CN114470304B - Chemoembolization composition and application thereof - Google Patents
Chemoembolization composition and application thereof Download PDFInfo
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- CN114470304B CN114470304B CN202111633590.8A CN202111633590A CN114470304B CN 114470304 B CN114470304 B CN 114470304B CN 202111633590 A CN202111633590 A CN 202111633590A CN 114470304 B CN114470304 B CN 114470304B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a chemoembolization composition and application thereof, and belongs to the technical field of medical materials. The chemoembolization composition is an oil-in-water-in-oil type composite emulsion, and comprises an outer continuous phase and an outer dispersed phase, wherein the outer continuous phase is an oil phase, the outer dispersed phase consists of an inner dispersed phase and an inner continuous phase, the inner dispersed phase is the oil phase, and the inner continuous phase is aqueous solution of temperature-sensitive nano gel and an aqueous developer. The chemoembolization composition has good embolization performance, secondary embolization chemotherapy is not needed, the balance requirement of fluidity and embolization performance required by the chemoembolization composition is met, the X-ray developing capability of the chemoembolization composition is obviously improved by the aqueous developer and the iodized oil, and the chemoembolization composition has good embolization effect while the X-ray developing capability is improved.
Description
Technical Field
The invention relates to the technical field of medical materials, in particular to a chemoembolization composition and application thereof.
Background
The iodized oil emulsion is widely applied to transcatheter Arterial Embolization chemotherapy (TACE) of liver tumors at present, has good fluidity, can smoothly pass through a microcatheter, and realizes tumor peripheral vascular Embolization, but the iodized oil emulsion has poor Embolization performance, is easily scoured and metabolized by blood, and is recanalized.
Aiming at the problem of poor embolization performance of an embolization agent iodized oil emulsion, the prior art discloses a developable composite microsphere embolization agent prepared by an oil-in-water-in-oil method, wherein the developable composite microsphere embolization agent contains 80-96 parts by mass of mixed gel consisting of carrageenan and gelatin, 2-12 parts by mass of biodegradable polymer, 0.5-5 parts by mass of emulsifier, 0.5-5 parts by mass of cross-linking agent and 0.5-5 parts by mass of contrast agent, wherein the mass ratio of the carrageenan to the gelatin is 1:1 to 1:6; the contrast agent is an oil-soluble iodine-containing contrast agent or a water-soluble iodine-containing contrast agent. The developable composite microsphere embolic agent mainly takes carrageenan-gelatin microspheres as a main body, and the microspheres are loaded with the contrast agent by an oil-in-water-in-oil method, so that the synchronous functionalization of development and embolization is realized, but the balance problem between the fluidity and the embolization of the embolic agent is not solved, and the embolic agent also has good embolization.
Disclosure of Invention
The invention aims to overcome the defects and defects that the conventional embolic agent has poor embolization performance and unbalanced fluidity and embolization performance, and provides a chemoembolization composition.
The invention also aims to provide application of the chemoembolization composition in preparing chemoembolization medicaments.
The above purpose of the invention is realized by the following technical scheme:
a chemoembolization composition, which is an oil-in-water-in-oil type composite emulsion comprising an external continuous phase and an external dispersed phase,
the outer continuous phase is an oil phase,
the external dispersed phase consists of an internal dispersed phase and an internal continuous phase, the internal dispersed phase is an oil phase, the internal continuous phase is the aqueous solution of the temperature-sensitive nano gel and the aqueous developer,
wherein the mass of the temperature-sensitive nano gel is 0.5-3% of the total mass of the chemoembolization composition, and the mass of the aqueous developer is 0.5-10% of the total mass of the chemoembolization composition.
Among them, it should be noted that:
the temperature-sensitive nanogel can be a poly N-isopropyl acrylamide polymer.
The inner dispersed phase oil phase and the outer continuous phase oil phase of the invention can be iodized oil.
