WO2015085666A1 - Irinotecan nanolipid preparation and preparation method therefor - Google Patents
Irinotecan nanolipid preparation and preparation method therefor Download PDFInfo
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- WO2015085666A1 WO2015085666A1 PCT/CN2014/070813 CN2014070813W WO2015085666A1 WO 2015085666 A1 WO2015085666 A1 WO 2015085666A1 CN 2014070813 W CN2014070813 W CN 2014070813W WO 2015085666 A1 WO2015085666 A1 WO 2015085666A1
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- WIPO (PCT)
- Prior art keywords
- irinotecan
- preparation
- lipid
- weight
- parts
- Prior art date
Links
- 229960004768 irinotecan Drugs 0.000 title claims abstract description 275
- 238000002360 preparation method Methods 0.000 title claims abstract description 226
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 title claims abstract description 111
- -1 polyethylene Polymers 0.000 claims abstract description 196
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 160
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 96
- 239000000243 solution Substances 0.000 claims abstract description 92
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 49
- 238000002347 injection Methods 0.000 claims abstract description 31
- 239000007924 injection Substances 0.000 claims abstract description 31
- 239000004698 Polyethylene Substances 0.000 claims abstract description 29
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- 239000003125 aqueous solvent Substances 0.000 claims abstract description 12
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- 238000000034 method Methods 0.000 claims description 33
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- 229940090044 injection Drugs 0.000 claims description 27
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- 239000002504 physiological saline solution Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 17
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 12
- 239000003002 pH adjusting agent Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 230000002528 anti-freeze Effects 0.000 claims description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229940093181 glucose injection Drugs 0.000 claims description 9
- 239000008215 water for injection Substances 0.000 claims description 8
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 7
- 229960000304 folic acid Drugs 0.000 claims description 7
- 235000019152 folic acid Nutrition 0.000 claims description 7
- 239000011724 folic acid Substances 0.000 claims description 7
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000004380 Cholic acid Substances 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 235000019416 cholic acid Nutrition 0.000 claims description 6
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 6
- 229960002471 cholic acid Drugs 0.000 claims description 6
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
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- 239000007798 antifreeze agent Substances 0.000 claims description 5
- 238000010253 intravenous injection Methods 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000010255 intramuscular injection Methods 0.000 claims description 3
- 239000007927 intramuscular injection Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000010254 subcutaneous injection Methods 0.000 claims description 3
- 239000007929 subcutaneous injection Substances 0.000 claims description 3
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 claims description 2
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
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- UOHPEWIBMAQKCN-UHFFFAOYSA-N 1,3,5,5,6-pentafluoro-1,3-diazinane-2,4-dione Chemical compound FC1C(C(N(C(N1F)=O)F)=O)(F)F UOHPEWIBMAQKCN-UHFFFAOYSA-N 0.000 description 1
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- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
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- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
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- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical group Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to the technical field of pharmaceutical nano-lipid preparations, in particular to an irinotecan nano-lipid preparation and a preparation method thereof.
- Irinotecan (CPT-11), approved by the FDA in 1998 for standard chemotherapy regimens, for the recurrence and exacerbation of metastatic colorectal cancer, was reapproved by the US FDA following pentafluorouracil (5-FU) for more than 40 years.
- Chemotherapy for first-line treatment of metastatic colorectal cancer It is a derivative of camptothecin that selectively binds to the topoisomerase I and covalently binds to the Topo-DNA complex to form a stable Topo-drug-DNA complex, thereby inhibiting the DNA re-ligation step, resulting in a DNA strand. The break, the appearance of apoptosis.
- CPT-11 has obvious toxicity, and it also affects normal cells while inhibiting cancer cells.
- the dosage form currently available on the market is irinotecan hydrochloride intravenous infusion concentrate, the drug name is Campto. It is mainly used for the treatment of patients with advanced colorectal cancer. As a single drug, it is treated in patients who have failed treatment with 5-fluorouracil chemotherapy. At the same time, irinotecan is being used in a variety of clinical trials for gastric cancer and esophageal cancer.
- the first method from the beginning to the application of the clinical cycle, consumes a lot of manpower and material resources; the second method greatly shortens the cycle of entering the clinic, saving manpower and material resources. Therefore, it is very important to use an appropriate drug carrier to achieve high efficiency, low toxicity, and reduce toxicity.
- Nano-sized drugs can increase the targeting of chemotherapeutic drugs to a certain extent and greatly reduce the toxic side effects of chemotherapeutic drugs.
- nano-drugs have unique advantages. Animal experiments have shown that nano-sized drugs, after intravenous injection, have higher concentrations of drugs in certain tumors than adjacent normal tissues. This provides a good way to expand the application of anti-tumor drugs.
- the nano-lipid bundle has a particle size of about 100 nm, and the drug can be encapsulated inside the lipid bundle to form an ultra-micro spherical carrier.
- Nanolipids have the following advantages: 1 Targeting: After intravenous administration, it is concentrated in the reticuloendothelial system, 80%-90% is concentrated in the liver and spleen; 2 sustained release: reducing renal excretion and metabolism in the body, prolonging the drug The action time; 3 reduce the toxicity of the drug: Because the nano drug is mainly concentrated in the rich organs of the endothelial reticuloendothelial cells such as the liver, and the concentration of the drug in the heart, kidney and bone marrow is low, thereby reducing the toxicity of the drug to other organs. Side effects; 4 improve the stability of the drug: the molecular layer of the lipid bundle protects the drug and improves stability.
- irinotecan in a nano-sized lipid bundle is one of the important options for reducing its toxic side effects.
- irinotecan nano-lipids there is no report or product application of irinotecan nano-lipids on the market, and its research and development is of great significance.
- the stability of the lipid tract in the blood circulation is the key to the action of the drug carrier.
- Liposomes composed of common phospholipids have a half-life of only ten minutes in vivo. There are many reasons for this: High-density lipoprotein in the blood is the main component that destroys liposomes; liposomes are easily penetrated and lysed by activation of the complement system; phospholipases can degrade phospholipids; serum albumin can combine with phospholipids to form complexes, thereby Reduce the stability of phospholipid composition nanoassemblies. It has been found that surface polyethylene glycol (PEG) can prolong the in vivo cycle time of nanoassemblies.
- PEG surface polyethylene glycol
- PEGylation can achieve steric hindrance and increase the hydrophilicity of the membrane surface.
- PEG-surfaced nanolipids can combine long-circulating, invisible, and steric stabilization to reduce macrophage swallowing It plays an important role in phagocytosis, improving drug targeting, and hindering the binding of blood protein components to phospholipids. Therefore, the traditional phospholipid and FDA-approved new polyethylene glycol-dodecyl stearate (Solutol HS15) can achieve the encapsulation and nanocrystallization of irinotecan, which is beneficial to meet the various needs of clinical applications. Cancer patients are of great significance.
- the object of the present invention is to provide an irinotecan nano-lipid preparation and a preparation method thereof, wherein the irinotecan nano-fat bundle preparation has a uniform particle size, and the lipid bundle preparation can reduce the toxicity of irinotecan and has a long circulation effect. It can enhance tumor targeted enrichment and increase patient compliance; the preparation method is simple in process, highly reproducible and industrially productive.
- the present invention provides an irinotecan nanolipid preparation comprising phospholipid, polyethylene glycol-dodecahydroxystearate, glycerin, ethanol and irinotecan, and an aqueous solution for injection.
- the aqueous solution for injection is a solvent which can be used for injection, which is a solute or a solute containing water, and is not particularly limited.
- the aqueous injection solution is selected from one or more of physiological saline, glucose injection, and water for injection.
- the preparation comprises 4 to 8 parts by weight of phospholipid, 10 to 20 parts by weight of polyethylene glycol-dodecyl stearate, 5 to 15 parts by weight of glycerin, 10 to 20 parts by weight of ethanol and 1 ⁇ 4 parts by weight of irinotecan.
- the content of the phospholipid in the preparation may be 5 parts by weight, 6 parts by weight or 7 parts by weight; the content of the polyethylene glycol-dodecyl stearate may be 12 parts by weight, 14 parts by weight, 16 Parts by weight or 18 parts by weight; glycerin may be 7 parts by weight, 9 parts by weight, 11 parts by weight or 13 parts by weight; the content of ethanol may be 12 parts by weight, 14 parts by weight, 16 parts by weight or 18 parts by weight; Lit The content may be 1.5 parts by weight, 2 parts by weight, 3 parts by weight or 3.5 parts by weight.
- the volume of the aqueous solution for injection is 5-100 times, for example, 6 times the total volume of the phospholipid, polyethylene glycol-dodecyl stearate, glycerin, ethanol, and irinotecan. 8, 8, 10, 15, 20, 80 or 90, preferably 5 to 80, more preferably 10 to 20.
- active targeting materials can be added to the formulation.
- the active targeting material is capable of enhancing the enrichment of the formulation in a tumor.
- the active targeting material is X-polyethylene glycol-distearoylphosphatidylethanolamine (X-PEG-DSPE), wherein X may be folic acid, pentapeptide CRGDK (wherein C represents cysteine, R represents arginine, G represents glycine, D represents aspartic acid, K represents lysine, or one or more of cholic acid, PEG represents polyethylene glycol, and DSPE represents distearoylphosphatidylethanolamine .
- X-PEG-DSPE X-polyethylene glycol-distearoylphosphatidylethanolamine
- the active targeting material X-PEG-DSPE is contained in the preparation in an amount of 0.01 to 2 parts by weight, for example, 0.02 parts by weight, 0.05 parts by weight, 0.1 parts by weight, 0.4 parts by weight, 0.5 parts by weight, 0.8 parts by weight, 1.2 parts by weight, 1.5 parts by weight or 1.8 parts by weight, more preferably 0.1 to 1 part by weight, most preferably 0.1 to 0.4 parts by weight.
- the present invention shows a typical formulation containing an active targeting material as follows: 4 to 8 parts by weight of phospholipid, 10 to 20 parts by weight of polyethylene glycol-dodecyl stearate, 5 to 15 parts by weight of glycerol, 10 to 20 parts by weight of ethanol, 1 to 4 parts by weight of irinotecan and 0.1 to 0.4 parts by weight of active targeting material X-PEG-DSPE, wherein X represents folic acid, pentapeptide CRGDK or cholic acid; and equivalent to the total volume of the above raw materials 10-20 times the aqueous solvent for injection.
- an antifreeze and/or a pH adjuster may be added to the formulation, wherein
- the antifreeze agent is selected from the group consisting of propylene glycol and sorbitol, etc.
- the pH adjuster is selected from the group consisting of citric acid, lactic acid, Na 2 CO 3 , NaOH, N C1, NaHC 0 3 and Ca(OH) 2 , and the like.
- the irinotecan nanolipid preparation can be administered by a conventional administration such as intravenous injection, intramuscular injection or subcutaneous injection.
- the present invention provides a method of preparing the irinotecan nanolipid preparation of the first aspect, comprising:
- the present invention utilizes the micelle function of polyethylene glycol-dodecyl stearate and the solubilizing function of irinotecan, and the size adjustment of phospholipids to polyethylene glycol-dodecyl stearate micelles. Function, after the self-emulsification process, the preparation of irinotecan nanolipids is achieved.
- the method for preparing the clear transparent solution in the step (1) can be various, and the phospholipid, the polyethylene glycol-dodecyl stearate, the glycerin, the ethanol and the y Liticon is mixed together and a clear, clear solution is obtained by external force such as magnetic stirring, mechanical agitation, ultrasonication, heating, homogenizer homogenization or a combination thereof.
- the ingredients in the above formula may be added to the container at one time for mixing treatment, or a part of the ingredients in the formula may be added first, and after stirring, another portion is added and mixed to obtain a clear transparent solution.
- the preferred two methods of formulating a clear, transparent solution of the invention are as follows:
- the first method is specifically:
- the second method is specifically:
- the clear transparent solution is a general concept, that is, the presence of invisible particles or precipitates in the naked eye, under the laser irradiation, there is no occurrence of Tyndall phenomenon, and the ultraviolet absorption spectrum is not caused by scattering of particles. extinction.
- the clear transparent solution prepared by the present invention i.e., the irinotecan nanolipid preparation precursor, can be sealed and stored under nitrogen protection conditions. If the formulated clear transparent solution is self-emulsified immediately, it can be stored unsealed.
- the self-emulsification process of the step (2) can be performed by an external force such as gentle or vigorous shock as needed.
- the aqueous solvent for injection is a solvent which can be used for injection, which is a solute containing or containing no solute, and is not particularly limited.
- the aqueous injection solution is selected from one or more of physiological saline, glucose injection, and water for injection.
- the clear transparent solution contains 4 to 8 parts by weight of phospholipid, 10 to 20 parts by weight of polyethylene glycol-dodecyl stearate, 5 to 15 parts by weight of glycerin, and 10 to 20 parts by weight of ethanol. And 1 to 4 parts by weight of irinotecan.
