CN114042042A - W/O/W type temperature-sensitive embolic agent - Google Patents
W/O/W type temperature-sensitive embolic agent Download PDFInfo
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- CN114042042A CN114042042A CN202111432174.1A CN202111432174A CN114042042A CN 114042042 A CN114042042 A CN 114042042A CN 202111432174 A CN202111432174 A CN 202111432174A CN 114042042 A CN114042042 A CN 114042042A
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- type temperature
- embolic agent
- temperature
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- 230000003073 embolic effect Effects 0.000 title claims abstract description 80
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 72
- 229920003213 poly(N-isopropyl acrylamide) Polymers 0.000 claims abstract description 14
- 239000012071 phase Substances 0.000 claims description 131
- 239000003921 oil Substances 0.000 claims description 70
- 235000019198 oils Nutrition 0.000 claims description 70
- 239000002246 antineoplastic agent Substances 0.000 claims description 21
- 239000003431 cross linking reagent Substances 0.000 claims description 17
- 239000004094 surface-active agent Substances 0.000 claims description 16
- 239000008346 aqueous phase Substances 0.000 claims description 15
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 claims description 15
- 229940044683 chemotherapy drug Drugs 0.000 claims description 13
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims description 10
- 229940127089 cytotoxic agent Drugs 0.000 claims description 9
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- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 claims description 8
- 229960001025 iohexol Drugs 0.000 claims description 8
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 claims description 8
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- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- LEJBBGNFPAFPKQ-UHFFFAOYSA-N 2-(2-prop-2-enoyloxyethoxy)ethyl prop-2-enoate Chemical compound C=CC(=O)OCCOCCOC(=O)C=C LEJBBGNFPAFPKQ-UHFFFAOYSA-N 0.000 claims description 6
- INQDDHNZXOAFFD-UHFFFAOYSA-N 2-[2-(2-prop-2-enoyloxyethoxy)ethoxy]ethyl prop-2-enoate Chemical compound C=CC(=O)OCCOCCOCCOC(=O)C=C INQDDHNZXOAFFD-UHFFFAOYSA-N 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
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- KUDUQBURMYMBIJ-UHFFFAOYSA-N 2-prop-2-enoyloxyethyl prop-2-enoate Chemical compound C=CC(=O)OCCOC(=O)C=C KUDUQBURMYMBIJ-UHFFFAOYSA-N 0.000 claims description 4
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- HVVWZTWDBSEWIH-UHFFFAOYSA-N [2-(hydroxymethyl)-3-prop-2-enoyloxy-2-(prop-2-enoyloxymethyl)propyl] prop-2-enoate Chemical compound C=CC(=O)OCC(CO)(COC(=O)C=C)COC(=O)C=C HVVWZTWDBSEWIH-UHFFFAOYSA-N 0.000 claims description 3
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- GJQRYIOSVPEUQJ-UHFFFAOYSA-N n-[3-(prop-2-enoylamino)propyl]prop-2-enamide Chemical compound C=CC(=O)NCCCNC(=O)C=C GJQRYIOSVPEUQJ-UHFFFAOYSA-N 0.000 claims description 2
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- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 1
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical group OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
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- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- IIYYSVCDYLYLRI-UHFFFAOYSA-N NC(=O)C=CCCCC=CC(N)=O Chemical compound NC(=O)C=CCCCC=CC(N)=O IIYYSVCDYLYLRI-UHFFFAOYSA-N 0.000 description 1
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- 229960004562 carboplatin Drugs 0.000 description 1
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- 230000010109 chemoembolization Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
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- 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
- A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a W/O/W type temperature-sensitive embolic agent, which comprises an external water phase, an oil phase and an internal water phase; the temperature-sensitive nanogel and a first aqueous developer are dispersed in the outer water phase; an oily developer is dispersed in the oil phase; the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure. The W/O/W type temperature-sensitive embolic agent is water-in-oil-in-water emulsion, developers are dispersed in an external water phase and an oil phase of the W/O/W type temperature-sensitive embolic agent, and meanwhile, a specific temperature-sensitive nanogel is selected to be dispersed in the external water phase, so that the overall better interaction is realized.
Description
Technical Field
The invention relates to the technical field of embolism, in particular to a W/O/W type temperature-sensitive embolic agent.
