remove insoluble substances to obtain the fatty acid/fatty acid derivatives containing the medicine-phospholipid complex;
2) Taking fatty acid/fatty acid derivative containing drug-phospholipid complex as oil phase, adding phospholipid, auxiliary lipid, surfactant and water phase, mixing to obtain colostrum, and uniformly dispersing to obtain the final product, wherein the drug-phospholipid complex participates in formation of phospholipid membrane.
11. The method of any one of claims 6 to 10, wherein the phospholipid comprises a glycerophospholipid and a sphingomyelin, wherein the glycerophospholipid comprises one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, and derivatives of the aforementioned phospholipids;
preferably, the helper lipid comprises one or more of fatty acid monoalcohol esters, fatty acid glycerides, glycerophospholipids, sphingomyelins, steroids, fat-soluble vitamins, and derivatives of the foregoing lipids;
preferably, the surfactant includes one or more of sorbitan fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene glyceryl ether fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymer, alkyl glycoside, sucrose fatty acid ester, mannosylerythritol ester, N-fatty acyl-N-methylglucamine, and cholate;
preferably, the aqueous phase comprises one or more of distilled water, 0.9% sodium chloride injection, 5% glucose injection, ringer's injection, sodium lactate injection, sodium bicarbonate injection, water-soluble contrast agent injection/solution, pH adjuster, water-soluble surfactant solution;
the pH regulator comprises one or more of acetate buffer solution, citrate buffer solution, phosphate buffer solution, tromethamine buffer solution, carbonate buffer solution, hydrochloric acid solution, sodium hydroxide solution and sodium carbonate solution;
the water-soluble surfactant solution comprises one or more of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene glyceryl ether fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymer, alkyl glycoside, sucrose fatty acid ester, mannosylerythritol ester, N-fatty acyl-N-methylglucamine and cholate, and is dissolved or dispersed in water to form a solution;
the water-soluble contrast agent injection/solution comprises a clinical injection or a water solution of raw material medicines containing any one of iotalopram, ioflunol, iopamidol, iohexol, iodixanol and iomeprol;
preferably, the volume ratio of the oil phase to the water phase is 1;
the total amount of the auxiliary lipid and the surfactant is 3 to 15 percent of the total system;
preferably, the mixing temperature of the primary emulsion is 25-60 ℃, and the stirring time is 10-30min;
preferably, the dispersion method comprises high-speed shearing homogenization, or high-pressure filter membrane extrusion, or ultrasonic dispersion, or high-pressure slit homogenization, or supercritical method dispersion; the rotating speed of the high-speed shearing homogenization method is 3000-30000rpm/min;
the extrusion pressure of the high-pressure filter membrane is 0.1-0.5MPa, and the membrane aperture is 0.22um;
the power of ultrasonic dispersion is 140-1000W, and the ultrasonic time is 10-30min;
the working pressure of the high-pressure slit homogenization is 10-100MPa, and the circulation is carried out for 2-5 times;
the reaction pressure of the supercritical method is 7-25 MPa, the reaction temperature is 40-60 ℃, and the action time is 1-4h.
12. The use of the drug-loaded fatty acid nanoemulsion of any one of claims 1-5 for the treatment of malignant tumors by local injection into arteries, veins, lymphatic vessels or tumors.
CN202210480219.0A 2022-05-05 2022-05-05 Drug-loaded fatty acid nanoemulsion and preparation method and application thereof Pending CN115400079A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200197534A1 (en) * 2017-05-18 2020-06-25 The Regents Of The University Of California Nano-enabled immunotherapy in cancer
CN112933044A (en) * 2020-12-17 2021-06-11 太阳雨林（厦门）生物医药有限公司 Drug-loaded oil preparation for treating malignant tumor, preparation method and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200197534A1 (en) * 2017-05-18 2020-06-25 The Regents Of The University Of California Nano-enabled immunotherapy in cancer
CN112933044A (en) * 2020-12-17 2021-06-11 太阳雨林（厦门）生物医药有限公司 Drug-loaded oil preparation for treating malignant tumor, preparation method and application

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