- the content of the phospholipid in the clear transparent solution may be 5 parts by weight, 6 parts by weight or 7 parts by weight; the content of polyethylene glycol-dodecyl stearate may be 12 parts by weight, 14 parts by weight, 16 parts by weight or 18 parts by weight; the content of glycerin may be 7 parts by weight, 9 parts by weight, 11 Parts by weight or 13 parts by weight; the content of ethanol may be 12 parts by weight, 14 parts by weight, 16 parts by weight or 18 parts by weight; the content of irinotecan may be 1.5 parts by weight, 2 parts by weight, 3 parts by weight or 3.5 parts by weight. .
- the clear transparent solution further contains 0.01 to 2 parts by weight of the active targeting material X-PEG-DSPE, wherein X represents one or more of folic acid, pentapeptide CRGDK or cholic acid.
- the clear transparent solution contains 4 to 8 parts by weight of phospholipid, 10 to 20 parts by weight of polyethylene glycol-dodecyl stearate, 5 to 15 parts by weight of glycerin, and 10 to 20 parts by weight of ethanol. 1 to 4 parts by weight of irinotecan and 0.1 to 0.4 parts by weight of the active targeting material X-PEG-DSPE, wherein X represents folic acid, pentapeptide CRGDK or cholic acid.
- the content of the phospholipid in the clear transparent solution may be 5 parts by weight, 6 parts by weight or 7 parts by weight; the content of the polyethylene glycol-dodecyl stearate may be 12 parts by weight and 14 parts by weight. , 16 parts by weight or 18 parts by weight; the content of glycerin may be 7 parts by weight, 9 parts by weight, 11 parts by weight or 13 parts by weight; the content of ethanol may be 12 parts by weight, 14 parts by weight, 16 parts by weight or 18 parts by weight.
- the content of irinotecan may be 1.5 parts by weight, 2 parts by weight, 3 parts by weight or 3.5 parts by weight; the active targeting material X-PEG-DSPE may be 0.02 parts by weight, 0.05 parts by weight, 0.1 parts by weight, 0.4. Parts by weight, 0.5 parts by weight, 0.8 parts by weight, 1.2 parts by weight, 1.5 parts by weight or 1.8 parts by weight.
- the "parts by weight” of the present invention generally means the weight ratio of other raw materials other than the aqueous solvent for injection.
- optional means “with or without” the object to which it refers, such as “optional active targeting material” means “with or without active targeting material”, “anything”
- optional active targeting material means “with or without active targeting material”
- optional active targeting material means "with or without active targeting material”
- anything The selected antifreeze and/or pH adjusting agent “includes” with or without antifreeze and/or pH adjusting agent.
- the volume of the aqueous solution for injection is the clear transparent solution. 5-100 times, for example, 6 times, 8 times, 10 times, 15 times, 20 times, 30 times, 50 times, 70 times, 80 times or 90 times, preferably 5-80 times, more preferably 10-20 times.
- the temperature of the aqueous solvent for injection can be determined empirically by those skilled in the art, and is generally room temperature.
- the temperature of the aqueous solution for injection used in the present invention may be any temperature in the range of 0-80 ° C, preferably 0-40. Any temperature in the °C range.
- the present invention provides a irinotecan nanolipid preparation prepared according to the method of the second aspect, which is administered by intravenous injection, intramuscular injection or subcutaneous injection.
- the irinotecan nano-lipid preparation prepared by the invention can be further processed by lyophilization and other reprocessing processes, and does not affect the redispersion and use of the nano-lipid drug, and the process involved can be industrialized. And directly applied to the development of large-scale drug production.
- the beneficial effects of the present invention are as follows:
- the present invention utilizes the micelle function of polyethylene glycol-dodecyl stearate and the solubilizing function for irinotecan, and the phospholipid to polyethylene glycol-dodecyl stearate
- the size adjustment of the acid ester micelles combined with a simple preparation process of the lipid bundle precursor, prepares the irinotecan nano-lipid preparation precursor (ie, a clear transparent solution); after the self-emulsification process, the irinotecan nano-lipid is realized.
- the preparation of the irinotecan nanolipid bundle prepared by the invention has uniform particle size distribution, and the lipid bundle preparation can reduce the toxicity of irinotecan, has a long circulation effect, can enhance tumor targeted enrichment and increase patient compliance;
- the invention fills the blank of irinotecan nano-lipid drug, and the developed formula has simple process and high repeatability, and can be directly applied to the industrial production of irinotecan nano drug.
- the addition of a primary targeting material to the formulation of the present invention can significantly enhance its enrichment in tumors.
- Fig. 1 is a schematic view showing the preparation of the irinotecan nanolipid precursor of the present invention and the process of obtaining the irinotecan nanolipid preparation after the self-emulsification process.
- Example 2 is an optical photograph showing the precursor of the irinotecan nanolipid preparation obtained in Example 1 of the present invention, showing It is a clear transparent solution.
- Fig. 3 is an optical photograph of the irinotecan nanolipid preparation obtained after self-emulsification of physiological saline, water for injection and glucose injection from left to right, showing that it is an emulsion.
- Fig. 4 is a dynamic light scattering result of the irinotecan nanolipid preparation obtained by the self-emulsification process of physiological saline in Example 1 of the present invention, showing that the particle diameter is uniform.
- Fig. 5 is a transmission electron micrograph of the irinotecan nanolipid preparation obtained after the self-emulsification of physiological saline in Example 1 of the present invention.
- Fig. 6 is a dynamic light scattering result of the irinotecan nanolipid preparation obtained by self-emulsification of water for injection in Example 9 of the present invention, showing that the particle diameter is uniform.
- Fig. 7 is a transmission electron micrograph of the irinotecan nanolipid preparation obtained by freeze-drying and then diluting the water after the self-emulsification process of Example 9 of the present invention.
- Fig. 8 is a dynamic light scattering result of the irinotecan nano-lipid preparation obtained by the self-emulsification process of the glucose injection solution according to the embodiment 10 of the present invention, showing that the particle diameter is uniform.
- Fig. 9 is a transmission electron micrograph of an irinotecan nanolipid preparation obtained by self-emulsification of a glucose injection solution according to Example 10 of the present invention.
- Figure 10 shows the aggregation of surface CRGDK-targeted lipid tract drugs at the tumor site.
- Small animal imaging shows that the lipid tract drug (prepared in Example 1) has obvious aggregation at the tumor site compared with the free drug (fluorescence molecular simulation (top)). (Intermediate), the comparison shows that the CRGDK-targeted lipid tract drug (prepared in Example 17) has a more pronounced tumor enrichment effect (bottom).
- Figure 11 is a tumor pharmacodynamic study of a surface folate-targeted lipid tract drug, and optical photographs show that the folic acid-targeted liposome drug (right) treated group of the tumor of Example 18 after 30 days of treatment and the Example 1
- the prepared lipid tract drug group (middle) was the smallest compared with the free drug group (left), indicating that folic acid targeting can enhance the therapeutic effect of lipid tract drugs because folate-targeted lipid tract drugs have more enhanced tumor enrichment. Effect.
- the process of preparing the irinotecan nano-lipid preparation of the present invention is shown in Figure 1.
- the irinotecan is mixed with phospholipid, polyethylene glycol-dodecyl stearate, glycerin and ethanol (auxiliary).
- the irinotecan nano-lipid drug precursor is prepared by self-emulsification by adding an aqueous solvent for injection to obtain a irinotecan nano-lipid preparation.
- the irinotecan lipid bundle preparation precursor prepared in the first step is diluted with 20 volumes of physiological saline to obtain Irinotecan nano preparations.
- the left tube in Figure 3 shows that the irinotecan lipid bundle formulation is in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England.
- the irinotecan lipid bundle preparation has an average particle diameter of 103.3 nm.
- Figure 4 shows that the irinotecan lipid bundle formulation has a uniform particle size distribution.
- a transmission electron micrograph of the irinotecan lipid bundle preparation prepared in this example is shown in Fig. 5, and shows that the prepared irinotecan lipid bundle preparation is a nanoparticle having a uniform particle diameter.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 4.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle formulation was measured using a ZS90 instrument from Malven Instruments, UK. The result is similar to Figure 4.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle formulation was measured using a ZS90 instrument from Malven Instruments, UK. The result is similar to Figure 4.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan nanoformulation was measured using a ZS90 instrument from Malven Instruments, UK. The result is similar to Figure 4.
- the irinotecan lipid bundle preparation precursor prepared in the first step is diluted with 20 volumes of physiological saline to obtain Irinotecan lipid bundle preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 4.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle formulation was measured using a ZS90 instrument from Malven Instruments, UK. The result is similar to Figure 4.
- irinotecan lipid bundle preparation The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan nanoformulation was measured using a ZS90 instrument from Malven Instruments, UK.
- the average particle size of the irinotecan nanoformulation was 105.9 nm. The result is similar to Figure 4.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of water for injection to obtain a irinotecan lipid bundle preparation.
- the middle tube in Figure 3 shows that the irinotecan lipid bundle formulation is in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England.
- the irinotecan lipid bundle preparation had an average particle diameter of 107.0 nm.
- Figure 6 shows that the irinotecan lipid bundle formulation has a uniform particle size distribution.
- a transmission electron micrograph of the irinotecan lipid bundle preparation prepared in this example is shown in Fig. 7, and shows that the prepared irinotecan lipid bundle preparation is a nanoparticle having a uniform particle diameter.
- Example 10 I Preparation of irinotecan lipid bundle preparation precursor
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of glucose injection to obtain a irinotecan lipid bundle preparation.
- the right tube in Figure 3 shows that the irinotecan lipid bundle formulation is in the form of an emulsion.
- the particle size of the irinotecan nanoformulation was measured using a ZS90 instrument from Malven Instruments, UK.
- Figure 8 shows: The irinotecan lipid bundle formulation has a uniform particle size distribution.
- a transmission electron micrograph of the irinotecan lipid bundle preparation prepared in this example is shown in Fig. 9, and shows that the prepared irinotecan lipid bundle preparation is a nanoparticle having a uniform particle diameter.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 10 volumes of physiological saline to obtain a irinotecan lipid bundle preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 4.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 80 volumes of water for injection to obtain a irinotecan lipid bundle preparation.
- the results were similar to the middle tube in Figure 3, and the irinotecan lipid bundle preparation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 6.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 5 volumes of glucose injection to obtain a irinotecan lipid bundle preparation.
- the results were similar to the right tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 8.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan nano preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England.
- the irinotecan lipid bundle preparation had an average particle diameter of 108 nm.
- the irinotecan lipid bundle preparation has a uniform particle size distribution.
- the results of transmission electron micrographs of the irinotecan lipid bundle preparation prepared in this example are similar to those of FIG.
- the prepared irinotecan drug lipid bundle preparation has a uniform particle size.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan nano preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England.
- the transmission electron micrograph of the irinotecan lipid bundle preparation prepared in this example is similar to that shown in Fig. 5, and the prepared irinotecan lipid bundle preparation is a drug particle having a uniform particle diameter.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan nano preparation.
- the results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the TEM results of the irinotecan lipid bundle preparation prepared in this example are similar to those of Fig. 5, and are all nanoparticles having a uniform particle size.
- the irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan nano preparation.
- the results were similar to the right tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- the irinotecan nanolipid bundle without the CRGDK-PEG-DSPE targeting group was prepared according to the method of Example 1 (the formula does not contain CRGDK-PEG-DSPE), and the DiR dye ethanol solution was added to the formulation, and the volume was 20 times.
- the physiological saline was diluted to obtain irinotecan nanolipid injection B.
- the irinotecan nanolipid bundle with CRGDK-PEG-DSPE targeting group prepared according to the method of Example 17 was added with DiR dye ethanol solution and diluted with 20 volumes of physiological saline to obtain irinotecan nanolipid. Bundle injection C.
- the irinotecan physiological saline solution is Injection A, to which an ethanol solution of DiR dye is added.
- concentrations of the DiR dyes in the above injections A, B and C were controlled to be the same.
- FIG. 10 shows the aggregation of the surface CRGDK-PEG-DSPE targeting lipid tract drug at the tumor site.
- Small animal imaging showed that the lipid tract drug (injection B) had significant aggregation at the tumor site compared with the free drug (injection A).
- the comparison shows that the CRGDK-PEG-DSPE targeting lipid tract drug (injection C) has a more pronounced tumor enrichment effect (bottom).
- Figure 10 illustrates: CRGDK-PEG-DSPE-targeted irinotecan liposome drug has a more pronounced aggregation at the tumor site, which can provide better therapeutic results.
- the irinotecan lipid bundle preparation precursor prepared in the first step is diluted with 20 volumes of physiological saline to obtain Irinotecan nano preparations.
- the results were similar to the right tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
- FIG. 11 shows a tumor pharmacodynamic study of a surface folate-PEG-DSPE targeting lipid tract drug, and an optical photograph showing the folate-PEG-DSPE targeted lipid tract drug prepared in Example 18 after 30 days of treatment ( Right) The tumor in the treatment group was the smallest compared with the liposome drug group (middle) and the free drug group (left) prepared in Example 1, indicating that folic acid-PEG-DSPE targeting can enhance the therapeutic effect of the lipid tract drug because Folic acid-PEG-DSPE targeting lipid tract drugs have a more enhanced tumor enrichment effect.
