CN114042042B - W/O/W type temperature-sensitive embolic agent - Google Patents

W/O/W type temperature-sensitive embolic agent Download PDF

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CN114042042B
CN114042042B CN202111432174.1A CN202111432174A CN114042042B CN 114042042 B CN114042042 B CN 114042042B CN 202111432174 A CN202111432174 A CN 202111432174A CN 114042042 B CN114042042 B CN 114042042B
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CN114042042A (en
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李涵
孙海霞
刘宏
杨祥良
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Guangdong Guangna Anyu Technology Co ltd
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GBA National Institute for Nanotechnology Innovation
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    • A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention provides a W/O/W type temperature-sensitive embolic agent, which comprises an outer water phase, an oil phase and an inner water phase; the temperature-sensitive nanogel and the first aqueous developer are dispersed in the outer aqueous 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, the external water phase and the oil phase of the water-in-oil emulsion are respectively dispersed with a developer, meanwhile, specific temperature-sensitive nanogel is selected to be dispersed in the external water phase, so that the overall better interaction is realized, on the basis of excellent X-ray development capability, the influence on the fluidity of the poly N-isopropyl acrylamide type temperature-sensitive nanogel and the gel phase change behavior of the poly N-isopropyl acrylamide type temperature-sensitive nanogel due to the excessively high use level of the developer in the external water phase can be avoided, the embolic effect of the temperature-sensitive embolic agent is ensured, the oily developer is dispersed in the oil phase, and the aqueous developer is dispersed in the external water phase, so that the developers with different polarities are stably stored in the same dosage form, and the stability is high.

Description

W/O/W type temperature-sensitive embolic agent
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 therapies for mid-to-late liver cancer at present, where Embolization plays a central role. The liquid embolic agent represented by the iodized oil emulsion is the most widely used liver tumor vascular embolic material at present, and the traditional chemoembolization based on the iodized oil emulsion is called C-TACE (concentration-TACE). The iodized oil emulsion has good fluidity, can smoothly pass through a microcatheter and realize tumor peripheral vascular embolism, but the iodized oil emulsion has poor embolism property and is easy to be eroded and metabolized by blood to carry out recanalization, and in such a case, the iodized oil emulsion is often required to be matched with solid embolic agents such as gelatin Sponge (gel), PVA and the like to carry out secondary embolic treatment, so that the operation of carrying out the secondary embolic treatment is complicated, the cost is increased, and embolic complications are sometimes caused.
The poly N-isopropyl acrylamide temperature-sensitive nano gel has lower viscosity in a sol state, and is converted from a good flowing state to a non-flowable gel state in a human body temperature environment, so that the poly N-isopropyl acrylamide temperature-sensitive nano gel has good fluidity and embolic property, can overcome the contradiction between the fluidity and embolic property of the traditional embolic agent, has drug-carrying slow-release property, and is expected to become a new generation of embolic agent for interventional therapy. The temperature-sensitive gel generally has no developing function and can be visually observed in operation after being blended with a developer. In actual operation, the developing capability is often improved by selectively increasing the amount of the developing agent; however, too much developer can cause an increase in gel viscosity, affecting its flowability, and can also cause a decrease in gel strength to become floppy, affecting the embolization effect.
Disclosure of Invention
Therefore, the invention aims to provide a W/O/W type temperature-sensitive embolic agent so as to coordinate the development capability and embolic effect of the temperature-sensitive embolic agent.
The invention provides a W/O/W type temperature-sensitive embolic agent, which comprises an outer water phase, an oil phase and an inner water phase;
the temperature-sensitive nanogel and the first aqueous developer are dispersed in the outer aqueous 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 polymer having a three-dimensional network structure includes one or more of a cross-linker cross-linked poly (N-isopropylacrylamide), a cross-linker cross-linked poly (NIP-co-AA), a cross-linker cross-linked poly (NIP-co-NNP), a cross-linker cross-linked poly (NIP-co-MMA), a cross-linker cross-linked poly (NIP-co-HEMA), a cross-linker cross-linked poly (NIP-co-HEA) and a cross-linker cross-linked 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 nano gel accounts for 1 to 6 percent of the total mass of the W/O/W type temperature-sensitive embolic agent, and the first aqueous developer accounts for 0.5 to 50 percent 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 iofluor alcohol.
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 agent 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 agents; the oily chemotherapeutic agent 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 developer selected from one or more of iohexol, iopamidol, iodixanol, and iofluor.