Background
Transcatheter Arterial Embolization chemotherapy (TACE) is one of the most important current treatments for middle and advanced liver cancer, in which Embolization agents play a very important role. The liquid embolic agent represented by the iodine oil emulsion is the liver tumor vascular embolization material which is most widely applied at present, and the traditional chemoembolization based on the iodine oil emulsion is called C-TACE (Convention-TACE). Although the iodized oil emulsion has good fluidity and can smoothly pass through a microcatheter to realize tumor peripheral vascular embolization, the iodized oil emulsion has poor embolization performance and is easily scoured and metabolized by blood to cause recanalization, under the condition, solid embolization agents such as gelatin Sponge (gelatin Sponge) and PVA (polyvinyl alcohol) are often needed to be matched for secondary embolization treatment, the operation of the secondary embolization treatment is complicated, the cost is increased, and embolization complications can be caused sometimes.
The poly-N-isopropylacrylamide temperature-sensitive nano gel has lower viscosity in a sol state, is converted into a non-flowable gel state from a good flowing state in a human body temperature environment, has good fluidity and embolization, can overcome the contradiction between the fluidity and the embolization of the traditional embolization agent, has drug-carrying slow-release performance, and is expected to become a new generation of embolization agents for interventional therapy. The temperature-sensitive gel does not have a developing function, and can be visualized in the operation only by blending with a developer. During the actual operation, the developing capability is often improved by increasing the dosage of the developing agent; however, an excessive amount of the developer increases the viscosity of the gel to impair the fluidity thereof, and also decreases the strength of the gel to soften the gel to impair the embolization effect.
Disclosure of Invention
In view of the above, the present invention is directed to a W/O/W type temperature-sensitive embolization agent to coordinate the development ability and embolization effect of the temperature-sensitive embolization agent.
The invention provides a W/O/W type temperature-sensitive embolic agent, which comprises an external water phase, an oil phase and an internal water phase;
the temperature-sensitive nanogel and a first aqueous developer are dispersed in the outer water phase;
an oily developer is dispersed in the oil phase;
the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure.
Preferably, the N-isopropylacrylamide-based polymer having a three-dimensional network structure includes one or more of cross-linker-crosslinked poly (N-isopropylacrylamide), cross-linker-crosslinked poly (NIP-co-AA), cross-linker-crosslinked poly (NIP-co-NNP), cross-linker-crosslinked poly (NIP-co-MMA), cross-linker-crosslinked poly (NIP-co-HEMA), cross-linker-crosslinked poly (NIP-co-HEA), and cross-linker-crosslinked poly (NIP-co-AAm);
the cross-linking agent is selected from one or more of N, N '-methylene bisacrylamide, N' -ethylene bisacrylamide, 1, 3-propylene bisacrylamide, ethylene diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, trimethylolpropane triacrylate and pentaerythritol triacrylate.
Preferably, the temperature-sensitive nanogel accounts for 1-6% of the total mass of the W/O/W type temperature-sensitive embolic agent, and the first aqueous developer accounts for 0.5-50% of the total mass of the W/O/W type temperature-sensitive embolic agent.
Preferably, the first aqueous developer is selected from one or more of iohexol, iopamidol, iodixanol and iofluranol.
Preferably, the solvent of the oil phase is iodized oil and/or vegetable oil for injection.
Preferably, the solvent of the oily developer and the oil phase is iodized oil, and the iodized oil accounts for 10-40% of the total mass of the W/O/W type temperature-sensitive embolic agent.
Preferably, the external aqueous phase further comprises:
an aqueous chemotherapeutic agent; the water-based chemotherapeutic drug accounts for 0.1-5% of the total mass of the W/O/W type temperature-sensitive embolic agent.
Preferably, the oil phase further comprises:
oily chemotherapeutic drugs; the oily chemotherapeutic drug accounts for 0.05-1.5% of the total mass of the W/O/W type temperature-sensitive embolic agent.
Preferably, the internal aqueous phase further comprises:
an aqueous chemotherapeutic agent and/or a second aqueous imaging agent selected from one or more of iohexol, iopamidol, iodixanol and iofluranol.
Preferably, the W/O/W type temperature-sensitive embolic agent further comprises:
a surfactant; the surfactant accounts for 0.01-2% of the total mass of the W/O/W type temperature-sensitive embolic agent.
The invention provides a W/O/W type temperature-sensitive embolic agent, which comprises an external water phase, an oil phase and an internal water phase; the temperature-sensitive nanogel and a first aqueous developer are dispersed in the outer water phase; an oily developer is dispersed in the oil phase; the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure. Compared with the prior art, the W/O/W type temperature-sensitive embolic agent provided by the invention is water-in-oil-in-water (W/O/W) emulsion, developers are dispersed in the external water phase and the oil phase of the W/O/W type temperature-sensitive embolic agent, and meanwhile, the specific temperature-sensitive nano gel is selected and dispersed in the external water phase, so that the overall better interaction is realized.