- Figure 11 shows that irinotecan liposome with folate-PEG-DSPE targeting function can better inhibit tumor growth after the same treatment, which has better therapeutic effect.
- the present invention provides an irinotecan nanolipid preparation prepared by the above examples, which, as a lipid bundle preparation, can reduce the toxicity of irinotecan, has a long circulation effect, can enhance tumor targeted enrichment and increase patient compliance.
Abstract
An irinotecan nanolipid preparation and preparation method therefor. The irinotecan nanolipid preparation comprises phospholipid, polyethylene glycol-12-hydroxystearate, glycerol, ethanol, irinotecan and aqueous solvent for injection. The preparation method comprises mixing phospholipid, polyethylene glycol-12-hydroxystearate, glycerol, ethanol and irinotecan to prepare a clear and transparent solution, then diluting the clear and transparent solution with aqueous solvent for injection, and self-emulsifying to obtain the irinotecan nanolipid preparation.
Description
说 明 书 一种伊立替康纳米脂束制剂及其制备方法 Irinotecan nano-lipid preparation and preparation method thereof
技术领域 Technical field
本发明涉及药物纳米脂束制剂技术领域， 尤其涉及一种伊立替康纳米脂束 制剂及其制备方法。 The invention relates to the technical field of pharmaceutical nano-lipid preparations, in particular to an irinotecan nano-lipid preparation and a preparation method thereof.
背景技术 Background technique
伊立替康 （Irinotecan, CPT-11 ), 1998年获 FDA批准用于标准化疗方案， 治疗转移性结肠直肠癌的复发和恶化， 是 40 多年来美国 FDA继五氟尿嘧啶 (5-FU) 以后再次批准用于转移性结直肠癌一线治疗的化疗药。 它是喜树碱的 衍生物， 选择性地结合抑制拓扑异构酶 I， 与 Topo-DNA复合物共价结合形成稳 定 Topo-药物 -DNA复合物，从而抑制 DNA重连步骤，以致导致 DNA链的断裂， 出现细胞凋亡。对拓扑异构酶 I高表达的小细胞肺癌、百小细胞肺癌、子宫颈癌、 卵巢癌、 结直肠癌等具有更高的疗效。 同其它有效抗肿瘤药物一样， CPT-11 具 有明显的毒性， 在抑制癌细胞的同时， 对正常细胞亦有影响。 目前市场上提供 的剂型为盐酸伊立替康静脉滴注射浓缩液， 药物名称为开普拓（Campto)。 主要 用于晚期大肠癌患者的治疗， 作为单一用药， 治疗经含 5-氟尿嘧啶化疗方案治 疗失败的患者。 同时， 伊立替康应用于胃癌和食管癌的多种临床试验正在进行 中， 就已得出的阶段性观察结果来看， 有很好的临床应用前景， 值得密切关注。 但其静脉滴注浓缩液给药存在着严重的毒副作用， 如： 迟发性腹泻、 恶心与呕 吐、 中性粒细胞减少症合并发热、 外周血小板减少症、 结膜炎、 鼻炎、 低血压、 血管舒张、 出汗、 寒战、 全身不适、 头晕、 视力障碍、 瞳孔缩小、 流泪、 呼吸 困难、 肌肉收缩、 痉挛及感觉异常等。 为了降低药物骨髓抑制、 胃肠道反应（严 重腹宵） 以及肝肾毒性等毒副作用， 研究人员从两方面入手： 一是合成药物的
衍生物； 二是建立新的给药途径。 第一种方法从开始到应用于临床周期长， 耗 费大量的人力、 物力； 第二种方法则大大缩短了进入临床的周期， 节省了人力、 物力。 因此选用适当的药物载体来达到高效低毒即降低毒性的目的就显得十分 重要。 Irinotecan (CPT-11), approved by the FDA in 1998 for standard chemotherapy regimens, for the recurrence and exacerbation of metastatic colorectal cancer, was reapproved by the US FDA following pentafluorouracil (5-FU) for more than 40 years. Chemotherapy for first-line treatment of metastatic colorectal cancer. It is a derivative of camptothecin that selectively binds to the topoisomerase I and covalently binds to the Topo-DNA complex to form a stable Topo-drug-DNA complex, thereby inhibiting the DNA re-ligation step, resulting in a DNA strand. The break, the appearance of apoptosis. It has higher therapeutic effect on small cell lung cancer, small cell lung cancer, cervical cancer, ovarian cancer and colorectal cancer with high expression of topoisomerase I. Like other effective anti-tumor drugs, CPT-11 has obvious toxicity, and it also affects normal cells while inhibiting cancer cells. The dosage form currently available on the market is irinotecan hydrochloride intravenous infusion concentrate, the drug name is Campto. It is mainly used for the treatment of patients with advanced colorectal cancer. As a single drug, it is treated in patients who have failed treatment with 5-fluorouracil chemotherapy. At the same time, irinotecan is being used in a variety of clinical trials for gastric cancer and esophageal cancer. According to the phased observations, there are good clinical application prospects, which deserve close attention. However, its intravenous infusion concentrate has serious toxic side effects such as: delayed diarrhea, nausea and vomiting, neutropenia with fever, peripheral thrombocytopenia, conjunctivitis, rhinitis, hypotension, blood vessels Diastole, sweating, chills, general malaise, dizziness, visual impairment, dilated pupils, tearing, difficulty breathing, muscle contraction, spasms and paresthesia. In order to reduce the side effects of drug myelosuppression, gastrointestinal reactions (severe abdominal cramps) and liver and kidney toxicity, the researchers started from two aspects: First, the synthesis of drugs Derivatives; the second is to establish a new route of administration. The first method, from the beginning to the application of the clinical cycle, consumes a lot of manpower and material resources; the second method greatly shortens the cycle of entering the clinic, saving manpower and material resources. Therefore, it is very important to use an appropriate drug carrier to achieve high efficiency, low toxicity, and reduce toxicity.
纳米尺寸的药物可在一定程度上提高化疗药物的靶向性并大幅度地降低化 疗药物的毒副作用， 与目前的其它抗肿瘤药物剂型相比， 纳米药物具有独特的 优点。 动物实验表明， 纳米尺寸的药物， 经静脉注射后在某些肿瘤中的药物浓 度高于邻近正常组织。 这为扩大抗肿瘤药物的应用提供了一条良好的途径。 纳 米脂束， 粒径在 lOOmn左右， 可以将药物包封于脂束内部形成超微型球状载体。 纳米脂束具有以下优点： ①靶向性： 静脉注射给药后集中于网状内皮系统， 80%-90%集中于肝、 脾； ②缓释性： 减少肾排泄和体内的代谢， 延长药物的作 用时间； ③降低药物的毒性： 由于纳米药物主要集中于内皮网状内皮细胞丰富 的器官如肝脏中， 而在心脏、 肾、 骨髓的药物的浓度低， 因此减少了药物对其 它器官的毒副作用； ④提高药物的稳定性： 脂束的分子层保护药物， 提高稳定 性。 将伊立替康包载于纳米尺寸的脂束是降低其毒副作用重要选择之一。 目前 市场上没有伊立替康纳米脂束的报道和产品应用， 其研究开发具有重要意义。 Nano-sized drugs can increase the targeting of chemotherapeutic drugs to a certain extent and greatly reduce the toxic side effects of chemotherapeutic drugs. Compared with other anti-tumor drug formulations, nano-drugs have unique advantages. Animal experiments have shown that nano-sized drugs, after intravenous injection, have higher concentrations of drugs in certain tumors than adjacent normal tissues. This provides a good way to expand the application of anti-tumor drugs. The nano-lipid bundle has a particle size of about 100 nm, and the drug can be encapsulated inside the lipid bundle to form an ultra-micro spherical carrier. Nanolipids have the following advantages: 1 Targeting: After intravenous administration, it is concentrated in the reticuloendothelial system, 80%-90% is concentrated in the liver and spleen; 2 sustained release: reducing renal excretion and metabolism in the body, prolonging the drug The action time; 3 reduce the toxicity of the drug: Because the nano drug is mainly concentrated in the rich organs of the endothelial reticuloendothelial cells such as the liver, and the concentration of the drug in the heart, kidney and bone marrow is low, thereby reducing the toxicity of the drug to other organs. Side effects; 4 improve the stability of the drug: the molecular layer of the lipid bundle protects the drug and improves stability. The inclusion of irinotecan in a nano-sized lipid bundle is one of the important options for reducing its toxic side effects. At present, there is no report or product application of irinotecan nano-lipids on the market, and its research and development is of great significance.
脂束在血液循环中的稳定性是发挥药物载体作用的关键。 普通磷脂组成的 脂质体在体内的半衰期仅为十几分钟。 原因很多： 血液中高密度脂蛋白是破坏 脂质体的主要成分； 由于能激活补体系统， 脂质体易于被渗透和裂解； 磷脂酶 能够降解磷脂； 血清白蛋白能够与磷脂结合形成复合物， 从而降低磷脂组成纳 米组装体的稳定性。研究发现表面聚乙二醇（PEG)化能延长纳米组装体的体内 循环时间。 原因在于 PEG化能够实现立体阻碍和提高膜表面的亲水性。 PEG表 面化的纳米脂束能够兼具长循环、 隐形和立体稳定的特点， 对减少巨唾细胞吞
噬、 提高药物靶向性、 阻碍血液蛋白成分与磷脂的结合等具有重要的作用。 因 此， 借助传统的磷脂和 FDA批准的新型聚乙二醇 -十二羟基硬脂酸酯 （Solutol HS15 ) 实现伊立替康的包载和纳米化， 对于满足临床应用的各种需求， 造福于 广大的癌症患者具有重大意义。 The stability of the lipid tract in the blood circulation is the key to the action of the drug carrier. Liposomes composed of common phospholipids have a half-life of only ten minutes in vivo. There are many reasons for this: High-density lipoprotein in the blood is the main component that destroys liposomes; liposomes are easily penetrated and lysed by activation of the complement system; phospholipases can degrade phospholipids; serum albumin can combine with phospholipids to form complexes, thereby Reduce the stability of phospholipid composition nanoassemblies. It has been found that surface polyethylene glycol (PEG) can prolong the in vivo cycle time of nanoassemblies. The reason is that PEGylation can achieve steric hindrance and increase the hydrophilicity of the membrane surface. PEG-surfaced nanolipids can combine long-circulating, invisible, and steric stabilization to reduce macrophage swallowing It plays an important role in phagocytosis, improving drug targeting, and hindering the binding of blood protein components to phospholipids. Therefore, the traditional phospholipid and FDA-approved new polyethylene glycol-dodecyl stearate (Solutol HS15) can achieve the encapsulation and nanocrystallization of irinotecan, which is beneficial to meet the various needs of clinical applications. Cancer patients are of great significance.
发明内容 Summary of the invention
本发明的目的在于提供一种伊立替康纳米脂束制剂及其制备方法， 所述伊 立替康纳米脂束制剂粒径均匀， 作为脂束制剂能降低伊立替康的毒性、 具有长 循环效果、 能增强肿瘤靶向富集作用和增加病人顺应性； 所述制备方法工艺简 单、 具高重复性且可工业化生产。 The object of the present invention is to provide an irinotecan nano-lipid preparation and a preparation method thereof, wherein the irinotecan nano-fat bundle preparation has a uniform particle size, and the lipid bundle preparation can reduce the toxicity of irinotecan and has a long circulation effect. It can enhance tumor targeted enrichment and increase patient compliance; the preparation method is simple in process, highly reproducible and industrially productive.
为实现本发明的目的， 采用以下技术方案： To achieve the objectives of the present invention, the following technical solutions are employed:
在第一方面， 本发明提供一种伊立替康纳米脂束制剂， 包含磷脂、 聚乙二 醇-十二羟基硬脂酸酯、 甘油、 乙醇和伊立替康， 及注射用水性溶剂。 In a first aspect, the present invention provides an irinotecan nanolipid preparation comprising phospholipid, polyethylene glycol-dodecahydroxystearate, glycerin, ethanol and irinotecan, and an aqueous solution for injection.
本发明的伊立替康纳米脂束制剂中， 注射用水性溶剂是主要基质为水的含 溶质或不含溶质的能够用于注射的溶剂， 不作特别地限定。 In the irinotecan nanolipid preparation of the present invention, the aqueous solution for injection is a solvent which can be used for injection, which is a solute or a solute containing water, and is not particularly limited.
作为本发明的优选， 所述注射用水性溶剂选自生理盐水、 葡萄糖注射液和 注射用水中的一种或多种。 As a preferred aspect of the present invention, the aqueous injection solution is selected from one or more of physiological saline, glucose injection, and water for injection.