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 outer water phase, an oil phase and an inner water phase; the temperature-sensitive nanogel and the first aqueous developer are dispersed in the outer aqueous 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 is a water-in-oil-in-water (W/O/W) type emulsion, the external water phase and the oil phase of the emulsion are both dispersed with the developer, meanwhile, the specific temperature-sensitive nanogel is dispersed in the external water phase, so that the overall better interaction is realized, on the basis of excellent X-ray development capability, the product can avoid influencing the fluidity of the poly N-isopropyl acrylamide type temperature-sensitive nanogel and the gel phase change behavior of the poly N-isopropyl acrylamide type temperature-sensitive nanogel due to the excessively high usage of the developer in the external water phase, the embolic effect of the temperature-sensitive embolic agent is ensured, the oily developer is dispersed in the oil phase, and the aqueous developer is dispersed in the external water phase, so that the developers with different polarities stably exist in the same dosage form, and the stability is high.
Drawings
FIG. 1 is a comparative image of X-ray radiography of the thermosensitive embolic agents provided in example 1 and comparative examples 1-2.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the 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 the first aqueous developer are dispersed in the external water phase;
an oily developer is dispersed in the oil phase;
the temperature-sensitive nano gel 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 outer water phase, an oil phase and an inner water phase, and preferably consists of the outer water phase, the oil phase and the inner water phase.
In the embodiment of the invention, the temperature-sensitive nanogel and the 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-based polymer having a three-dimensional network structure preferably includes one or more of a cross-linker-crosslinked poly (N-isopropylacrylamide), a cross-linker-crosslinked poly (NIP-co-AA), a cross-linker-crosslinked poly (NIP-co-NNP), a cross-linker-crosslinked poly (NIP-co-MMA), a cross-linker-crosslinked poly (NIP-co-HEMA), a cross-linker-crosslinked poly (NIP-co-HEA) and a cross-linker-crosslinked poly (NIP-co-AAm), more preferably a cross-linker-crosslinked poly (N-isopropylacrylamide), a cross-linker-crosslinked poly (NIP-co-AA), a cross-linker-crosslinked poly (NIP-co-NNP), a cross-linker-crosslinked poly (NIP-co-MMA), a cross-linker-crosslinked poly (NIP-co-HEMA) or a cross-linker-crosslinked poly (NIP-co-AAm). It is understood that NIP represents N-isopropylacrylamide, AA represents acrylic acid, NNP represents N-N-propylacrylamide, MMA represents methyl methacrylate, HEMA represents hydroxyethyl methacrylate, HEA represents hydroxyethyl acrylate, and AAm represents acrylamide.
In an embodiment of the present invention, the crosslinking agent is preferably selected from one or more of N, N ' -methylenebisacrylamide, N ' -ethylenebisacrylamide, 1, 3-propylenebisacrylamide, ethylene diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, trimethylolpropane triacrylate, pentaerythritol triacrylate, more preferably N, N ' -methylenebisacrylamide.
The sources of the temperature-sensitive nanogel and the cross-linking agent are not particularly limited, and commercially available products well known to those skilled in the art can be adopted, and the products obtained by preparation can also be prepared by adopting conventional technical means in the art.
Taking N, N' -methylenebisacrylamide crosslinked poly (N-isopropylacrylamide) as an example, the preparation method is preferably specifically as follows:
adding N-isopropyl acrylamide, sodium dodecyl sulfate and N, N' -methylene bisacrylamide into a three-necked flask provided with a reflux condenser pipe and an air guide device, dissolving the mixture under magnetic stirring by using ultrapure water, introducing high-purity nitrogen into the reaction system for 20 to 40 minutes, heating the reaction system to 65 to 75 ℃, adding an initiator potassium persulfate, and adding the initiator potassium persulfate into the mixture to obtain a mixture of N, N-isopropyl acrylamide, sodium dodecyl sulfate and N-methyl methacrylate 2 Reacting for 4-5 h at 65-75 ℃ in the atmosphere to obtain 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 to 6 percent of the total mass of the W/O/W type temperature-sensitive embolic agent, and more preferably 2.8 to 5.9 percent; on the basis, the embolic agent has good embolic effect and good fluidity.