Drawings
FIG. 1 is a comparative graph of X-ray photographs taken of the temperature-sensitive embolizing agents provided in example 1 and comparative examples 1-2.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The embodiment of the invention provides a W/O/W type temperature-sensitive embolic agent, which comprises an external water phase, an oil phase and an internal water phase;
the temperature-sensitive nanogel and a first aqueous developer are dispersed in the external water phase;
an oily developer is dispersed in the oil phase;
the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure.
In the embodiment of the invention, the W/O/W type temperature-sensitive embolic agent comprises an external water phase, an oil phase and an internal water phase, and preferably consists of the external water phase, the oil phase and the internal water phase.
In an embodiment of the invention, a temperature sensitive nanogel and a first aqueous developer are dispersed in an external aqueous phase. In the embodiment of the invention, the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure, and is different from a conventional linear poly N-isopropyl acrylamide polymer. The N-isopropylacrylamide polymer with the three-dimensional network structure preferably comprises one or more of cross-linking agent crosslinked poly (N-isopropylacrylamide), cross-linking agent crosslinked poly (NIP-co-AA), cross-linking agent crosslinked poly (NIP-co-NNP), cross-linking agent crosslinked poly (NIP-co-MMA), cross-linking agent crosslinked poly (NIP-co-HEMA), cross-linking agent crosslinked poly (NIP-co-HEA) and cross-linking agent crosslinked poly (NIP-co-AAm), more preferably cross-linking agent crosslinked poly (N-isopropylacrylamide), cross-linking agent crosslinked poly (NIP-co-AA), cross-linking agent crosslinked poly (NIP-co-NNP), cross-linking agent crosslinked poly (NIP-co-MMA), cross-linking agent crosslinked poly (NIP-co-HEMA), Cross-linker cross-linked poly (NIP-co-HEA) or cross-linker cross-linked poly (NIP-co-AAm). It is understood that NIP represents N-isopropyl acrylamide, AA represents acrylic acid, NNP represents N-propyl acrylamide, MMA represents methyl methacrylate, HEMA represents hydroxyethyl methacrylate, HEA represents hydroxyethyl acrylate, and AAm represents acrylamide.
In the embodiment of the present invention, the crosslinking agent is preferably one or more selected from N, N ' -methylenebisacrylamide, N ' -ethylenebisacrylamide, 1, 3-propylenediacrylamide, ethyleneglycol diacrylate, diethyleneglycol diacrylate, triethyleneglycol diacrylate, trimethylolpropane triacrylate, pentaerythritol triacrylate, and more preferably N, N ' -methylenebisacrylamide.
The sources of the temperature-sensitive nanogel and the cross-linking agent are not particularly limited, and the temperature-sensitive nanogel and the cross-linking agent can be commercially available products well known to those skilled in the art, or can be prepared into products by adopting the conventional technical means in the art.
Taking N, N' -methylene bisacrylamide crosslinked poly (N-isopropyl acrylamide) as an example, the preparation method is preferably as follows:
adding N-isopropyl acrylamide, sodium dodecyl sulfate and N, N '-methylene bisacrylamide into a three-necked bottle provided with a reflux condenser tube and an air guide device, dissolving the N-isopropyl acrylamide, sodium dodecyl sulfate and N, N' -methylene bisacrylamide with ultrapure water under magnetic stirring, introducing high-purity nitrogen into the reaction system for 20-40 min, heating the reaction system to 65-75 ℃, adding an initiator potassium persulfate, and adding N into the reaction system2Reacting for 4-5 h at 65-75 ℃ in the atmosphere to obtain a white turbid suspension, dialyzing and purifying the suspension in ultrapure water, freeze-drying, and collecting freeze-dried powder to obtain the product.
In the embodiment of the invention, the temperature-sensitive nanogel preferably accounts for 1-6% of the total mass of the W/O/W type temperature-sensitive embolic agent, and more preferably accounts for 2.8-5.9%; on the basis, the embolic agent has good fluidity while ensuring good embolization effect.
In the present embodiment, the first aqueous developer is preferably selected from one or more of iohexol, iopamidol, iodixanol and ioflurol, and more preferably iohexol, iopamidol, iodixanol or ioflurol. The source of the aqueous developer in the present invention is not particularly limited, and commercially available products known to those skilled in the art may be used.