作为本发明的优选， 所述制剂包含 4〜8重量份磷脂、 10〜20重量份聚乙二 醇-十二羟基硬脂酸酯、 5〜15重量份甘油、 10〜20重量份乙醇和 1〜4重量份伊立 替康。 Preferably, the preparation comprises 4 to 8 parts by weight of phospholipid, 10 to 20 parts by weight of polyethylene glycol-dodecyl stearate, 5 to 15 parts by weight of glycerin, 10 to 20 parts by weight of ethanol and 1 ~ 4 parts by weight of irinotecan.
具体实施中， 所述制剂中磷脂的含量可以是 5重量份、 6重量份或 7重量 份； 聚乙二醇 -十二羟基硬脂酸酯的含量可以是 12重量份、 14重量份、 16重量 份或 18重量份； 甘油的含量可以是 7重量份、 9重量份、 11重量份或 13重量 份; 乙醇的含量可以是 12重量份、 14重量份、 16重量份或 18重量份； 伊立替
康的含量可以是 1.5重量份、 2重量份、 3重量份或 3.5重量份。 In a specific implementation, the content of the phospholipid in the preparation may be 5 parts by weight, 6 parts by weight or 7 parts by weight; the content of the polyethylene glycol-dodecyl stearate may be 12 parts by weight, 14 parts by weight, 16 Parts by weight or 18 parts by weight; glycerin may be 7 parts by weight, 9 parts by weight, 11 parts by weight or 13 parts by weight; the content of ethanol may be 12 parts by weight, 14 parts by weight, 16 parts by weight or 18 parts by weight; Lit The content may be 1.5 parts by weight, 2 parts by weight, 3 parts by weight or 3.5 parts by weight.
作为本发明的优选， 所述注射用水性溶剂的体积是所述磷脂、 聚乙二醇-十 二羟基硬脂酸酯、 甘油、 乙醇和伊立替康总体积的 5-100倍， 例如 6倍、 8倍、 10倍、 15倍、 20倍、 30倍、 50倍、 70倍、 80倍或 90倍， 优选 5-80倍， 更优 选 10-20倍。 As a preferred embodiment of the present invention, the volume of the aqueous solution for injection is 5-100 times, for example, 6 times the total volume of the phospholipid, polyethylene glycol-dodecyl stearate, glycerin, ethanol, and irinotecan. 8, 8, 10, 15, 20, 80 or 90, preferably 5 to 80, more preferably 10 to 20.
作为本发明的优选， 所述制剂配方中可增加主动靶向材料。 所述主动靶向 材料能够增强所述制剂在肿瘤中的富集作用。 优选地， 所述主动靶向材料为 X- 聚乙二醇 -二硬脂酰基磷脂酰乙醇胺（X-PEG-DSPE) , 其中 X可以是叶酸、 五肽 CRGDK (其中 C表示半胱氨酸、 R表示精氨酸、 G表示甘氨酸、 D表示天冬氨 酸、 K表示赖氨酸）或胆酸中的一种或多种， PEG表示聚乙二醇， DSPE表示二 硬脂酰基磷脂酰乙醇胺。 需要说明的是： 所述主动靶向材料并不局限于上述几 种， 任何能够增强所述制剂在肿瘤中的富集作用并且药学上可以接受的主动靶 向材料均可用于本发明。 As a preferred embodiment of the invention, active targeting materials can be added to the formulation. The active targeting material is capable of enhancing the enrichment of the formulation in a tumor. Preferably, the active targeting material is X-polyethylene glycol-distearoylphosphatidylethanolamine (X-PEG-DSPE), wherein X may be folic acid, pentapeptide CRGDK (wherein C represents cysteine, R represents arginine, G represents glycine, D represents aspartic acid, K represents lysine, or one or more of cholic acid, PEG represents polyethylene glycol, and DSPE represents distearoylphosphatidylethanolamine . It should be noted that the active targeting material is not limited to the above, and any active targeting material capable of enhancing the enrichment of the preparation in the tumor and pharmaceutically acceptable can be used in the present invention.
优选地， 所述制剂中主动靶向材料 X-PEG-DSPE的含量为 0.01-2重量份， 例如 0.02重量份、 0.05重量份、 0.1重量份、 0.4重量份、 0.5重量份、 0.8重量 份、 1.2重量份、 1.5重量份或 1.8重量份， 更优选 0.1-1重量份， 最优选 0.1-0.4 重量份。 Preferably, the active targeting material X-PEG-DSPE is contained in the preparation in an amount of 0.01 to 2 parts by weight, for example, 0.02 parts by weight, 0.05 parts by weight, 0.1 parts by weight, 0.4 parts by weight, 0.5 parts by weight, 0.8 parts by weight, 1.2 parts by weight, 1.5 parts by weight or 1.8 parts by weight, more preferably 0.1 to 1 part by weight, most preferably 0.1 to 0.4 parts by weight.
本发明示出一个典型的含有主动靶向材料的制剂例子如下： 含 4〜8重量份 磷脂、 10〜20重量份聚乙二醇-十二羟基硬脂酸酯、 5〜15重量份甘油、 10〜20重 量份乙醇、 1〜4重量份伊立替康和 0.1-0.4重量份主动靶向材料 X-PEG-DSPE, 其中 X表示叶酸、 五肽 CRGDK或胆酸； 以及相当于上述原料总体积的 10-20 倍的注射用水性溶剂。 The present invention shows a typical formulation containing an active targeting material as follows: 4 to 8 parts by weight of phospholipid, 10 to 20 parts by weight of polyethylene glycol-dodecyl stearate, 5 to 15 parts by weight of glycerol, 10 to 20 parts by weight of ethanol, 1 to 4 parts by weight of irinotecan and 0.1 to 0.4 parts by weight of active targeting material X-PEG-DSPE, wherein X represents folic acid, pentapeptide CRGDK or cholic acid; and equivalent to the total volume of the above raw materials 10-20 times the aqueous solvent for injection.
作为本发明的优选， 所述制剂配方中可增加防冻剂和 /或 pH调节剂， 其中
所述防冻剂选自丙二醇和山梨糖醇等； 所述 pH 调节剂选自柠檬酸、 乳酸、 Na2C03、 NaOH、 N C1、 NaHC03和 Ca(OH)2等。 As a preferred embodiment of the present invention, an antifreeze and/or a pH adjuster may be added to the formulation, wherein The antifreeze agent is selected from the group consisting of propylene glycol and sorbitol, etc.; the pH adjuster is selected from the group consisting of citric acid, lactic acid, Na 2 CO 3 , NaOH, N C1, NaHC 0 3 and Ca(OH) 2 , and the like.
作为本发明的优选， 所述伊利替康纳米脂束制剂可通过静脉注射、 肌肉注 射或皮下注射等常规给药方式给药。 As a preferred embodiment of the present invention, the irinotecan nanolipid preparation can be administered by a conventional administration such as intravenous injection, intramuscular injection or subcutaneous injection.
在第二方面， 本发明提供一种制备如第一方面所述的伊立替康纳米脂束制 剂的方法， 包括： In a second aspect, the present invention provides a method of preparing the irinotecan nanolipid preparation of the first aspect, comprising:
( 1 )将磷脂、 聚乙二醇-十二羟基硬脂酸酯、 甘油、 乙醇和伊立替康以及任 选的主动靶向材料、 任选的防冻剂和 /或 pH调节剂混合， 配成澄清透明溶液； (1) mixing phospholipids, polyethylene glycol-dodecyl stearate, glycerol, ethanol and irinotecan, and optionally active targeting materials, optional antifreeze and/or pH adjusting agents, to formulate Clearing the clear solution;
(2)用注射用水性溶剂稀释所述澄清透明溶液， 自乳化得到所述伊立替康 纳米脂束制剂。 (2) The clear transparent solution was diluted with an aqueous solution for injection, and the irinotecan nanolipid preparation was obtained by self-emulsification.
本发明利用聚乙二醇 -十二羟基硬脂酸酯的成胶束功能和对伊立替康的增溶 功能， 以及磷脂对聚乙二醇-十二羟基硬脂酸酯胶束的尺寸调节作用， 经自乳化 过程后， 实现伊立替康纳米脂束的制备。 The present invention utilizes the micelle function of polyethylene glycol-dodecyl stearate and the solubilizing function of irinotecan, and the size adjustment of phospholipids to polyethylene glycol-dodecyl stearate micelles. Function, after the self-emulsification process, the preparation of irinotecan nanolipids is achieved.
本发明制备伊立替康纳米脂束制剂的方法中， 步骤 （1 )配制澄清透明溶液 的方法有多种， 可以将磷脂、 聚乙二醇-十二羟基硬脂酸酯、 甘油、 乙醇和伊立 替康混合在一起， 借助磁力搅拌、 机械搅拌、 超声、 加热、 匀浆器匀浆或其组 合等外力作用得到澄清透明溶液。 具体实施中， 可以将上述配方中的成分一次 性全部加入容器中进行混合处理， 也可以先加一部分配方中的物质， 搅拌均匀 后， 再加另一部分并混合处理得到澄清透明溶液。 本发明优选的两种配制澄清 透明溶液的方法如下： In the method for preparing the irinotecan nano-lipid preparation of the present invention, the method for preparing the clear transparent solution in the step (1) can be various, and the phospholipid, the polyethylene glycol-dodecyl stearate, the glycerin, the ethanol and the y Liticon is mixed together and a clear, clear solution is obtained by external force such as magnetic stirring, mechanical agitation, ultrasonication, heating, homogenizer homogenization or a combination thereof. In a specific implementation, the ingredients in the above formula may be added to the container at one time for mixing treatment, or a part of the ingredients in the formula may be added first, and after stirring, another portion is added and mixed to obtain a clear transparent solution. The preferred two methods of formulating a clear, transparent solution of the invention are as follows:
第一种方法具体为： The first method is specifically:
( la) 将磷脂与乙醇混合溶解， 配成第一溶液； (la) mixing phospholipids with ethanol to form a first solution;
( lb) 将聚乙二醇-十二羟基硬脂酸酯、 甘油、 乙醇和伊立替康以及任选的
主动靶向材料、 任选的防冻剂和 /或 pH调节剂混合溶解， 配成第二溶液； ( lb) polyethylene glycol-dodecyl stearate, glycerol, ethanol and irinotecan and optionally The active targeting material, the optional antifreeze and/or the pH adjuster are mixed and dissolved to form a second solution;
( l c ) 将所述第一溶液与所述第二溶液混合， 搅拌混匀得到所述澄清透明 溶液。 ( l c ) mixing the first solution with the second solution, and stirring and mixing to obtain the clear transparent solution.
第二种方法具体为： The second method is specifically:
将磷脂、 聚乙二醇-十二羟基硬脂酸酯、 甘油、 乙醇和伊立替康以及任选的 主动靶向材料、 任选的防冻剂和 /或 pH调节剂混合， 搅拌混匀配成澄清透明溶 液。 Mixing phospholipids, polyethylene glycol-dodecyl stearate, glycerol, ethanol and irinotecan, and optionally active targeting materials, optional antifreeze and/or pH adjusters, stirring and mixing Clarify the clear solution.
本发明中， 澄清透明溶液是一般意义上的概念， 即肉眼不可见颗粒物或析 出物的存在， 激光照射下， 没有丁达尔现象的发生， 紫外吸收光谱中不会有源 于颗粒散射所导致的消光。 In the present invention, the clear transparent solution is a general concept, that is, the presence of invisible particles or precipitates in the naked eye, under the laser irradiation, there is no occurrence of Tyndall phenomenon, and the ultraviolet absorption spectrum is not caused by scattering of particles. extinction.
本发明配制的澄清透明溶液即伊立替康纳米脂束制剂前体， 可以在氮气保 护条件下密封保存。 如果配制的澄清透明溶液马上进行自乳化也可以不密封保 存。 The clear transparent solution prepared by the present invention, i.e., the irinotecan nanolipid preparation precursor, can be sealed and stored under nitrogen protection conditions. If the formulated clear transparent solution is self-emulsified immediately, it can be stored unsealed.
本发明中， 步骤 （2) 的自乳化过程， 根据需要可借助外力， 比如轻柔或剧 烈震荡均可。 In the present invention, the self-emulsification process of the step (2) can be performed by an external force such as gentle or vigorous shock as needed.
本发明制备伊立替康纳米脂束制剂的方法中， 注射用水性溶剂是主要基质 为水的含溶质或不含溶质的能够用于注射的溶剂， 不作特别地限定。 In the method for producing an irinotecan nanolipid preparation according to the present invention, the aqueous solvent for injection is a solvent which can be used for injection, which is a solute containing or containing no solute, and is not particularly limited.
作为本发明的优选， 所述注射用水性溶剂选自生理盐水、 葡萄糖注射液和 注射用水中的一种或多种。 As a preferred aspect of the present invention, the aqueous injection solution is selected from one or more of physiological saline, glucose injection, and water for injection.