In an embodiment of the present invention, the first aqueous developer is preferably selected from one or more of iohexol, iopamidol, iodixanol and iofluor, more preferably iohexol, iopamidol, iodixanol or iofluor. The source of the aqueous developer is not particularly limited and commercially available commercial products known to those skilled in the art can 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 embolic agent, more preferably 1.12-30%, and the first aqueous developer and the dosage of the temperature-sensitive nanogel are coordinated to ensure that the embolic agent has good embolic effect and developing capability and good fluidity. Further, the mass of the temperature-sensitive nano gel in each 100mL of the external water phase is preferably 1 g-8 g; the quality of the first aqueous developer is compounded, so that the gel phase change behavior is ensured to be normally operated.
In the embodiment of the invention, the external water phase is preferably further dispersed with an aqueous chemotherapeutic drug; the invention is not particularly limited with respect to the specific 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 0.5-3%.
According to the invention, the external water phase composed of the specific content is adopted, and the specific aqueous developer is dispersed in the external water phase, so that on one hand, the purpose of increasing the developing capability of the preparation can be achieved by cooperating with the oily developer in the oil phase part, and on the other hand, the dosage of the aqueous developer in the external water phase is adjustable, the influence on the fluidity and gel phase change behavior of the specific temperature-sensitive nanogel adopted by the invention due to the excessively high dosage of the aqueous developer in the external water phase can be avoided, the embolism effect of the temperature-sensitive embolic agent is ensured (in the prior art, the poly N-isopropyl acrylamide temperature-sensitive nanogel is blended with the developer, the excessively large dosage of the developer can cause the increase of the gel viscosity, influence the fluidity thereof, and meanwhile, the decrease of the gel strength and influence on the embolism effect), thereby reflecting the influence of the developer on the embolism effect of the temperature-sensitive nanogel; 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 embolism effect.
In the embodiment of the invention, 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 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 use level of the oily developer in the embolic agent can be ensured to be maximized; in addition, by forming the W/O/W emulsion, the water-soluble poly-N-isopropyl acrylamide temperature-sensitive nanogel can stably coexist with iodized oil, so that the stability of the preparation is obviously improved while the embolism effect is improved.
In the embodiment of the invention, when the developer dispersed in the oil phase is an oily developer, the first aqueous developer and the oily 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 20-34%; under the limit of the specific dosage, the stability of the preparation can be ensured, and demulsification caused by excessive iodized oil can be prevented.
In the embodiment of the invention, the oily chemotherapeutic medicine is preferably dispersed in the oil phase; the specific type and source of the oily chemotherapeutic agent is not particularly limited. In the embodiment of the invention, the oily chemotherapeutic medicine preferably accounts for 0.05 to 1.5 percent of the total mass of the W/O/W type temperature-sensitive embolic agent, and more preferably 0.07 to 1 percent.
In an embodiment of the invention, the inner aqueous phase further comprises dispersed therein an aqueous chemotherapeutic agent and/or a second aqueous developing agent; the concentration of the second aqueous developer dispersed in the internal aqueous phase is not particularly limited in the present invention, and a concentration value within the range of 0 to a saturated concentration, which is well known to those skilled in the art, may be employed. The invention disperses the second aqueous developer in the internal water phase, which is beneficial to increasing the developer dosage in the temperature sensitive embolic agent, thereby further improving the X-ray developing capability.
In an embodiment of the present invention, the second aqueous developer is preferably selected from one or more of iohexol, iopamidol, iodixanol and iofluor, more preferably iohexol, iopamidol, iodixanol or iofluor. The source of the second aqueous developer 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 second aqueous developer preferably accounts for 0.1-5% of the total mass of the W/O/W type temperature-sensitive embolic agent, and more preferably 0.5-2%.
In the embodiment of the invention, the internal water phase is preferably further dispersed with an aqueous chemotherapeutic drug; the invention is not particularly limited with respect to the specific 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 embodiment of the invention, the volume ratio of the internal water phase to the oil phase is preferably 1: (1 to 8), more preferably 1: (2-3).
In the embodiment of the present invention, the volume ratio of the sum of the inner water phase and the oil phase to the outer water phase is preferably 1: (1 to 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 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 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, and is converted into solid after injection, so that the contradiction between fluidity and embolism faced by the existing embolic agent can be effectively solved.
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 performing first emulsification to obtain water-in-oil emulsion;
b) Mixing the water-in-oil emulsion obtained in the step a) with external water phase, and then performing secondary emulsification under ice bath condition.
In the embodiment of the invention, the internal water phase and the oil phase are mixed at first, and then are emulsified for the first time to obtain the water-in-oil emulsion. In the embodiment of the present invention, the inner aqueous phase and the oil phase are the same as those in the above technical solutions, and are not described herein.