In the embodiment of the invention, the first aqueous developer preferably accounts for 0.5-50% of the total mass of the W/O/W type temperature-sensitive embolization agent, more preferably accounts for 1.12-30%, and the embolization agent is ensured to have good embolization effect and developing capability and good fluidity by cooperating with the dosage of the temperature-sensitive nanogel. Furthermore, the mass of the temperature-sensitive nanogel in each 100mL of external water phase is preferably 1 g-8 g; the quality of the first aqueous developer is compounded, so that the normal running of the gel phase change behavior is ensured.
In the present embodiment, the external aqueous phase preferably further comprises an aqueous chemotherapeutic agent dispersed therein; the invention is not particularly limited with respect to the particular type and source of the aqueous chemotherapeutic agent. In the embodiment of the invention, the water-based chemotherapeutic drug preferably accounts for 0.1-5% of the total mass of the W/O/W type temperature-sensitive embolic agent, and more preferably accounts for 0.5-3%.
According to the invention, the external water phase consisting of the specific content is adopted, and the specific aqueous developer is dispersed in the external water phase, so that on one hand, the specific aqueous developer can cooperate with the oily developer in the oil phase part to achieve the purpose of increasing the developing capability of the preparation, on the other hand, the amount of the aqueous developer in the external water phase can be adjusted, the influence on the fluidity of the specific temperature-sensitive nano gel and the gel phase change behavior of the specific temperature-sensitive nano gel adopted by the invention due to overhigh amount of the aqueous developer in the external water phase can be avoided, and the embolism effect of the temperature-sensitive embolism agent is ensured (in the prior art, the poly-N-isopropylacrylamide temperature-sensitive nano gel is blended with the developer, the gel viscosity is increased due to overhigh amount of the developer, the fluidity is influenced, the gel strength is reduced, and the embolism effect is influenced), so that the influence of the developer on the embolism effect of the temperature-sensitive nano gel is reflected; it is worth noting that when the dosage of the temperature-sensitive nanogel and the developer in the preparation is controlled within a certain range, the preparation can be ensured to have excellent embolization effect.
In the present embodiment, an oily developer is dispersed in the oil phase; the solvent of the oil phase is preferably iodized oil and/or vegetable oil for injection, wherein the vegetable oil for injection includes, but is not limited to, castor oil, soybean oil, etc., and the present invention is not particularly limited thereto; the solvent of the oil phase is more preferably iodized oil. The invention disperses the oily developer in the oil phase, which is beneficial to improving the stability of the preparation.
In a preferred embodiment of the present invention, the solvent of the oily developer and the oil phase is iodized oil; the iodized oil is used as an oil phase matrix and a developer, so that the dosage of the oily developer in the embolic agent can be maximized; in addition, by forming W/O/W type emulsion, the water-soluble poly N-isopropyl acrylamide temperature-sensitive nano gel can stably coexist with the iodized oil, so that the stability of the preparation is obviously improved while the embolization effect is improved.
In the embodiment of the invention, when the developer dispersed in the oil phase is the oil developer, the first aqueous developer and the oil developer can be well compatible in the same preparation, and the stability is high.
In the embodiment of the invention, the iodized oil preferably accounts for 10-40% of the total mass of the W/O/W type temperature-sensitive embolic agent, and more preferably accounts for 20-34%; under the specific dosage limit, the preparation stability can be ensured, and demulsification caused by excessive iodized oil can be prevented.
In the embodiment of the invention, the oily chemotherapeutic medicament is preferably dispersed in the oil phase; the invention has no special limitation on the specific types and sources of the oily chemotherapeutic drugs. In the embodiment of the invention, the oily chemotherapeutic drug preferably accounts for 0.05-1.5% of the total mass of the W/O/W type temperature-sensitive embolic agent, and more preferably accounts for 0.07-1%.
In embodiments of the invention, the inner aqueous phase also has dispersed therein an aqueous chemotherapeutic agent and/or a second aqueous imaging agent; the concentration of the second aqueous developer dispersed in the internal aqueous phase in the present invention is not particularly limited, and a concentration value in the range of 0 to the saturation concentration well known to those skilled in the art may be used. The invention disperses the second aqueous developer in the internal aqueous phase, which is beneficial to improving the amount of the developer in the temperature-sensitive suppository, thereby further improving the X-ray developing capability.