作为本发明的优选， 所述澄清透明溶液含 4〜8重量份磷脂、 10〜20重量份 聚乙二醇-十二羟基硬脂酸酯、 5〜15重量份甘油、 10〜20重量份乙醇和 1〜4重量 份伊立替康。 Preferably, the clear transparent solution contains 4 to 8 parts by weight of phospholipid, 10 to 20 parts by weight of polyethylene glycol-dodecyl stearate, 5 to 15 parts by weight of glycerin, and 10 to 20 parts by weight of ethanol. And 1 to 4 parts by weight of irinotecan.
具体实施中， 所述澄清透明溶液中磷脂的含量可以是 5重量份、 6重量份或
7重量份； 聚乙二醇 -十二羟基硬脂酸酯的含量可以是 12重量份、 14重量份、 16 重量份或 18重量份； 甘油的含量可以是 7重量份、 9重量份、 11重量份或 13 重量份； 乙醇的含量可以是 12重量份、 14重量份、 16重量份或 18重量份； 伊 立替康的含量可以是 1.5重量份、 2重量份、 3重量份或 3.5重量份。 In a specific implementation, the content of the phospholipid in the clear transparent solution may be 5 parts by weight, 6 parts by weight or 7 parts by weight; the content of polyethylene glycol-dodecyl stearate may be 12 parts by weight, 14 parts by weight, 16 parts by weight or 18 parts by weight; the content of glycerin may be 7 parts by weight, 9 parts by weight, 11 Parts by weight or 13 parts by weight; the content of ethanol may be 12 parts by weight, 14 parts by weight, 16 parts by weight or 18 parts by weight; the content of irinotecan may be 1.5 parts by weight, 2 parts by weight, 3 parts by weight or 3.5 parts by weight. .
作为本发明的优选， 所述澄清透明溶液还含 0.01-2 重量份主动靶向材料 X-PEG-DSPE, 其中 X表示叶酸、 五肽 CRGDK或胆酸中的一种或多种。 As a preferred embodiment of the present invention, the clear transparent solution further contains 0.01 to 2 parts by weight of the active targeting material X-PEG-DSPE, wherein X represents one or more of folic acid, pentapeptide CRGDK or cholic acid.
作为本发明的优选， 所述澄清透明溶液含 4〜8重量份磷脂、 10〜20重量份 聚乙二醇-十二羟基硬脂酸酯、 5〜15重量份甘油、 10〜20重量份乙醇、 1〜4重量 份伊立替康和 0.1-0.4重量份主动靶向材料 X-PEG-DSPE, 其中 X表示叶酸、 五 肽 CRGDK或胆酸。 Preferably, the clear transparent solution contains 4 to 8 parts by weight of phospholipid, 10 to 20 parts by weight of polyethylene glycol-dodecyl stearate, 5 to 15 parts by weight of glycerin, and 10 to 20 parts by weight of ethanol. 1 to 4 parts by weight of irinotecan and 0.1 to 0.4 parts by weight of the active targeting material X-PEG-DSPE, wherein X represents folic acid, pentapeptide CRGDK or cholic acid.
具体实施中， 所述澄清透明溶液中磷脂的含量可以是 5重量份、 6重量份或 7重量份； 聚乙二醇 -十二羟基硬脂酸酯的含量可以是 12重量份、 14重量份、 16 重量份或 18重量份； 甘油的含量可以是 7重量份、 9重量份、 11重量份或 13 重量份； 乙醇的含量可以是 12重量份、 14重量份、 16重量份或 18重量份； 伊 立替康的含量可以是 1.5重量份、 2重量份、 3重量份或 3.5重量份； 主动靶向 材料 X-PEG-DSPE的含量可以是 0.02重量份、 0.05重量份、 0.1重量份、 0.4重 量份、 0.5重量份、 0.8重量份、 1.2重量份、 1.5重量份或 1.8重量份。 In a specific implementation, the content of the phospholipid in the clear transparent solution may be 5 parts by weight, 6 parts by weight or 7 parts by weight; the content of the polyethylene glycol-dodecyl stearate may be 12 parts by weight and 14 parts by weight. , 16 parts by weight or 18 parts by weight; the content of glycerin may be 7 parts by weight, 9 parts by weight, 11 parts by weight or 13 parts by weight; the content of ethanol may be 12 parts by weight, 14 parts by weight, 16 parts by weight or 18 parts by weight. The content of irinotecan may be 1.5 parts by weight, 2 parts by weight, 3 parts by weight or 3.5 parts by weight; the active targeting material X-PEG-DSPE may be 0.02 parts by weight, 0.05 parts by weight, 0.1 parts by weight, 0.4. Parts by weight, 0.5 parts by weight, 0.8 parts by weight, 1.2 parts by weight, 1.5 parts by weight or 1.8 parts by weight.
需要说明，本发明述及"重量份 "的地方一般是指除注射用水性溶剂以外的其 它原料的重量比例关系。 It is to be noted that the "parts by weight" of the present invention generally means the weight ratio of other raw materials other than the aqueous solvent for injection.
本发明中， "任选的"的含义是指"包含或不包含 "其所指的对象， 例如"任选 的主动靶向材料"意指"包含或不包含主动靶向材料"， "任选的防冻剂和 /或 pH调 节剂"意指"包含或不包含防冻剂和 /或 pH调节剂"。 In the present invention, the meaning of "optional" means "with or without" the object to which it refers, such as "optional active targeting material" means "with or without active targeting material", "anything" The selected antifreeze and/or pH adjusting agent "includes" with or without antifreeze and/or pH adjusting agent.
作为本发明的优选， 所述注射用水性溶剂的体积是所述澄清透明溶液的
5-100倍， 例如 6倍、 8倍、 10倍、 15倍、 20倍、 30倍、 50倍、 70倍、 80倍 或 90倍， 优选 5-80倍， 更优选 10-20倍。 As a preferred embodiment of the present invention, the volume of the aqueous solution for injection is the clear transparent solution. 5-100 times, for example, 6 times, 8 times, 10 times, 15 times, 20 times, 30 times, 50 times, 70 times, 80 times or 90 times, preferably 5-80 times, more preferably 10-20 times.
注射用水性溶剂的温度是本领域的技术人员可以根据经验确定的， 一般室 温即可， 本发明所用的注射用水性溶剂的温度可以是 0-80°C范围内的任意温 度， 优选 0-40°C范围内的任意温度。 The temperature of the aqueous solvent for injection can be determined empirically by those skilled in the art, and is generally room temperature. The temperature of the aqueous solution for injection used in the present invention may be any temperature in the range of 0-80 ° C, preferably 0-40. Any temperature in the °C range.
在第三方面， 本发明提供一种根据第二方面所述的方法制备得到的伊立替 康纳米脂束制剂， 所述制剂通过静脉注射、 肌肉注射或皮下注射给药。 In a third aspect, the present invention provides a irinotecan nanolipid preparation prepared according to the method of the second aspect, which is administered by intravenous injection, intramuscular injection or subcutaneous injection.
为储存的方便， 本发明制备得到的伊立替康纳米脂束制剂， 可以选择冻干 等再加工工艺进行后续处理， 并不影响纳米脂束药物的再分散和使用， 所涉及 工艺可产业化生产， 并直接应用于大批量药物生产开发。 For convenience of storage, the irinotecan nano-lipid preparation prepared by the invention can be further processed by lyophilization and other reprocessing processes, and does not affect the redispersion and use of the nano-lipid drug, and the process involved can be industrialized. And directly applied to the development of large-scale drug production.
本发明的有益效果为： 本发明利用聚乙二醇-十二羟基硬脂酸酯的成胶束功 能和对伊立替康的增溶功能， 以及磷脂对聚乙二醇-十二羟基硬脂酸酯胶束的尺 寸调节作用， 结合简单的脂束前体制备工艺， 配制出伊立替康纳米脂束制剂前 体 （即澄清透明溶液） ； 经自乳化过程后， 实现伊立替康纳米脂束的制备； 本 发明制备的伊立替康纳米脂束的粒径分布均匀， 作为脂束制剂能降低伊立替康 的毒性、 具有长循环效果、 能增强肿瘤靶向富集作用和增加病人顺应性； 本发 明填补了伊立替康纳米脂束药物的空白， 所发展的配方工艺简单、 具高重复性 可直接应用于伊立替康纳米药物的产业化生产。 此外， 在本发明的制剂加入主 动靶向材料能够显著增强其在肿瘤中的富集效果。 The beneficial effects of the present invention are as follows: The present invention utilizes the micelle function of polyethylene glycol-dodecyl stearate and the solubilizing function for irinotecan, and the phospholipid to polyethylene glycol-dodecyl stearate The size adjustment of the acid ester micelles, combined with a simple preparation process of the lipid bundle precursor, prepares the irinotecan nano-lipid preparation precursor (ie, a clear transparent solution); after the self-emulsification process, the irinotecan nano-lipid is realized. The preparation of the irinotecan nanolipid bundle prepared by the invention has uniform particle size distribution, and the lipid bundle preparation can reduce the toxicity of irinotecan, has a long circulation effect, can enhance tumor targeted enrichment and increase patient compliance; The invention fills the blank of irinotecan nano-lipid drug, and the developed formula has simple process and high repeatability, and can be directly applied to the industrial production of irinotecan nano drug. Furthermore, the addition of a primary targeting material to the formulation of the present invention can significantly enhance its enrichment in tumors.
附图说明 DRAWINGS
图 1 为本发明伊立替康纳米脂束前体的制备及经自乳化过程后得到伊立替 康纳米脂束制剂的过程示意图。 Fig. 1 is a schematic view showing the preparation of the irinotecan nanolipid precursor of the present invention and the process of obtaining the irinotecan nanolipid preparation after the self-emulsification process.
图 2为本发明实施例 1所得伊立替康纳米脂束制剂前体的光学照片， 显示
其为澄清透明溶液。 2 is an optical photograph showing the precursor of the irinotecan nanolipid preparation obtained in Example 1 of the present invention, showing It is a clear transparent solution.
图 3 从左到右依次为经生理盐水、 注射用水、 葡萄糖注射液自乳化过程后 得到的伊立替康纳米脂束制剂的光学照片， 显示其为乳状液。 Fig. 3 is an optical photograph of the irinotecan nanolipid preparation obtained after self-emulsification of physiological saline, water for injection and glucose injection from left to right, showing that it is an emulsion.
图 4为本发明实施例 1经生理盐水自乳化过程后得到的伊立替康纳米脂束 制剂的动态光散射结果， 显示其粒径均匀。 Fig. 4 is a dynamic light scattering result of the irinotecan nanolipid preparation obtained by the self-emulsification process of physiological saline in Example 1 of the present invention, showing that the particle diameter is uniform.
图 5为本发明实施例 1经生理盐水自乳化过程后得到的伊立替康纳米脂束 制剂的透射电镜照片。 Fig. 5 is a transmission electron micrograph of the irinotecan nanolipid preparation obtained after the self-emulsification of physiological saline in Example 1 of the present invention.
图 6为本发明实施例 9经注射用水自乳化过程后得到的伊立替康纳米脂束 制剂的动态光散射结果， 显示其粒径均匀。 Fig. 6 is a dynamic light scattering result of the irinotecan nanolipid preparation obtained by self-emulsification of water for injection in Example 9 of the present invention, showing that the particle diameter is uniform.
图 7为本发明实施例 9经注射用水自乳化过程后冻干， 再稀释后得到的伊 立替康纳米脂束制剂的透射电镜照片。 Fig. 7 is a transmission electron micrograph of the irinotecan nanolipid preparation obtained by freeze-drying and then diluting the water after the self-emulsification process of Example 9 of the present invention.
图 8为本发明实施例 10经葡萄糖注射液自乳化过程后得到的伊立替康纳米 脂束制剂的动态光散射结果， 显示其粒径均匀。 Fig. 8 is a dynamic light scattering result of the irinotecan nano-lipid preparation obtained by the self-emulsification process of the glucose injection solution according to the embodiment 10 of the present invention, showing that the particle diameter is uniform.
图 9为本发明实施例 10经葡萄糖注射液自乳化过程后得到的伊立替康纳米 脂束制剂的透射电镜照片。 Fig. 9 is a transmission electron micrograph of an irinotecan nanolipid preparation obtained by self-emulsification of a glucose injection solution according to Example 10 of the present invention.
图 10为表面 CRGDK靶向脂束药物在肿瘤部位的聚集情况， 小动物成像显 示与游离药物 （荧光分子模拟 （上）） 比较， 脂束药物 （实施例 1制备） 在肿瘤 部位有明显的聚集（中间）， 比较显示， CRGDK靶向脂束药物（实施例 17制备） 具有更加明显的肿瘤富集作用 （下）。 Figure 10 shows the aggregation of surface CRGDK-targeted lipid tract drugs at the tumor site. Small animal imaging shows that the lipid tract drug (prepared in Example 1) has obvious aggregation at the tumor site compared with the free drug (fluorescence molecular simulation (top)). (Intermediate), the comparison shows that the CRGDK-targeted lipid tract drug (prepared in Example 17) has a more pronounced tumor enrichment effect (bottom).