The mixing mode of the embodiment of the invention is not particularly limited, and the technical scheme of manual stirring or mechanical stirring which are well known to those skilled in the art can be adopted, so that the purpose of uniform mixing is achieved.
In the embodiment of the present invention, the process of the first emulsification is preferably specifically:
mixing the internal water phase and the oil phase, and shearing and emulsifying for 1-10 min at the rotating speed of 6000-10000 r/min to obtain water-in-oil emulsion;
in the embodiment of the present invention, the process of the first emulsification preferably further includes:
the surfactant is added prior to shear emulsification. On this basis, the process of the first emulsification is preferably specifically:
mixing the internal water phase, the oil phase and the surfactant, and then shearing and emulsifying for 1-10 min at the rotating speed of 6000-10000 r/min to obtain water-in-oil emulsion;
after the water-in-oil emulsion is obtained, the embodiment of the invention mixes the obtained water-in-oil emulsion with external water, and then carries out secondary emulsification to obtain the W/O/W type temperature-sensitive embolic agent. In the embodiment of the present invention, the outer aqueous phase is the same as that in the above technical solution, and will not be described herein again. Similarly, the mixing mode is not particularly limited, and the invention can adopt the technical scheme of manual stirring or mechanical stirring which are well known to the person skilled in the art, and the aim of uniformly mixing is to realize the purpose of uniform mixing.
In the embodiment of the present invention, the process of the second emulsification is preferably:
mixing the water-in-oil emulsion with the external water phase, and shearing and emulsifying for 2-10 min at the rotation speed of 6000-10000 r/min under the ice bath condition
It can be understood that in the process of the second emulsification and emulsification, a continuous emulsification method can be adopted, 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 2 to 10 minutes at the rotating speed of 6000 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 the first aqueous developer are dispersed in the external water phase; an oily developer is dispersed in the oil phase; the temperature-sensitive nano gel 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 is a water-in-oil-in-water (W/O/W) type emulsion, the external water phase and the oil phase of the emulsion are both dispersed with the developer, meanwhile, the specific temperature-sensitive nanogel is dispersed in the external water phase, so that the overall better interaction is realized, on the basis of excellent X-ray development capability, the product can avoid influencing the fluidity of the poly N-isopropyl acrylamide type temperature-sensitive nanogel and the gel phase change behavior of the poly N-isopropyl acrylamide type temperature-sensitive nanogel due to the excessively high usage of the developer in the external water phase, the embolic effect of the temperature-sensitive embolic agent is ensured, the oily developer is dispersed in the oil phase, and the aqueous developer is dispersed in the external water phase, so that the developers with different polarities stably exist in the same dosage form, and the stability is high.
It will be understood that the purpose of adding the aqueous chemotherapeutic agent and the oily chemotherapeutic agent in the embodiments of the present invention is to improve the chemotherapeutic effect, and certainly, the aqueous chemotherapeutic agent and the oily chemotherapeutic agent may be omitted without affecting the preparation of the above-mentioned composite emulsion, and the above-mentioned drugs include, but are not limited to, doxorubicin hydrochloride, paclitaxel, cisplatin, carboplatin, oxaliplatin, docetaxel, gemcitabine, mitomycin, vincristine, and tennines antitumor drugs.
In order to further illustrate the present invention, the following examples are provided. The starting materials used in the following examples of the invention are all commercially available, wherein polyglycerol polyricinoleate is denoted PGPR.
Example 1
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided in the embodiment 1 of the 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 is as follows:
2.263g N-isopropyl acrylamide, 0.032g sodium dodecyl sulfate and 0.032g N, N' -methylene bisacrylamide are added into a 250ml three-necked flask equipped with a reflux condenser and an air guide device, 170ml ultrapure water is used for dissolution under magnetic stirring, high-purity nitrogen is introduced into the reaction system for 30min, the reaction system is heated to 70 ℃, and an initiator potassium persulfate of 0.095g is added into the mixture, and the mixture is cooled to N 2 Reacting for 4.5 hours 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 product.
(2) Dissolving doxorubicin hydrochloride in water to a concentration of 5mg/ml, and taking the solution as an inner water phase;
dissolving paclitaxel in iodized oil to obtain paclitaxel solution with concentration of 3mg/ml, and taking the solution as oil phase;
mixing the inner water phase and the oil phase according to the mass ratio in table 1, wherein the volume ratio is 3:7, adding a surfactant polyglycerol polyricinoleate (PGPR) to make the mixture account for 2 percent (mass fraction) of the total system; after fully stirring and mixing, shearing and emulsifying for 5min at 8000r/min to obtain water-in-oil emulsion serving as a disperse phase.