In the present embodiment, the second aqueous developer is preferably selected from one or more of iohexol, iopamidol, iodixanol and iofluranol, and more preferably iohexol, iopamidol, iodixanol or iofluranol. The source of the second aqueous developer in the present invention is not particularly limited, and commercially available products known to those skilled in the art may be used.
In the embodiment of the present invention, the second aqueous developer preferably accounts for 0.1% to 5%, more preferably 0.5% to 2% of the total mass of the W/O/W type temperature-sensitive plugging agent.
In the present embodiment, the inner aqueous phase preferably further comprises an aqueous chemotherapeutic agent dispersed therein; the invention is not particularly limited with respect to the particular type and source of the aqueous chemotherapeutic agent. In the embodiment of the invention, the water-based chemotherapeutic drug preferably accounts for 0.05-3% of the total mass of the W/O/W type temperature-sensitive embolic agent.
In the present embodiment, the volume ratio of the internal aqueous phase and the oil phase is preferably 1: (1 to 8), more preferably 1: (2-3).
In the present embodiment, the volume ratio of the sum of the internal aqueous phase and the oil phase to the external aqueous phase is preferably 1: (1-5), more preferably 1: (1-2).
In the embodiment of the invention, the W/O/W type temperature-sensitive embolic agent preferably further comprises:
a surfactant; the surfactant is preferably polyglycerol polyricinoleate or tween. The source of the surfactant in the present invention is not particularly limited, and commercially available products known to those skilled in the art may be used.
In the embodiment of the invention, the surfactant preferably accounts for 0.01-2% of the total mass of the W/O/W type temperature-sensitive embolic agent, and more preferably accounts for 0.67-1.14%.
In addition, the embodiment of the invention can fully dissolve and disperse chemotherapeutic drugs with different solubilities (water solubility and oil solubility), and has broad-spectrum drug-loading property.
In addition, the embodiment of the invention has temperature sensitivity, is liquid at normal temperature, is changed into solid after injection, and can effectively solve the contradiction between fluidity and embolism in the conventional embolic agent.
The preparation method of the W/O/W type temperature-sensitive embolic agent provided by the embodiment of the invention can refer to the conventional method in the field, and in some embodiments, the preparation method of the W/O/W type temperature-sensitive embolic agent comprises the following steps:
a) mixing the internal water phase and the oil phase, and emulsifying for the first time to obtain a water-in-oil emulsion;
b) mixing the water-in-oil emulsion obtained in the step a) with an external water phase, and then carrying out secondary emulsification under the ice bath condition.
In the embodiment of the invention, the internal water phase and the oil phase are mixed and then emulsified for the first time to obtain the water-in-oil emulsion. In the embodiment of the present invention, the internal water phase and the oil phase are the same as those in the above technical solution, and are not described herein again.
The embodiment of the present invention does not specifically limit the mixing manner, and any technical scheme of manual stirring or mechanical stirring known to those skilled in the art may be adopted, so as to achieve uniform mixing.
In the embodiment of the present invention, the first emulsification process preferably includes:
mixing the internal water phase and the oil phase, and shearing and emulsifying at the rotating speed of 6000 r/min-10000 r/min for 1 min-10 min to obtain a water-in-oil emulsion;
in the embodiment of the present invention, the first emulsification process preferably further includes:
the surfactant is added before shear emulsification. On the basis, the first emulsification process is preferably specifically as follows:
mixing the internal water phase, the oil phase and the surfactant, and then shearing and emulsifying at the rotating speed of 6000 r/min-10000 r/min for 1 min-10 min to obtain a water-in-oil emulsion;
after the water-in-oil emulsion is obtained, the obtained water-in-oil emulsion is mixed with external water, and then the mixture is emulsified for the second time, so that the W/O/W type temperature-sensitive embolic agent is obtained. In the embodiment of the present invention, the external aqueous phase is the same as that in the above technical solution, and is not described herein again. Likewise, the mixing method of the present invention is not particularly limited, and the technical scheme of manual stirring or mechanical stirring known to those skilled in the art can be adopted, so as to achieve uniform mixing.
In the embodiment of the present invention, the process of the second emulsification is preferably:
mixing the water-in-oil emulsion and the external water phase, and shearing and emulsifying at the rotating speed of 6000 r/min-10000 r/min for 2 min-10 min under the ice bath condition
It can be understood that in the process of the second emulsification, a continuous emulsification method or an intermittent emulsification method can be adopted, so that the mixture of the water-in-oil emulsion and the external water phase is sheared and emulsified for 2min to 10min at the rotating speed of 6000r/min to 10000r/min under the ice bath condition.