图 11为表面叶酸靶向脂束药物在的肿瘤药效学研究， 光学照片显示， 经 30 天治疗后， 实施例 18制备的叶酸靶向的脂束药物 （右） 治疗组的肿瘤与实施例 1制备的脂束药物组（中）和游离药物组 （左）相比最小， 这表明叶酸靶向能增 强脂束药物的治疗效果， 原因在于叶酸靶向脂束药物具有更加增强的肿瘤富集
效果。 Figure 11 is a tumor pharmacodynamic study of a surface folate-targeted lipid tract drug, and optical photographs show that the folic acid-targeted liposome drug (right) treated group of the tumor of Example 18 after 30 days of treatment and the Example 1 The prepared lipid tract drug group (middle) was the smallest compared with the free drug group (left), indicating that folic acid targeting can enhance the therapeutic effect of lipid tract drugs because folate-targeted lipid tract drugs have more enhanced tumor enrichment. Effect.
具体实 J ^r式 Concrete J ^r
下面将结合实施例对本发明的实施方案进行详细描述。 本领域技术人员将 会理解， 以下实施例仅为本发明的优选实施例， 以便于更好地理解本发明， 因 而不应视为限定本发明的范围。 对于本领域的技术人员来说， 本发明可以有各 种更改和变化， 凡在本发明的精神和原则之内， 所作的任何修改、 等同替换或 改进等， 均应包含在本发明的保护范围之内。 下述实施例中的实验方法， 如无 特殊说明， 均为常规方法； 所用的实验材料， 如无特殊说明， 均为自常规生化 试剂厂商购买得到的。 Embodiments of the present invention will be described in detail below with reference to the embodiments. Those skilled in the art will appreciate that the following examples are merely preferred embodiments of the present invention in order to facilitate a better understanding of the present invention and therefore should not be construed as limiting the scope of the invention. It will be apparent to those skilled in the art that various modifications and changes can be made in the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and scope of the present invention are intended to be included in the scope of the present invention. within. The experimental methods in the following examples, unless otherwise specified, are conventional methods; the experimental materials used, unless otherwise specified, are purchased from conventional biochemical reagent manufacturers.
本发明制备伊立替康纳米脂束制剂的工艺过程示意图如图 1 所示， 将伊立 替康与磷脂、 聚乙二醇-十二羟基硬脂酸酯、 甘油和乙醇 （助剂） 混合均匀配制 成伊立替康纳米脂束药物前体， 然后加入注射用水性溶剂进行自乳化得到伊立 替康纳米脂束制剂。 The process of preparing the irinotecan nano-lipid preparation of the present invention is shown in Figure 1. The irinotecan is mixed with phospholipid, polyethylene glycol-dodecyl stearate, glycerin and ethanol (auxiliary). The irinotecan nano-lipid drug precursor is prepared by self-emulsification by adding an aqueous solvent for injection to obtain a irinotecan nano-lipid preparation.
实施例 1 Example 1
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.5g伊立替康、 2.5g乙醇、 3.0g Solutol HS15 (德国 BASF公司）、2. Weigh 0.5g irinotecan, 2.5g ethanol, 3.0g Solutol HS15 (BASF, Germany),
1.8g甘油， 常温溶解， 得到溶液8。 1.8 g of glycerin was dissolved at room temperature to obtain a solution 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 图 2显示： 伊立替康脂束制剂前体为澄清透 明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. Figure 2 shows: The irinotecan lipid bundle formulation precursor is a clear, transparent liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到
伊立替康纳米制剂。 图 3中左侧试管显示伊立替康脂束制剂呈乳状液。 三、 伊立替康脂束制剂的粒径测定 The irinotecan lipid bundle preparation precursor prepared in the first step is diluted with 20 volumes of physiological saline to obtain Irinotecan nano preparations. The left tube in Figure 3 shows that the irinotecan lipid bundle formulation is in the form of an emulsion. Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 伊立 替康脂束制剂的平均粒径为 103.3nm。 图 4显示： 伊立替康脂束制剂粒径分布均 匀。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The irinotecan lipid bundle preparation has an average particle diameter of 103.3 nm. Figure 4 shows that the irinotecan lipid bundle formulation has a uniform particle size distribution.
本实施例制备的伊立替康脂束制剂的透射电镜照片如图 5所示， 显示制备 的伊立替康脂束制剂为粒径均匀的纳米颗粒。 A transmission electron micrograph of the irinotecan lipid bundle preparation prepared in this example is shown in Fig. 5, and shows that the prepared irinotecan lipid bundle preparation is a nanoparticle having a uniform particle diameter.
实施例 2 Example 2
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.2g伊立替康、 2.5g乙醇、 3.0g Solutol HS15 (德国 BASF公司）、2. Weigh 0.2g irinotecan, 2.5g ethanol, 3.0g Solutol HS15 (BASF, Germany),
1.8g甘油， 常温溶解， 得到溶液8。 1.8 g of glycerin was dissolved at room temperature to obtain a solution 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康脂束制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 结果 与图 4类似。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 4.
实施例 3 Example 3
一、 伊立替康脂束制剂前体的制备
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。I. Preparation of irinotecan lipid bundle preparation precursor 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.8g伊立替康、 2.5g乙醇、 3.0g Solutol HS15 (德国 BASF公司）、2. Weigh 0.8g irinotecan, 2.5g ethanol, 3.0g Solutol HS15 (BASF, Germany),
1.8g甘油， 常温溶解， 得到溶液8。 1.8 g of glycerin was dissolved at room temperature to obtain a solution 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康脂束制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康纳米制剂的粒径测定 Third, the determination of the particle size of irinotecan nano preparations
用英国 Malven仪器公司的 ZS90 仪器检测伊立替康脂束制剂的粒径。 结果 与图 4类似。 The particle size of the irinotecan lipid bundle formulation was measured using a ZS90 instrument from Malven Instruments, UK. The result is similar to Figure 4.
实施例 4 Example 4
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.5g伊立替康、 1.7g乙醇、 3.0g Solutol HS15 (德国 BASF公司）、2. Weigh 0.5g irinotecan, 1.7g ethanol, 3.0g Solutol HS15 (BASF, Germany),
3.0g甘油， 常温溶解， 得到溶液8。 3.0 g of glycerin was dissolved at room temperature to obtain a solution of 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康脂束制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。
三、 伊立替康脂束制剂的粒径测定 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion. Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90 仪器检测伊立替康脂束制剂的粒径。 结果 与图 4类似。 The particle size of the irinotecan lipid bundle formulation was measured using a ZS90 instrument from Malven Instruments, UK. The result is similar to Figure 4.
实施例 5 Example 5
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
称取 1.2g磷脂 （德国 Lipoid公司） 、 0.5g伊立替康、 2.8g无水乙醇、 3.0g Solutol HS15 (德国 BASF公司）和 1.8g甘油， 搅拌溶解， 得到溶液澄清透明的 伊立替康脂束制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束 制剂前体为澄清透明液体。 1.2 g of phospholipid (Lipoid, Germany), 0.5 g of irinotecan, 2.8 g of absolute ethanol, 3.0 g of Solutol HS15 (BASF, Germany) and 1.8 g of glycerin were weighed and dissolved to obtain a clear and transparent irinotecan lipid bundle. Formulation precursor, nitrogen protection, sealed and stored. The results are similar to those in Figure 2, where the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康脂束制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康纳米制剂的粒径。 结果 与图 4类似。 The particle size of the irinotecan nanoformulation was measured using a ZS90 instrument from Malven Instruments, UK. The result is similar to Figure 4.
实施例 6 Example 6
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
称取 1.2g磷脂 （德国 Lipoid公司） 、 0.2g伊立替康、 2.8g无水乙醇、 3.0g Solutol HS15 (德国 BASF公司）和 1.8g甘油， 搅拌溶解， 得到溶液澄清透明的 伊立替康脂束制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束 制剂前体为澄清透明液体。 1.2 g of phospholipid (Lipoid, Germany), 0.2 g of irinotecan, 2.8 g of absolute ethanol, 3.0 g of Solutol HS15 (BASF, Germany) and 1.8 g of glycerin were weighed and dissolved to obtain a clear and transparent irinotecan lipid bundle. Formulation precursor, nitrogen protection, sealed and stored. The results are similar to those in Figure 2, where the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到
伊立替康脂束制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 三、 伊立替康脂束制剂的粒径测定 The irinotecan lipid bundle preparation precursor prepared in the first step is diluted with 20 volumes of physiological saline to obtain Irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion. Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 结果 与图 4类似。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 4.
实施例 7 Example 7
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
称取 1.2g磷脂 （德国 Lipoid公司） 、 0.8g伊立替康、 2.8g无水乙醇、 3.0g Solutol HS15 (德国 BASF公司）和 1.8g甘油， 搅拌溶解， 得到溶液澄清透明的 伊立替康脂束制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束 制剂前体为澄清透明液体。 1.2 g of phospholipid (Lipoid, Germany), 0.8 g of irinotecan, 2.8 g of absolute ethanol, 3.0 g of Solutol HS15 (BASF, Germany) and 1.8 g of glycerin were weighed and dissolved to obtain a clear and transparent irinotecan lipid bundle. Formulation precursor, nitrogen protection, sealed and stored. The results are similar to those in Figure 2, where the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康脂束制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90 仪器检测伊立替康脂束制剂的粒径。 结果 与图 4类似。 The particle size of the irinotecan lipid bundle formulation was measured using a ZS90 instrument from Malven Instruments, UK. The result is similar to Figure 4.
实施例 8 Example 8
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
称取 1.2g磷脂 （德国 Lipoid公司） 、 0.5g伊立替康、 1.7g无水乙醇、 3.0g Solutol HS15 (德国 BASF公司）和 3.0g甘油， 搅拌溶解， 得到溶液澄清透明的 伊立替康脂束制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束 制剂前体为澄清透明液体。 1.2 g of phospholipid (Lipoid, Germany), 0.5 g of irinotecan, 1.7 g of absolute ethanol, 3.0 g of Solutol HS15 (BASF, Germany) and 3.0 g of glycerol were weighed and dissolved to obtain a clear and transparent irinotecan lipid bundle. Formulation precursor, nitrogen protection, sealed and stored. The results are similar to those in Figure 2, where the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康脂束制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 2. Preparation of irinotecan lipid bundle preparation The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康纳米制剂的粒径。 伊立 替康纳米制剂的平均粒径为 105.9nm。 结果与图 4类似。 The particle size of the irinotecan nanoformulation was measured using a ZS90 instrument from Malven Instruments, UK. The average particle size of the irinotecan nanoformulation was 105.9 nm. The result is similar to Figure 4.
实施例 9 Example 9
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂（德国 Lipoid公司）和 0.3g乙醇， 溶解， 加入 3.0g Solutol HS15 (德国 BASF公司） ， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, dissolve, and add 3.0 g of Solutol HS15 (BASF, Germany) to obtain solution VIII.
2、 称取 0.5g伊立替康、 2.5g乙醇、 1.8g甘油， 常温溶解， 得到溶液8。 2. Weigh 0.5 g of irinotecan, 2.5 g of ethanol, and 1.8 g of glycerin, and dissolve at room temperature to obtain a solution of 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的注射用水稀释， 得到 伊立替康脂束制剂。 图 3中中间试管显示伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of water for injection to obtain a irinotecan lipid bundle preparation. The middle tube in Figure 3 shows that the irinotecan lipid bundle formulation is in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 伊立 替康脂束制剂的平均粒径为 107.0nm。 图 6显示： 伊立替康脂束制剂粒径分布均 匀。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The irinotecan lipid bundle preparation had an average particle diameter of 107.0 nm. Figure 6 shows that the irinotecan lipid bundle formulation has a uniform particle size distribution.
本实施例制备的伊立替康脂束制剂的透射电镜照片如图 7所示， 显示制备 的伊立替康脂束制剂为粒径均匀的纳米颗粒。 A transmission electron micrograph of the irinotecan lipid bundle preparation prepared in this example is shown in Fig. 7, and shows that the prepared irinotecan lipid bundle preparation is a nanoparticle having a uniform particle diameter.
实施例 10
一、 伊立替康脂束制剂前体的制备 Example 10 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.5g伊立替康、 2.5g乙醇、 3.0g Solutol HS15 (德国 BASF公司）、 2. Weigh 0.5g irinotecan, 2.5g ethanol, 3.0g Solutol HS15 (BASF, Germany),
3.0g甘油， 常温溶解， 得到溶液8。 3.0 g of glycerin was dissolved at room temperature to obtain a solution of 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的葡萄糖注射液稀释， 得到伊立替康脂束制剂。 图 3中右侧试管显示伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of glucose injection to obtain a irinotecan lipid bundle preparation. The right tube in Figure 3 shows that the irinotecan lipid bundle formulation is in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康纳米制剂的粒径。 图 8 显示： 伊立替康脂束制剂粒径分布均匀。 The particle size of the irinotecan nanoformulation was measured using a ZS90 instrument from Malven Instruments, UK. Figure 8 shows: The irinotecan lipid bundle formulation has a uniform particle size distribution.