(3) Preparing an outer aqueous phase as a continuous phase according to the mass ratio in table 1;
the dispersed phase and the continuous phase are mixed and stirred according to the mass ratio shown in the table 1, and the volume ratio is 4:6, preparing a base material; under the ice bath condition, shearing and emulsifying for 3min at the rotation speed of 6000r/min to obtain the developable and drug-carrying temperature-sensitive embolic agent.
Example 2
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided in the embodiment 2 of the invention is shown in the 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) The temperature sensitive nanogel was weighed according to the formulation of table 2.
(2) According to the formula of Table 2, an inner water phase and an oil phase are prepared, the inner water phase and the oil phase are mixed according to a proportion, a surfactant is added, and after the mixture is fully stirred and mixed, the mixture is sheared and emulsified for 7 minutes at a rotating speed of 7000r/min, so that a water-in-oil emulsion is obtained and is used as a disperse phase.
(3) Preparing an external aqueous phase as a continuous phase according to the formulation of table 2; and (3) mixing the disperse 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 composite material.
Example 3
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided in the embodiment 3 of the invention is shown in the 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) The temperature sensitive nanogel was weighed according to the formulation of table 3.
(2) According to the formula of Table 3, an inner water phase and an oil phase are prepared, the inner water phase and the oil phase are mixed according to a proportion, a surfactant is added, and after the mixture is fully stirred and mixed, the mixture is sheared and emulsified for 10 minutes at a rotating speed of 8000r/min, so that a water-in-oil emulsion is obtained and is used as a disperse phase.
(3) Preparing an external aqueous phase as a continuous phase according to the formulation of table 3; and (3) mixing the disperse 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 composite material.
Example 4
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided in the embodiment 4 of the 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) The temperature sensitive nanogel was weighed according to the formulation of table 4.
(2) According to the formula of Table 4, an inner water phase and an oil phase are prepared, the inner water phase and the oil phase are mixed according to a proportion, a surfactant is added, and after the mixture is fully stirred and mixed, the mixture is sheared and emulsified for 10 minutes at the rotating speed of 9000r/min, so that a water-in-oil emulsion is obtained and is used as a disperse phase.
(3) Preparing an external aqueous phase as a continuous phase according to the formulation of table 4; and (3) mixing the disperse 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 composite material.
Example 5
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided in the embodiment 5 of the invention is shown in table 5; wherein the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked PNIP.
TABLE 5 specific composition of temperature-sensitive embolic agent provided in EXAMPLE 5
The preparation method comprises the following steps:
(1) The temperature sensitive nanogel was weighed according to the formulation of table 5.
(2) According to the formula of Table 5, an inner water phase and an oil phase are prepared, the inner water phase and the oil phase are mixed according to a proportion, a surfactant is added, and after the mixture is fully stirred and mixed, the mixture is sheared and emulsified for 10 minutes at a rotating speed of 6000r/min, so that a water-in-oil emulsion is obtained and is used as a disperse phase.
(3) Preparing an external aqueous phase as a continuous phase according to the formulation of table 5; and (3) mixing the disperse phase and the continuous phase prepared in the step (2) in proportion, and shearing and emulsifying for 5min at 7000r/min under the ice bath condition to obtain the composite material.
Example 6
The formula comprises the following components:
the specific composition of the temperature-sensitive embolic agent provided in the embodiment 6 of the invention is shown in the table 6; wherein the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked poly (NIP-co-NNP).
TABLE 6 concrete composition of temperature-sensitive embolic agent provided in EXAMPLE 6
The preparation method comprises the following steps:
(1) The temperature sensitive nanogel was weighed according to the formulation of table 6.
(2) According to the formula of Table 6, an inner water phase and an oil phase are prepared, the inner water phase and the oil phase are mixed according to a proportion, a surfactant is added, and after the mixture is fully stirred and mixed, the emulsion is sheared and emulsified for 7min at a rotating speed of 6000r/min, so that a water-in-oil emulsion is obtained and is used as a disperse phase.
(3) Preparing an external aqueous phase as a continuous phase according to the formulation of table 6; and (3) mixing the disperse 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 composite material.