The embodiment of the invention provides a W/O/W type temperature-sensitive embolic agent, which comprises an external water phase, an oil phase and an internal water phase; the temperature-sensitive nanogel and a first aqueous developer are dispersed in the external water phase; an oily developer is dispersed in the oil phase; the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure. Compared with the prior art, the W/O/W type temperature-sensitive embolic agent provided by the invention is water-in-oil-in-water (W/O/W) emulsion, developers are dispersed in the external water phase and the oil phase of the W/O/W type temperature-sensitive embolic agent, and meanwhile, the specific temperature-sensitive nano gel is selected and dispersed in the external water phase, so that the overall better interaction is realized.
It is understood that the aqueous chemotherapy drugs and the oily chemotherapy drugs mentioned in the embodiments of the present invention are added for the purpose of improving the chemotherapy effect, and may be omitted without affecting the preparation of the composite emulsion, where the drugs include, but are not limited to, doxorubicin hydrochloride, paclitaxel, cisplatin, carboplatin, oxaliplatin, docetaxel, gemcitabine, mitomycin, vincristine, and tinib-type antitumor drugs.
To further illustrate the present invention, the following examples are provided for illustration. The starting materials used in the following examples of the invention are all commercially available, with the polyglycerol polyricinoleate being indicated as PGPR.
Example 1
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided by embodiment 1 of the present invention is shown in table 1; wherein the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked PNIP.
Table 1 specific composition of temperature sensitive embolic agent provided in example 1
The preparation method comprises the following steps:
(1) the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked poly (N-isopropyl acrylamide), and the preparation method comprises the following steps:
2.263g N-isopropyl acrylamide, 0.032g sodium dodecyl sulfate and 0.032g N, N' -methylene bisacrylamide are added into a 250ml three-necked bottle provided with a reflux condenser and an air guide device, 170ml ultrapure water is used for dissolving under magnetic stirring, high-purity nitrogen is introduced into the reaction system for 30min, the reaction system is heated to 70 ℃, 0.095g potassium persulfate as an initiator is added, and N is added2Reacting for 4.5h at 70 +/-1 ℃ in the atmosphere to obtain a white turbid suspension, dialyzing and purifying the suspension in ultrapure water, freeze-drying, and collecting freeze-dried powder to obtain the compound.
(2) Dissolving doxorubicin hydrochloride in water to a concentration of 5mg/ml, and using the solution as an internal aqueous phase;
dissolving paclitaxel in iodized oil to 3mg/ml, and using the solution as oil phase;
mixing the internal water phase and the oil phase according to the mass ratio in the table 1, wherein the volume ratio is 3: 7, adding a surfactant of polyglycerol polyricinoleate (PGPR) to account for 2 percent of the total system by mass; stirring thoroughly, emulsifying at 8000r/min for 5min to obtain water-in-oil emulsion as disperse phase.
(3) Preparing an external water phase as a continuous phase according to the mass ratio in the table 1;
mixing and stirring the dispersed phase and the continuous phase according to the mass ratio in the table 1, wherein the volume ratio is 4: 6; and under the ice bath condition, shearing and emulsifying at the rotating speed of 6000r/min for 3min to obtain the temperature-sensitive embolic agent capable of developing and carrying the medicine.
Example 2
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided by embodiment 2 of the present invention is shown in table 2; wherein the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked poly (NIP-co-NNP).
Table 2 specific composition of temperature sensitive embolic agent provided in example 2
The preparation method comprises the following steps:
(1) weighing the temperature-sensitive nanogel according to the formula shown in Table 2.
(2) Preparing an internal water phase and an oil phase according to the formula shown in the table 2, mixing the internal water phase and the oil phase according to the proportion, adding a surfactant, fully stirring and mixing, and shearing and emulsifying at the rotating speed of 7000r/min for 7min to obtain a water-in-oil emulsion as a dispersed phase.
(3) Preparing an external water phase as a continuous phase according to a formula shown in a table 2; and (3) mixing the dispersed phase and the continuous phase prepared in the step (2) in proportion, and shearing and emulsifying for 9min at the rotating speed of 6000r/min under the ice bath condition to obtain the emulsion.
Example 3
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided by embodiment 3 of the present invention is shown in table 3; wherein the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked poly (NIP-co-HEMA).