The chemoembolization composition is an O/W/O type composite emulsion, so that hydrophilic poly N-isopropylacrylamide temperature-sensitive nano-gel can be stably dispersed in an internal dispersed phase iodized oil system, the N-isopropylacrylamide temperature-sensitive nano-gel can be converted into a non-flowable gel state according to the change of temperature signals inside and outside a human body, has a gel phase change behavior, realizes the step-by-step cast embolization from a large blood vessel to a tumor capillary network, makes up the defect of poor embolization of the iodized oil, has good embolization performance, does not need secondary embolization chemotherapy, has good fluidity before the conversion into the gel state, has low viscosity, and is easy to inject and convenient to operate.
Meanwhile, the inner continuous phase of the invention is also uniformly dispersed with aqueous developer which is in cooperation with the inner dispersed phase iodized oil, thus being beneficial to improving the X-ray developing capability of the chemoembolization composition.
The quality of the aqueous developer is 0.5-10% of the total weight of the chemoembolization composition, and the quality control of the temperature-sensitive nanogel is cooperated, so that the influence on the fluidity and the gel phase transition behavior of the poly N-isopropyl acrylamide temperature-sensitive nanogel caused by overhigh consumption of the aqueous developer can be avoided, and the favorable embolization effect is ensured while the X-ray developing capability is improved.
The chemoembolization composition has temperature sensitivity, is liquid at normal temperature, is changed into solid after injection, can effectively solve the contradiction between fluidity and embolization of the conventional embolization agent, and can meet the balance requirement of fluidity and embolization required by the chemoembolization composition.
In a specific embodiment, in order to achieve better embolization effect, the mass of the temperature-sensitive nanogel is 2.5-3% of the total mass of the chemoembolization composition, and the mass of the aqueous developer is 1-10% of the total mass of the chemoembolization composition.
In a specific embodiment, the aqueous developer of the present invention may be one or more of iohexol, iopamidol, iodixanol or iofluranol.
In a specific embodiment, the temperature-sensitive nanogel is a poly (N-isopropylacrylamide) polymer with a three-dimensional network structure.
For example, the following may be: one or more of poly N-isopropyl acrylamide, poly NIP-co-AA, poly NIP-co-NNP, poly NIP-co-MMA, poly NIP-co-HEMA, poly NIP-co-HEA and poly NIP-co-AAm.
Wherein NIP represents N-isopropyl acrylamide, AA represents acrylic acid, NNP represents N-N-propyl acrylamide, MMA represents methyl methacrylate, HEMA represents hydroxyethyl methacrylate, HEA represents hydroxyethyl acrylate, and AAm represents acrylamide.
In a specific embodiment, in order to ensure that the stable emulsion is formed and simultaneously the effect of the temperature-sensitive nanogel is maximized, and the fluidity and the embolization property of the preparation are coordinated, so that the preparation is endowed with a good application effect, the volume ratio of the inner dispersed phase to the inner continuous phase is preferably 1: (1-8).
In a specific embodiment, in order to further form a stable O/W/O type composite emulsion, it is preferable that the mass ratio of the external continuous phase is 50 to 80% of the total mass of the chemoembolization composition.
In a specific embodiment, preferably, the chemoembolization composition further comprises a surfactant, and the mass of the surfactant is 0.01-2% of the total mass of the chemoembolization composition.
Among them, it should be noted that: the chemoembolization composition of the invention can contain a surfactant, the quality of the surfactant is controlled to be 0.01-2% of the total mass of the chemoembolization composition, and the chemoembolization composition can further promote the formation of stable O/W/O type composite emulsion.
The surfactant added to the chemoembolizing composition of the present invention may be a commercially available conventional surfactant, such as polyglycerol polyricinoleate PGPR, tween.
Further preferably, the mass of the surfactant is 0.2-2% of the total mass of the chemoembolization composition.
Preferably, the chemoembolization composition further comprises an anti-tumor drug.
Further preferably, an oil-soluble antitumor drug is added to the outer continuous phase and/or the inner dispersed phase, and a water-soluble antitumor drug is added to the inner continuous phase.
In order to further improve the effect of chemotherapy, the chemoembolization composition may further comprise a related anti-tumor drug, for example, a drug for treating liver cancer tumor, which includes but is not limited to doxorubicin, doxorubicin hydrochloride, paclitaxel, cisplatin, carboplatin, oxaliplatin, docetaxel, gemcitabine, mitomycin, vincristine, and tinib-type anti-tumor drugs. More specifically, an oil-soluble drug may be added to the outer continuous phase and/or the inner dispersed phase, and a water-soluble drug may be added to the inner continuous phase.