本实施例制备的伊立替康脂束制剂的透射电镜照片如图 9所示， 显示制备 的伊立替康脂束制剂为粒径均匀的纳米颗粒。 A transmission electron micrograph of the irinotecan lipid bundle preparation prepared in this example is shown in Fig. 9, and shows that the prepared irinotecan lipid bundle preparation is a nanoparticle having a uniform particle diameter.
实施例 11 Example 11
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 lg磷脂 （德国 Lipoid公司） 和 0.5g乙醇， 溶解， 得到溶液八。 1. Weigh lg phospholipid (Lipoid, Germany) and 0.5 g of ethanol, and dissolve to obtain solution VIII.
2、 称取 0.25g伊立替康、 2g乙醇、 2.5g Solutol HS15 (德国 BASF公司 )、 1.25g甘油， 常温溶解， 得到溶液8。 2. Weigh 0.25 g of irinotecan, 2 g of ethanol, 2.5 g of Solutol HS15 (BASF, Germany), 1.25 g of glycerol, and dissolve at room temperature to obtain a solution 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。
二、 伊立替康脂束制剂的制备 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid. 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 10倍体积的生理盐水稀释， 得到 伊立替康脂束制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 10 volumes of physiological saline to obtain a irinotecan lipid bundle preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 结果 与图 4类似。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 4.
实施例 12 Example 12
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
称取 2g磷脂 （德国 Lipoid公司） 、 lg伊立替康、 5g无水乙醇、 5g Solutol HS15 (德国 BASF公司） 和 3.75g甘油， 搅拌溶解， 得到溶液澄清透明的伊立 替康脂束制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂 前体为澄清透明液体。 2 g of phospholipid (Lipoid, Germany), lg irinotecan, 5 g of absolute ethanol, 5 g of Solutol HS15 (BASF, Germany) and 3.75 g of glycerol were weighed and dissolved to obtain a clear and transparent irinotecan lipid bundle preparation. Nitrogen protection, sealed and stored. The results are similar to those in Figure 2, where the irinotecan lipid bundle formulation is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 80倍体积的注射用水稀释， 得到 伊立替康脂束制剂。 结果类似图 3中中间试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 80 volumes of water for injection to obtain a irinotecan lipid bundle preparation. The results were similar to the middle tube in Figure 3, and the irinotecan lipid bundle preparation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 结果 与图 6类似。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 6.
实施例 13 Example 13
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
称取 1.5g磷脂 （德国 Lipoid公司） 、 0.6g伊立替康、 3.5g无水乙醇、 3.5g Solutol HS15 (德国 BASF公司）和 2.8g甘油， 搅拌溶解， 得到溶液澄清透明的 伊立替康脂束制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束
制剂前体为澄清透明液体。 1.5 g of phospholipid (Lipoid, Germany), 0.6 g of irinotecan, 3.5 g of absolute ethanol, 3.5 g of Solutol HS15 (BASF, Germany) and 2.8 g of glycerol were weighed and dissolved to obtain a clear and transparent irinotecan lipid bundle. Formulation precursor, nitrogen protection, sealed and stored. The results are similar to Figure 2, irinotecan lipid bundle The formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 5倍体积的葡萄糖注射液稀释， 得到伊立替康脂束制剂。 结果类似图 3 中右侧试管， 伊立替康脂束制剂呈乳状 液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 5 volumes of glucose injection to obtain a irinotecan lipid bundle preparation. The results were similar to the right tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 结果 与图 8类似。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The result is similar to Figure 8.
实施例 14 Example 14
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.5g 伊立替康、 2.5g 乙醇、 丙二醇 1.8g， 柠檬酸 0.01g， 3.0g Solutol HS15 (德国 BASF公司） 、 1.8g甘油， 常温溶解， 得到溶液8。 2. Weigh 0.5 g of irinotecan, 2.5 g of ethanol, 1.8 g of propylene glycol, 0.01 g of citric acid, 3.0 g of Solutol HS15 (BASF, Germany), 1.8 g of glycerin, and dissolve at room temperature to obtain a solution 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康纳米制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan nano preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 伊立 替康脂束制剂的平均粒径为 108nm。 伊立替康脂束制剂粒径分布均匀。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England. The irinotecan lipid bundle preparation had an average particle diameter of 108 nm. The irinotecan lipid bundle preparation has a uniform particle size distribution.
本实施例制备的伊立替康脂束制剂的透射电镜照片结果与图 5类似， 所制
备的伊立替康药物脂束制剂粒径均匀。 The results of transmission electron micrographs of the irinotecan lipid bundle preparation prepared in this example are similar to those of FIG. The prepared irinotecan drug lipid bundle preparation has a uniform particle size.
实施例 15 Example 15
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.5g 伊立替康、 2.5g 乙醇、 丙二醇 1.8g， Na2C03 0.01g， 3.0g Solutol HS15 (德国 BASF公司） 、 1.8g甘油， 常温溶解， 得到溶液8。 2. Weigh 0.5 g of irinotecan, 2.5 g of ethanol, 1.8 g of propylene glycol, 0.01 g of Na 2 C0 3 , 3.0 g of Solutol HS15 (BASF, Germany), 1.8 g of glycerin, and dissolve at room temperature to obtain a solution 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康纳米制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan nano preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的粒径测定 Third, the determination of the particle size of irinotecan lipid bundle preparation
用英国 Malven仪器公司的 ZS90仪器检测伊立替康脂束制剂的粒径。 The particle size of the irinotecan lipid bundle preparation was measured using a ZS90 instrument from Malven Instruments, England.
本实施例制备的伊立替康脂束制剂的透射电镜照片类似图 5所示， 制备的 伊立替康脂束制剂为粒径均匀的药物颗粒。 The transmission electron micrograph of the irinotecan lipid bundle preparation prepared in this example is similar to that shown in Fig. 5, and the prepared irinotecan lipid bundle preparation is a drug particle having a uniform particle diameter.
实施例 16 Example 16
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.5g 伊立替康、 2.5g 乙醇、 丙二醇 1.8g， 乙二胺 0.01g， 3.0g Solutol HS15 (德国 BASF公司） 、 1.8g甘油， 常温溶解， 得到溶液8。 2. Weigh 0.5 g of irinotecan, 2.5 g of ethanol, 1.8 g of propylene glycol, 0.01 g of ethylenediamine, 3.0 g of Solutol HS15 (BASF, Germany), 1.8 g of glycerin, and dissolve at room temperature to obtain a solution 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄
清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to those in Figure 2, and the precursor of irinotecan lipid bundle preparation is Cheng Cheng. Clear transparent liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康纳米制剂。 结果类似图 3中左侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan nano preparation. The results were similar to the left tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
本实施例制备的伊立替康脂束制剂的透射电镜结果与图 5类似， 均为粒径 均匀的纳米颗粒。 The TEM results of the irinotecan lipid bundle preparation prepared in this example are similar to those of Fig. 5, and are all nanoparticles having a uniform particle size.
实施例 17 Example 17
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.5g伊立替康、 2.5g乙醇、 3.0g Solutol HS15 (德国 BASF公司）、 1.8g甘油， 0.05g CRGDK-PEG-DSPE, 常温溶解， 得到溶液8。 2. Weigh 0.5 g of irinotecan, 2.5 g of ethanol, 3.0 g of Solutol HS15 (BASF, Germany), 1.8 g of glycerol, 0.05 g of CRGDK-PEG-DSPE, and dissolve at room temperature to obtain a solution 8.
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到 伊立替康纳米制剂。 结果类似图 3中右侧试管， 伊立替康脂束制剂呈乳状液。 The irinotecan lipid bundle preparation precursor prepared in the first step was diluted with 20 volumes of physiological saline to obtain a irinotecan nano preparation. The results were similar to the right tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion.
三、 伊立替康脂束制剂的肿瘤靶向效果验证 Third, irinotecan lipid bundle preparation tumor targeting effect verification
小动物活体成像技术被用于研究表面 CRGDK-PEG-DSPE靶向的伊立替康 脂束药物在肿瘤部位的靶向聚集效果。 具体实验方法如下所示： Small animal in vivo imaging techniques were used to study the targeted aggregation of irinotecan liposome drugs targeted by CRGDK-PEG-DSPE at the tumor site. The specific experimental method is as follows:
按照实施例 1 的方法制备不带有 CRGDK-PEG-DSPE靶向基团的伊立替康 纳米脂束（配方中不含有 CRGDK-PEG-DSPE)，配方中加入 DiR染料乙醇溶液， 用 20倍体积的生理盐水稀释， 得到伊立替康纳米脂束注射剂 B。
按照实施例 17的方法制备的带有 CRGDK-PEG-DSPE靶向基团的伊立替康 纳米脂束， 配方中加入 DiR染料乙醇溶液， 用 20倍体积的生理盐水稀释， 得到 伊立替康纳米脂束注射剂 C。 The irinotecan nanolipid bundle without the CRGDK-PEG-DSPE targeting group was prepared according to the method of Example 1 (the formula does not contain CRGDK-PEG-DSPE), and the DiR dye ethanol solution was added to the formulation, and the volume was 20 times. The physiological saline was diluted to obtain irinotecan nanolipid injection B. The irinotecan nanolipid bundle with CRGDK-PEG-DSPE targeting group prepared according to the method of Example 17 was added with DiR dye ethanol solution and diluted with 20 volumes of physiological saline to obtain irinotecan nanolipid. Bundle injection C.
伊立替康生理盐水溶液为注射剂 A， 其中加入了 DiR染料的乙醇溶液。 上述注射剂 A、 B和 C中 DiR染料的浓度控制相同。 The irinotecan physiological saline solution is Injection A, to which an ethanol solution of DiR dye is added. The concentrations of the DiR dyes in the above injections A, B and C were controlled to be the same.
取三只皮下荷瘤小鼠， 分别注射等体积的注射剂 A、 B和 C， 24小时后取 出实体瘤， 用多光谱小动物活体成像系统 （CRI Maestro 2) 观察肿瘤处药物富 集效果。 图 10显示了表面 CRGDK-PEG-DSPE靶向脂束药物在肿瘤部位的聚集 情况， 小动物成像显示与游离药物（注射剂 A) 比较， 脂束药物（注射剂 B)在 肿瘤部位有明显的聚集 （中间）， 比较显示， CRGDK-PEG-DSPE靶向脂束药物 (注射剂 C)具有更加明显的肿瘤富集作用（下）。图 10说明： CRGDK-PEG-DSPE 靶向功能的伊立替康脂束药物在肿瘤部位有更加明显的聚集， 从而能够起到更 好的治疗效果。 Three subcutaneous tumor-bearing mice were injected with equal volumes of injections A, B and C, and solid tumors were taken 24 hours later. The multi-spectral small animal in vivo imaging system (CRI Maestro 2) was used to observe the drug enrichment effect at the tumor site. Figure 10 shows the aggregation of the surface CRGDK-PEG-DSPE targeting lipid tract drug at the tumor site. Small animal imaging showed that the lipid tract drug (injection B) had significant aggregation at the tumor site compared with the free drug (injection A). In the middle, the comparison shows that the CRGDK-PEG-DSPE targeting lipid tract drug (injection C) has a more pronounced tumor enrichment effect (bottom). Figure 10 illustrates: CRGDK-PEG-DSPE-targeted irinotecan liposome drug has a more pronounced aggregation at the tumor site, which can provide better therapeutic results.
实施例 18 Example 18
一、 伊立替康脂束制剂前体的制备 I. Preparation of irinotecan lipid bundle preparation precursor
1、 称取 1.2g磷脂 （德国 Lipoid公司） 和 0.3g乙醇， 溶解， 得到溶液八。 1. Weigh 1.2 g of phospholipid (Lipoid, Germany) and 0.3 g of ethanol, and dissolve to obtain a solution of 8.
2、 称取 0.5g伊立替康、 2.5g乙醇、 3.0g Solutol HS15 (德国 BASF公司）、 1.8g甘油， 0.05g叶酸 -PEG-DSPE, 常温溶解， 得到溶液^ 2. Weigh 0.5 g irinotecan, 2.5 g ethanol, 3.0 g Solutol HS15 (BASF, Germany), 1.8 g glycerol, 0.05 g folic acid-PEG-DSPE, dissolve at room temperature, and obtain a solution^
3、 将溶液 A和溶液 B混合， 室温搅拌、 混匀， 得到澄清透明伊立替康脂束 制剂前体， 氮气保护， 密封保存。 结果类似图 2， 伊立替康脂束制剂前体为澄 清透明液体。 3. Mix solution A and solution B, stir at room temperature, and mix to obtain a clear transparent irinotecan lipid bundle preparation precursor, protected by nitrogen, and sealed. The results are similar to Figure 2, in which the irinotecan lipid bundle formulation precursor is a clear, clear liquid.