Table 3 specific composition of temperature sensitive embolic agent provided in example 3
The preparation method comprises the following steps:
(1) weighing the temperature-sensitive nanogel according to the formula shown in Table 3.
(2) Preparing an internal water phase and an oil phase according to the formula shown in the table 3, mixing the internal water phase and the oil phase according to the proportion, adding a surfactant, fully stirring and mixing, and shearing and emulsifying at the rotating speed of 8000r/min for 10min to obtain a water-in-oil emulsion as a dispersed phase.
(3) Preparing an external water phase as a continuous phase according to a formula shown in a table 3; and (3) mixing the dispersed phase and the continuous phase prepared in the step (2) in proportion, and shearing and emulsifying for 2min at the rotating speed of 10000r/min under the ice bath condition to obtain the nano-emulsion.
Example 4
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided by embodiment 4 of the present invention is shown in table 4; wherein the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked poly (NIP-co-HEA).
Table 4 specific composition of temperature sensitive embolic agent provided in example 4
The preparation method comprises the following steps:
(1) weighing the temperature-sensitive nanogel according to the formula in the table 4.
(2) Preparing an internal water phase and an oil phase according to the formula shown in the table 4, mixing the internal water phase and the oil phase according to the proportion, adding a surfactant, fully stirring and mixing, and shearing and emulsifying at the rotating speed of 9000r/min for 10min to obtain a water-in-oil emulsion as a dispersed phase.
(3) Preparing an external water phase as a continuous phase according to a formula shown in a table 4; and (3) mixing the dispersed phase and the continuous phase prepared in the step (2) in proportion, and shearing and emulsifying for 4min at the rotating speed of 9000r/min under the ice bath condition to obtain the nano-emulsion.
Example 5
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided by embodiment 5 of the present invention is shown in table 5; wherein the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked PNIP.
Table 5 specific compositions of temperature sensitive embolic agents provided in example 5
The preparation method comprises the following steps:
(1) the temperature sensitive nanogels were weighed according to the formula in table 5.
(2) Preparing an internal water phase and an oil phase according to the formula shown in the table 5, mixing the internal water phase and the oil phase according to the proportion, adding a surfactant, fully stirring and mixing, and shearing and emulsifying at the rotating speed of 6000r/min for 10min to obtain a water-in-oil emulsion as a dispersed phase.
(3) Preparing an external water phase as a continuous phase according to a formula shown in a table 5; and (3) mixing the dispersed phase and the continuous phase prepared in the step (2) in proportion, and shearing and emulsifying for 5min at the rotating speed of 7000r/min under the ice bath condition to obtain the nano-emulsion.
Example 6
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided by embodiment 6 of the present invention is shown in table 6; wherein the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked poly (NIP-co-NNP).
Table 6 specific composition of temperature sensitive embolic agent provided in example 6
The preparation method comprises the following steps:
(1) the temperature sensitive nanogels were weighed according to the formula in table 6.
(2) Preparing an internal water phase and an oil phase according to the formula shown in the table 6, mixing the internal water phase and the oil phase according to the proportion, adding a surfactant, fully stirring and mixing, and shearing and emulsifying at the rotating speed of 6000r/min for 7min to obtain a water-in-oil emulsion as a dispersed phase.
(3) Preparing an external water phase as a continuous phase according to a formula shown in Table 6; and (3) mixing the dispersed phase and the continuous phase prepared in the step (2) in proportion, and shearing and emulsifying for 3min at the rotating speed of 8000r/min under the ice bath condition to obtain the emulsion.
Comparative example 1
The temperature-sensitive embolic agent is prepared by the preparation method provided by the embodiment 1; the difference lies in that: the iodized oil was replaced with soybean oil for injection.
Comparative example 2
The temperature-sensitive embolic agent is prepared by the preparation method provided by the embodiment 1; the difference lies in that: the external water phase does not contain aqueous developer, and the amount of the aqueous developer is supplemented to water, so that the water in the external water phase accounts for 52.41 percent of the total amount of the temperature-sensitive embolic agent.
Test example
1. The temperature-sensitive embolic agents provided in the embodiment 1 and the comparative examples 1 to 2 are taken for X-ray photography, and as shown in FIG. 1, the X-ray contrast capability of the embodiment 1 is obviously better than that of the comparative examples 1 to 2.