Comparative example 1
The preparation method provided in the example 1 is adopted to prepare the temperature-sensitive embolic agent; the difference is that: the iodized oil is replaced by soybean oil for injection.
Comparative example 2
The preparation method provided in the example 1 is adopted to prepare the temperature-sensitive embolic agent; the difference is that: the external water phase contains no aqueous developer, and the dosage of the aqueous developer is supplemented to water, so that the water in the external water phase accounts for 52.41% of the total amount of the temperature-sensitive embolic agent.
Test case
1. X-ray radiography was performed by taking the temperature-sensitive embolic agents provided in example 1 and comparative examples 1 to 2, and as shown in FIG. 1, the X-ray contrast ability of example 1 was significantly better than that of comparative examples 1 to 2.
2. The temperature-sensitive embolic agents of examples 1-6 are taken and stored for 14 days at 37 ℃, and the phase change of the outer water phase part of each temperature-sensitive embolic agent is found at 37 ℃, so that the outer water phase part is changed from liquid to solid, and the appearance is uniform after the temperature-sensitive embolic agent is stored for 14 days, and no demulsification is caused, so that the temperature-sensitive embolic agent provided by the invention has good stability, and the stable embolic effect can be ensured for a long time after the temperature-sensitive embolic agent is injected into a human body.
3. The temperature-sensitive embolic agents of examples 1-6 are stored for 7 days at the temperature of minus 5 ℃, and after storage, the appearance of each temperature-sensitive embolic agent is found to be uniform, demulsification, excessive thickening and good fluidity, which indicates that the cold storage stability of the temperature-sensitive embolic agent provided by the invention is qualified.
4. Each performance test was performed using the temperature-sensitive embolic agents provided in examples 1-6, and the test results are shown in table 7. As the results show, the amount of the aqueous developer of example 5 was increased from 1.12% to 21.12% relative to example 1, thereby resulting in a decrease in modulus and a decrease in embolization effect, but the modulus and dissipation rate thereof were still within acceptable ranges. Similarly, the amount of the aqueous developer of example 6 was also greatly increased relative to example 2, and the embolization effect was correspondingly decreased.
TABLE 7 various 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 (6)

1. A W/O/W type temperature-sensitive embolic agent comprises an outer water phase, an oil phase and an inner water phase;
the temperature-sensitive nanogel and the first aqueous developer are dispersed in the outer aqueous 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 N-isopropyl acrylamide polymer with the three-dimensional network structure is cross-linked poly (N-isopropyl acrylamide), cross-linked poly (NIP-co-AA), cross-linked poly (NIP-co-NNP), cross-linked poly (NIP-co-MMA), cross-linked poly (NIP-co-HEMA), cross-linked poly (NIP-co-HEA) or cross-linked poly (NIP-co-AAm);
the cross-linking agent is N, N' -methylene bisacrylamide;
the temperature-sensitive nano gel accounts for 2.8-5.9% of the total mass of the W/O/W type temperature-sensitive embolic agent, and the first aqueous developer accounts for 1.12-30% of the total mass of the W/O/W type temperature-sensitive embolic agent;
the solvent of the oily developer and the oil phase is iodized oil, and the iodized oil accounts for 20-34% of the total mass of the W/O/W type temperature-sensitive embolic agent.
2. The W/O/W-type thermosensitive embolic agent according to claim 1, wherein the first aqueous developer is selected from one or more of iohexol, iopamidol, iodixanol and iofluor alcohol.
3. The W/O/W-type thermosensitive embolic agent according to any one of claims 1-2, wherein said external aqueous phase further comprises:
an aqueous chemotherapeutic agent; the water-based chemotherapeutic agent accounts for 0.1% -5% of the total mass of the W/O/W type temperature-sensitive embolic agent.
4. The W/O/W-type temperature-sensitive embolic agent of any of claims 1-2, wherein said oil phase further comprises:
oily chemotherapeutic agents; the oily chemotherapeutic agent accounts for 0.05-1.5% of the total mass of the W/O/W type temperature-sensitive embolic agent.
5. The W/O/W-type thermosensitive embolic agent according to any one of claims 1-2, wherein said internal aqueous phase further comprises:
an aqueous chemotherapeutic agent and/or a second aqueous developer selected from one or more of iohexol, iopamidol, iodixanol, and iofluor.
6. The W/O/W-type thermosensitive embolic agent according to any one of claims 1-2, wherein the W/O/W-type thermosensitive 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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