二、 伊立替康脂束制剂的制备 2. Preparation of irinotecan lipid bundle preparation
将步骤一制备的伊立替康脂束制剂前体用 20倍体积的生理盐水稀释， 得到
伊立替康纳米制剂。 结果类似图 3中右侧试管， 伊立替康脂束制剂呈乳状液。 三、 伊立替康脂束制剂的肿瘤靶向效果验证 The irinotecan lipid bundle preparation precursor prepared in the first step is diluted with 20 volumes of physiological saline to obtain Irinotecan nano preparations. The results were similar to the right tube in Figure 3, and the irinotecan lipid bundle formulation was in the form of an emulsion. Third, irinotecan lipid bundle preparation tumor targeting effect verification
药效学研究显示， 叶酸 -PEG-DSPE靶向的伊立替康脂束药物具有更好地肿 瘤抑制效果。图 11显示了表面叶酸 -PEG-DSPE靶向脂束药物在的肿瘤药效学研 究， 光学照片显示， 经 30天治疗后， 实施例 18制备的叶酸 -PEG-DSPE靶向的 脂束药物 （右） 治疗组的肿瘤与实施例 1 制备的脂束药物组 （中） 和游离药物 组 （左） 相比最小， 这表明叶酸 -PEG-DSPE靶向能增强脂束药物的治疗效果， 原因在于叶酸 -PEG-DSPE靶向脂束药物具有更加增强的肿瘤富集效果。 图 11说 明： 同样的时间治疗后， 具有叶酸 -PEG-DSPE靶向功能的伊立替康脂束药物能 更好的的抑制肿瘤生长， 即具有更好的治疗效果。 Pharmacodynamic studies have shown that folic acid-PEG-DSPE-targeted irinotecan lipid tract drugs have better tumor suppressive effects. Figure 11 shows a tumor pharmacodynamic study of a surface folate-PEG-DSPE targeting lipid tract drug, and an optical photograph showing the folate-PEG-DSPE targeted lipid tract drug prepared in Example 18 after 30 days of treatment ( Right) The tumor in the treatment group was the smallest compared with the liposome drug group (middle) and the free drug group (left) prepared in Example 1, indicating that folic acid-PEG-DSPE targeting can enhance the therapeutic effect of the lipid tract drug because Folic acid-PEG-DSPE targeting lipid tract drugs have a more enhanced tumor enrichment effect. Figure 11 shows that irinotecan liposome with folate-PEG-DSPE targeting function can better inhibit tumor growth after the same treatment, which has better therapeutic effect.
本发明通过上述实施例制备得到伊立替康纳米脂束制剂， 作为脂束制剂它 能降低伊立替康的毒性、 具有长循环效果、 能增强肿瘤靶向富集作用和增加病 人顺应性。 The present invention provides an irinotecan nanolipid preparation prepared by the above examples, which, as a lipid bundle preparation, can reduce the toxicity of irinotecan, has a long circulation effect, can enhance tumor targeted enrichment and increase patient compliance.
以上详细描述了本发明的实施方式， 但是， 本发明并不限于上述实施方式 中的具体细节， 在本发明的技术构思范围内， 可以对本发明的技术方案进行多 种简单变型， 这些简单变型均属于本发明的保护范围。 The embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details in the above embodiments, and various simple modifications can be made to the technical solutions of the present invention within the scope of the technical idea of the present invention. It belongs to the scope of protection of the present invention.
另外需要说明的是， 在上述具体实施方式中所描述的各个具体技术特征， 在不矛盾的情况下， 可以通过任何合适的方式进行组合， 为了避免不必要的重 复， 本发明对各种可能的组合方式不再另行说明。 It should be further noted that the specific technical features described in the above specific embodiments may be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention has various possibilities. The combination method will not be described separately.
此外， 本发明的各种不同的实施方式之间也可以进行任意组合， 只要其不 违背本发明的思想， 其同样应当视为本发明所公开的内容。
Furthermore, any combination of the various embodiments of the invention may be made, as long as it does not deviate from the spirit of the invention, and should be considered as the disclosure of the invention.
Claims
1、 一种伊立替康纳米脂束制剂， 包含磷脂、 聚乙二醇-十二羟基硬脂酸 酯、 甘油、 乙醇和伊立替康， 及注射用水性溶剂。 1. An irinotecan lipid bundle preparation, containing phospholipid, polyethylene glycol-dodecylhydroxystearate, glycerin, ethanol and irinotecan, and an aqueous solvent for injection.
2、 根据权利要求 1 所述的伊立替康纳米脂束制剂， 其特征在于， 所述注 射用水性溶剂选自生理盐水、 葡萄糖注射液和注射用水中的一种或多种。 2. The lipid bundle preparation of irinoteconanib according to claim 1, characterized in that the water-based solvent for injection is selected from one or more of physiological saline, glucose injection and water for injection.
3、 根据权利要求 1或 2所述的伊立替康纳米脂束制剂， 其特征在于， 所述 制剂包含 4〜8重量份磷脂、 10〜20重量份聚乙二醇-十二羟基硬脂酸酯、 5〜15重 量份甘油、 10〜20重量份乙醇和 1〜4重量份伊立替康； 优选地， 所述注射用水性溶剂的体积是所述磷脂、 聚乙二醇-十二羟基硬脂 酸酯、 甘油、 乙醇和伊立替康总体积的 5-100倍， 进一步优选 5-80倍， 更进一 步优选 10-20倍。 3. The irinotecanamide lipid bundle preparation according to claim 1 or 2, characterized in that the preparation contains 4 to 8 parts by weight of phospholipids and 10 to 20 parts by weight of polyethylene glycol-dodecahydroxystearic acid. Ester, 5 to 15 parts by weight of glycerin, 10 to 20 parts by weight of ethanol and 1 to 4 parts by weight of irinotecan; Preferably, the volume of the aqueous solvent for injection is the phospholipid, polyethylene glycol-dodecahydroxyharden The total volume of fatty acid ester, glycerin, ethanol and irinotecan is 5-100 times, more preferably 5-80 times, and even more preferably 10-20 times.
4、 根据权利要求 1-3任一项所述的伊立替康纳米脂束制剂， 其特征在于， 所述制剂还包含主动靶向材料； 优选地，所述主动靶向材料为 X-PEG-DSPE，其中 X表示叶酸、五肽 CRGDK 或胆酸中的一种或多种， PEG表示聚乙二醇， DSPE表示二硬脂酰基磷脂酰乙 醇胺； 4. The irinotecanamide lipid beam preparation according to any one of claims 1 to 3, characterized in that the preparation also contains an active targeting material; Preferably, the active targeting material is X-PEG- DSPE, where X represents one or more of folic acid, pentapeptide CRGDK or cholic acid, PEG represents polyethylene glycol, and DSPE represents distearoylphosphatidylethanolamine;
优选地， 所述制剂中主动靶向材料 X-PEG-DSPE的含量为 0.01-2重量份， 更优选 0.1-1重量份， 最优选 0.1-0.4重量份； 优选地， 所述制剂还包含防冻剂和 /或 pH调节剂； 其中所述防冻剂选自丙 二醇和山梨糖醇； 所述 pH 调节剂选自柠檬酸、 乳酸、 Na2C03、 NaOH、 N C1、 NaHC03和 Ca(OH)2。 Preferably, the content of the active targeting material X-PEG-DSPE in the preparation is 0.01-2 parts by weight, more preferably 0.1-1 parts by weight, and most preferably 0.1-0.4 parts by weight; Preferably, the preparation also contains antifreeze agent and/or pH adjuster; wherein the antifreeze is selected from propylene glycol and sorbitol; the pH adjuster is selected from citric acid, lactic acid, Na 2 CO 3 , NaOH, N Cl, NaHCO 3 and Ca(OH) 2 .
5、 一种制备权利要求 1-4任一项所述的伊立替康纳米脂束制剂的方法， 包 括： 5. A method for preparing the irinoteconanib lipid bundle preparation according to any one of claims 1 to 4, including:
( 1 ) 将磷脂、 聚乙二醇-十二羟基硬脂酸酯、 甘油、 乙醇和伊立替康以及
任选的主动靶向材料、 任选的防冻剂和 /或 pH 调节剂混合， 配成澄清透明溶 液； (1) Combine phospholipid, polyethylene glycol-dodecahydroxystearate, glycerol, ethanol and irinotecan and Optional active targeting material, optional antifreeze and/or pH adjuster are mixed to form a clear and transparent solution;
(2)用注射用水性溶剂稀释所述澄清透明溶液， 自乳化得到所述伊立替康 纳米脂束制剂。 (2) Dilute the clear and transparent solution with an aqueous solvent for injection and self-emulsify to obtain the irinotecan nanolipid bundle preparation.
6、 根据权利要求 5所述的方法， 其特征在于， 所述步骤 （1 ) 具体为： ( la) 将磷脂与乙醇混合溶解， 配成第一溶液； 6. The method according to claim 5, characterized in that the step (1) is specifically: (la) mixing and dissolving phospholipid and ethanol to prepare the first solution;
( lb)将聚乙二醇-十二羟基硬脂酸酯、 甘油、 乙醇和伊立替康以及任选的 主动靶向材料、 任选的防冻剂和 /或 pH调节剂混合溶解， 配成第二溶液； (lb) Mix and dissolve polyethylene glycol-dodecahydroxystearate, glycerol, ethanol and irinotecan as well as optional active targeting materials, optional antifreeze and/or pH adjuster to formulate the third Two solutions;
( lc) 将所述第一溶液与所述第二溶液混合， 搅拌混匀得到所述澄清透明 溶液。 (lc) Mix the first solution and the second solution, stir and mix to obtain the clear and transparent solution.
7、 根据权利要求 5所述的方法， 其特征在于， 所述步骤 （1 ) 具体为： 将磷脂、 聚乙二醇-十二羟基硬脂酸酯、 甘油、 乙醇和伊立替康以及任选 的主动靶向材料、 任选的防冻剂和 /或 pH调节剂混合， 搅拌混匀配成澄清透明 溶液。 7. The method according to claim 5, characterized in that the step (1) is specifically: combining phospholipid, polyethylene glycol-dodecahydroxystearate, glycerin, ethanol and irinotecan and optionally Mix the active targeting material, optional antifreeze and/or pH adjuster, stir and mix to form a clear and transparent solution.
8、 根据权利要求 5-7任一项所述的方法， 其特征在于， 所述注射用水性溶 剂选自生理盐水、 葡萄糖注射液和注射用水中的一种或多种。 8. The method according to any one of claims 5 to 7, characterized in that the aqueous solvent for injection is selected from one or more of physiological saline, glucose injection and water for injection.
9、 根据权利要求 5-8任一项所述的方法， 其特征在于， 所述澄清透明溶液 含 4〜8重量份磷脂、 10〜20重量份聚乙二醇-十二羟基硬脂酸酯、 5〜15重量份甘 油、 10〜20重量份乙醇和 1〜4重量份伊立替康； 9. The method according to any one of claims 5 to 8, characterized in that the clear and transparent solution contains 4 to 8 parts by weight of phospholipid and 10 to 20 parts by weight of polyethylene glycol-dodecahydroxystearate. , 5 to 15 parts by weight of glycerin, 10 to 20 parts by weight of ethanol and 1 to 4 parts by weight of irinotecan;
优选地，所述澄清透明溶液还含 0.01-2重量份主动靶向材料 X-PEG-DSPE, 其中 X表示叶酸、 五肽 CRGDK或胆酸中的一种或多种； Preferably, the clear and transparent solution also contains 0.01-2 parts by weight of the active targeting material X-PEG-DSPE, where X represents one or more of folic acid, pentapeptide CRGDK or cholic acid;
优选地， 所述注射用水性溶剂的体积是所述澄清透明溶液的 5-100倍， 优 选 5-80倍， 更优选 10-20倍；
Preferably, the volume of the aqueous solvent for injection is 5-100 times that of the clear and transparent solution, preferably 5-80 times, and more preferably 10-20 times;
10、 一种根据权利要求 5-9任一项所述的方法制备得到的伊立替康纳米脂 束制剂， 其特征在于， 所述制剂通过静脉注射、 肌肉注射或皮下注射给药。
10. An irinoteconanib lipid bundle preparation prepared according to the method of any one of claims 5 to 9, characterized in that the preparation is administered by intravenous injection, intramuscular injection or subcutaneous injection.
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| CN104257628B (en) * | 2014-09-15 | 2017-01-11 | 中国人民解放军第二军医大学 | Salinomycin-loaded micelle as well as preparation method and application thereof |
| CN112891551B (en) * | 2021-01-27 | 2023-11-17 | 中国药科大学 | Nanometer medicine with irinotecan as carrier and its prepn and application |
| CN114796110A (en) * | 2021-01-28 | 2022-07-29 | 北京德立福瑞医药科技有限公司 | Insoluble drug concentrated solution without ethanol and micelle solution prepared from insoluble drug concentrated solution |
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| CN101091890A (en) * | 2007-07-26 | 2007-12-26 | 沈阳药科大学 | Composite type emulsifier, and emulsion prepared by using the emulsifier, and preparation method |
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