2. The temperature-sensitive embolic agents of the embodiments 1 to 6 are stored for 14 days at 37 ℃, and the fact that the external water phase part of each temperature-sensitive embolic agent is subjected to phase change at 37 ℃, liquid is changed into solid, the appearance is uniform after the temperature-sensitive embolic agent is stored for 14 days, and no demulsification occurs shows that the temperature-sensitive embolic agent provided by the invention has good stability, and can ensure a stable embolic effect for a long time after being injected into a human body.
3. The temperature-sensitive embolic agents of the embodiments 1 to 6 are stored for 7 days at the temperature of-5 ℃, and after storage, the temperature-sensitive embolic agents are found to have uniform appearance, no demulsification, no excessive thickening and good fluidity, which indicates that the temperature-sensitive embolic agents provided by the invention are qualified in cold storage stability.
4. Various performance tests were performed on the temperature-sensitive embolic agents provided in examples 1 to 6, and the test results are shown in table 7. As shown by the results, the amount of the aqueous developer of example 5 used was increased from 1.12% to 21.12% relative to example 1, thereby resulting in a decrease in modulus and a decrease in the embolization effect, but the modulus and dissipation rate were still within acceptable ranges. Similarly, the amount of the aqueous developer used in example 6 was increased significantly compared to that used in example 2, and the embolization effect was also reduced.
TABLE 7 Performance data for temperature sensitive embolic agents provided in examples 1-6
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A W/O/W type temperature-sensitive embolic agent comprises an external water phase, an oil phase and an internal water phase;
the temperature-sensitive nanogel and a first aqueous developer are dispersed in the outer water phase;
an oily developer is dispersed in the oil phase;
the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure.
2. The W/O/W type temperature-sensitive embolic agent according to claim 1, wherein the N-isopropylacrylamide-based polymer having a three-dimensional network structure comprises one or more of cross-linker-crosslinked poly (N-isopropylacrylamide), cross-linker-crosslinked poly (NIP-co-AA), cross-linker-crosslinked poly (NIP-co-NNP), cross-linker-crosslinked poly (NIP-co-MMA), cross-linker-crosslinked poly (NIP-co-HEMA), cross-linker-crosslinked poly (NIP-co-HEA), and cross-linker-crosslinked poly (NIP-co-AAm);
the cross-linking agent is selected from one or more of N, N '-methylene bisacrylamide, N' -ethylene bisacrylamide, 1, 3-propylene bisacrylamide, ethylene diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, trimethylolpropane triacrylate and pentaerythritol triacrylate.
3. The W/O/W type temperature-sensitive embolic agent according to claim 1, wherein the temperature-sensitive nanogel accounts for 1-6% of the total mass of the W/O/W type temperature-sensitive embolic agent, and the first aqueous developer accounts for 0.5-50% of the total mass of the W/O/W type temperature-sensitive embolic agent.
4. The W/O/W-type temperature-sensitive embolic agent according to claim 1, wherein the first aqueous developer is selected from one or more of iohexol, iopamidol, iodixanol, and ioflunol.
5. The W/O/W type temperature-sensitive embolic agent according to claim 1, wherein the solvent of the oil phase is iodized oil and/or vegetable oil for injection.
6. The W/O/W type temperature-sensitive embolic agent according to claim 5, wherein the solvent of the oily developer and the oil phase is iodized oil, and the iodized oil accounts for 10-40% of the total mass of the W/O/W type temperature-sensitive embolic agent.
7. The W/O/W-type temperature-sensitive embolic agent according to any of claims 1 to 6, wherein the external aqueous phase further comprises:
an aqueous chemotherapeutic agent; the water-based chemotherapeutic drug accounts for 0.1-5% of the total mass of the W/O/W type temperature-sensitive embolic agent.
8. The W/O/W-type temperature-sensitive embolic agent according to any of claims 1 to 6, wherein the oil phase further comprises:
oily chemotherapeutic drugs; the oily chemotherapeutic drug accounts for 0.05-1.5% of the total mass of the W/O/W type temperature-sensitive embolic agent.
9. The W/O/W-type temperature-sensitive embolic agent according to any of claims 1 to 6, wherein the internal aqueous phase further comprises:
an aqueous chemotherapeutic agent and/or a second aqueous imaging agent selected from one or more of iohexol, iopamidol, iodixanol and iofluranol.
10. The W/O/W type temperature-sensitive embolic agent according to any of claims 1 to 6, wherein the W/O/W type temperature-sensitive embolic agent further comprises:
a surfactant; the surfactant accounts for 0.01-2% of the total mass of the W/O/W type temperature-sensitive embolic agent.
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