The chemoembolization composition provided by the invention can fully dissolve and disperse chemotherapeutics with different solubilities (water solubility and oil solubility), and has a broad spectrum of drug-loading properties.
The invention also specifically protects the application of the chemoembolization composition in preparing an embolization chemotherapeutical medicine.
Compared with the prior art, the invention has the beneficial effects that:
(1) The chemoembolization composition is oil-in-water-in-oil (O/W/O) emulsion, and the hydrophilic temperature-sensitive nano gel can be stably dispersed in an iodophor oil system, is converted into a non-flowable gel state according to the change of temperature signals inside and outside a human body, has good embolization property and does not need secondary embolization chemotherapy.
(2) The chemoembolization composition has temperature sensitivity, is liquid at normal temperature, has low viscosity, is changed into solid after injection, can effectively solve the contradiction between fluidity and embolization of the conventional embolization agent, can meet the balance requirement of fluidity and embolization required by the chemoembolization composition, is easy to inject and is convenient to operate.
(3) The water-based developer is dispersed in the inner continuous phase of the chemoembolization composition, the X-ray developing capability of the chemoembolization composition is obviously improved by cooperating with the iodized oil, and the dosage of the water-based developer is cooperated with the dosage of the temperature-sensitive nanogel, so that the chemoembolization composition has a good embolization effect while the X-ray developing capability is improved.
(4) The chemoembolization composition can also fully dissolve and disperse chemotherapeutics with different solubilities (water solubility and oil solubility), and has broad-spectrum drug-loading property.
Detailed Description
The present invention will be further described with reference to specific embodiments, but the present invention is not limited to the examples in any way. The starting reagents employed in the examples of the present invention are, unless otherwise specified, those that are conventionally purchased.
Example 1
A chemoembolization composition, which is an oil-in-water-in-oil (O/W/O) type composite emulsion, comprises an external continuous phase and an external dispersed phase,
the outer continuous phase is an oil phase, the outer dispersed phase consists of an inner dispersed phase and an inner continuous phase, the inner dispersed phase is the oil phase, the inner continuous phase is the aqueous solution of the temperature-sensitive nano gel and the aqueous developer,
the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked PNIP, and the specific composition is shown in Table 1 below.
TABLE 1 composition of chemoembolizing compositions
Example 2
A chemoembolization composition is an oil-in-water-in-oil (O/W/O) type composite emulsion, which comprises an external continuous phase and an external dispersed phase,
the external continuous phase is an oil phase, the external dispersed phase consists of an internal dispersed phase and an internal continuous phase, the internal dispersed phase is the oil phase, the internal continuous phase is the aqueous solution of the temperature-sensitive nano gel and the aqueous developer,
the temperature-sensitive nanogel is selected from N, N' -methylene bisacrylamide crosslinked poly (NIP-co-AA), and the specific composition is shown in the following table 2.
TABLE 2 composition of chemoembolizing compositions
Example 3
A chemoembolization composition, which is an oil-in-water-in-oil (O/W/O) type composite emulsion, comprises an external continuous phase and an external dispersed phase,
the external continuous phase is an oil phase, the external dispersed phase consists of an internal dispersed phase and an internal continuous phase, the internal dispersed phase is the oil phase, the internal continuous phase is the aqueous solution of the temperature-sensitive nano gel and the aqueous developer,
the temperature-sensitive nanogel is selected from N, N' -methylene bisacrylamide crosslinked poly (NIP-co-MAA), and the specific composition is shown in the following table 3.
TABLE 3 composition of chemoembolizing compositions
Example 4
A chemoembolization composition, which is an oil-in-water-in-oil (O/W/O) type composite emulsion, comprises an external continuous phase and an external dispersed phase,
the external continuous phase is an oil phase, the external dispersed phase consists of an internal dispersed phase and an internal continuous phase, the internal dispersed phase is the oil phase, the internal continuous phase is the aqueous solution of the temperature-sensitive nano gel and the aqueous developer,
the temperature-sensitive nanogel is selected from N, N' -methylene bisacrylamide crosslinked poly (NIP-co-HEA), and the specific composition is shown in the following table 4.
TABLE 4 composition of chemoembolizing compositions
Example 5
A chemoembolization composition is an oil-in-water-in-oil (O/W/O) type composite emulsion, which comprises an external continuous phase and an external dispersed phase,
the outer continuous phase is an oil phase, the outer dispersed phase consists of an inner dispersed phase and an inner continuous phase, the inner dispersed phase is the oil phase, the inner continuous phase is the aqueous solution of the temperature-sensitive nano-gel and the aqueous developer,
the temperature-sensitive nanogel is selected from N, N' -methylene bisacrylamide crosslinked poly (NIP-co-AAm), and the specific composition is shown in the following table 5.
TABLE 5 composition of chemoembolizing compositions
Example 6
A chemoembolization composition, which is an oil-in-water-in-oil (O/W/O) type composite emulsion, comprises an external continuous phase and an external dispersed phase,
the external continuous phase is an oil phase, the external dispersed phase consists of an internal dispersed phase and an internal continuous phase, the internal dispersed phase is the oil phase, the internal continuous phase is the aqueous solution of the temperature-sensitive nano gel and the aqueous developer,
the temperature-sensitive nanogel is selected from N, N' -methylene bisacrylamide crosslinked poly (NIP-co-NNP), and the specific composition is shown in the following table 6.
TABLE 6 composition of chemoembolizing compositions
Comparative example 1
A chemoembolization composition, which is an oil-in-water-in-oil (O/W/O) type composite emulsion, comprises an external continuous phase and an external dispersed phase,
the outer continuous phase is an oil phase, the outer dispersed phase consists of an inner dispersed phase and an inner continuous phase, the inner dispersed phase is the oil phase, the inner continuous phase is the aqueous solution of the temperature-sensitive nano-gel and the aqueous developer,
the temperature-sensitive nanogel is selected from N, N' -methylene bisacrylamide crosslinked PNIP, and the specific composition is shown in the following table 7.
TABLE 7 composition of chemoembolizing compositions
Result detection
(1) Embolic effect detection
The chemoembolization compositions of examples 1-6 were stored at 37 ℃ for 14 days, and it was found that the aqueous phase of each chemoembolization composition rapidly underwent gel phase transition and demixing at 37 ℃, with the upper layer being an O/W type gel microparticle emulsion and the lower layer being iodized oil, indicating that the chemoembolization compositions provided by the present application can synergistically exert the embolization effect of iodized oil and temperature sensitive gel after being injected into a human body, ensuring good embolization effect.
(2) O/W/O type composite emulsion stability detection
The chemoembolizing compositions of examples 1-6 and comparative example 1 were stored at-5 ℃ for 7 days, and after storage, the chemoembolizing compositions were found to have uniform appearance, no demulsification, no excessive thickening, and good fluidity, indicating that the chemoembolizing compositions provided by the present application have acceptable cold storage stability.
Chemoembolizing compositions provided in examples 1-6 were used and the following performance tests were performed:
1) Viscosity of the oil
According to the China pharmacopoeia 2020 edition four-part general rule 0633 third method (1), a coaxial cylinder rotation viscometer (absolute viscometer) is tested at 25 ℃;
the TACE requires that the material for chemoembolization should have good fluidity, the fluidity of the material is represented by viscosity, and the higher the viscosity is, the lower the fluidity is, and the more difficult the material is injected into a lesion part needing embolization through a catheter;
2) Modulus ratio
Performing modulus detection on a sample at different temperatures by using a rotational rheometer and selecting a strain control variable temperature gel point detection method, wherein the modulus of a gel state/the modulus of a sol state is a modulus ratio, and the unit of the modulus is Pa;
the modulus ratio represents the gel strength, and the higher the gel strength is, the certain relation exists with the capability of resisting blood flow scouring;
3) Gelation time
Taking a test sample at the temperature of 20-28 ℃, and standing for 30min for later use. A100 ml beaker is filled with about 50ml of normal saline, and the beaker is placed into a water bath at 37 ℃ for heating. After the normal saline reaches the set temperature, unscrewing a luer connector at the top of the sample, suspending an injector above the liquid level of the normal saline by about 5cm, dropwise adding the sample into the normal saline at 37 ℃, recording the time from water entry to conversion of each drop of the sample into white floccule (less than 1s is counted by 1 s), and averaging 5 times of results to obtain the gelation time of the sample;
TACE requires that a material for chemoembolization has reasonable gelation time, the gelation time corresponds to the time of gel phase change of the material due to temperature response, when the gelation time is too long, the material is easy to disperse due to the influence of blood flow scouring, and when the gelation time is too short, the material does not reach a focus part, namely gel is formed, so that false embolization is easy to cause;
4) Dissipation rate
Injecting a sample into physiological saline at 37 ℃ through a 2.7F microcatheter, and collecting unformed dissipation gel, wherein the dissipation rate is defined as the mass of the unformed gel/the total mass of the injected gel multiplied by 100%;
the dissipation rate characterizes the degree of dispersion of the solution environment of the gel, reflecting the embolization effect, the higher the dissipation rate, the worse the embolization effect.
Table 8 shows the results of the tests, and as indicated by the results, the chemoembolizing compositions provided in examples 1-6 achieved the balance of fluidity and embolization required for TACE. Wherein, compared with example 1, the iohexol dosage of comparative example 1 is increased to 11%, thereby resulting in a significant decrease in the modulus ratio of the material, a gel that becomes soft, and a divergent behavior, a decrease in the blood flow scouring resistance, and a deterioration in the embolization effect. The amount of iodooil of example 6 was significantly increased compared to example 1, thereby resulting in a decrease in the modulus ratio of the material, indicating that the amount of iodooil also affects the gelling behaviour of the chemoembolic composition to some extent.
TABLE 8
Note: N/A indicates that no specific value was detected
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (9)
1. A chemoembolization composition, which is an oil-in-water-in-oil type composite emulsion comprising an external continuous phase and an external dispersed phase,
the outer continuous phase is an oil phase,
the external dispersed phase consists of an internal dispersed phase and an internal continuous phase, the internal dispersed phase is an oil phase, the internal continuous phase is the aqueous solution of the temperature-sensitive nano gel and the aqueous developer,
wherein the mass of the temperature-sensitive nano gel is 0.5-3% of the total mass of the chemoembolization composition, the mass of the aqueous developer is 0.5-10% of the total mass of the chemoembolization composition,
the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure,
the solvent of the outer continuous phase is iodized oil, and the solvent of the inner dispersed phase is iodized oil.
2. The chemoembolization composition according to claim 1, wherein the mass of the temperature-sensitive nanogel is 2.5 to 3% of the total mass of the chemoembolization composition, and the mass of the aqueous developer is 1 to 10% of the total mass of the chemoembolization composition.
3. The chemoembolization composition of claim 1, wherein the aqueous imaging agent comprises one or more of iohexol, iopamidol, iodixanol, or iofluranol.
4. The chemoembolization composition of claim 1, wherein the temperature-sensitive nanogel is one or more of poly-N-isopropylacrylamide, poly-NIP-co-AA, poly-NIP-co-NNP, poly-NIP-co-MMA, poly-NIP-co-HEMA, poly-NIP-co-HEA, and poly-NIP-co-AAm.
5. The chemoembolic composition of claim 1, wherein the volume ratio of the inner dispersed phase to the inner continuous phase is 1: (1~8).
6. The chemoembolization composition according to claim 1, wherein the mass ratio of the outer continuous phase is 50 to 80% of the total mass of the chemoembolization composition.
7. The chemoembolization composition according to claim 1, further comprising a surfactant, wherein the surfactant accounts for 0.01 to 2% of the total mass of the chemoembolization composition.
8. The chemoembolization composition of claim 1, further comprising an anti-tumor drug.
9. Use of a chemoembolizing composition of any one of claims 1~8 in the preparation of an embolizing chemotherapeutic agent.
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