CN116115819A - Developable in-situ crosslinking embolic composition and method of use thereof - Google Patents
Developable in-situ crosslinking embolic composition and method of use thereof Download PDFInfo
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- CN116115819A CN116115819A CN202310186717.9A CN202310186717A CN116115819A CN 116115819 A CN116115819 A CN 116115819A CN 202310186717 A CN202310186717 A CN 202310186717A CN 116115819 A CN116115819 A CN 116115819A
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
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- 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
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Abstract
The application provides a developable in-situ crosslinking embolic composition, which is characterized in that the composition is characterized by liquid delivery and solid embolization, wherein the composition comprises a gel solution and a crosslinking promoting solution, and the volume ratio of the gel solution to the crosslinking promoting solution is (0.8-2): 1, a step of; the crosslinking promoting solution is 0.05-10wt% of an aqueous solution containing divalent cations; the gel solution comprises the following components: sodium alginate, a C6-C18 compound with a cyclic structure and at least 1 polar group, a linear polyalcohol substance and a nonionic developer; the composition is subjected to in-situ crosslinking in the catheter to generate gel, does not adhere to the wall of the catheter, has good trafficability of the catheter, excellent coating property and sustained-release effect, safer real-time development in operation, good development effect, high use safety and simple and convenient operation.
Description
Technical Field
The invention relates to the technical field of medical embolism technology and embolic material, in particular to a developable in-situ crosslinking embolic composition and a use method thereof.
Background
The embolism technology belongs to a key technology in interventional therapy, is widely applied to the treatment of various diseases such as cardiac ducts, nerves, orthopaedics and the like at present, and mainly blocks blood supply of tumor tissues through a duct embolic agent so as to make tumor cells necrotize and achieve the treatment purpose; the existing materials for embolism mainly comprise gelatin, chitosan, hyaluronic acid and the like, and although the materials have the characteristics of colloid formation, non-toxicity, biodegradability and the like, the crosslinking performance of the materials is still low, the materials are easy to break after being conveyed by a catheter, are not easy to bear blood impact, the size of embolic particles is uneven, and the elastic strain force is poor, so that the embolism effect is reduced; in addition, in the common embolic operation treatment, most embolic agents have no developing function, and contrast agents are required to be added into the embolic agents to observe the embolic effect in the operation, but the embolic agents have limited wrapping effect on the developing agents, so that the developing agents are easily discharged out of the body along with blood flow, the developing degree is low, the duration is short, and the operation performance or the postoperative review is influenced.
Chinese patent CN112043859a discloses a visual composite microsphere for embolism, in which a matrix formed by high molecular polymer bletilla striata polysaccharide and colloid such as gelatin, acacia gum or agar is adopted in the technology to embed a drug and a developing material, so as to achieve the effects of slow release and embolism, but the coating performance of the matrix on the liquid metal particles of the developer is insufficient, the metal may overflow to poison human body, and the slow release and embolism time is required to be improved. Chinese patent CN101544701B discloses a developable iodic polymer and a developable iodic polymer embolic material, wherein the esterified polymer material is complexed with iodide ions, and the prepared iodic polymer material is dissolved in an organic solvent to be used as the embolic material, and although the embolic time is prolonged, the catheter passing property is poor, embolic particles are not uniform, and the embolic effect is low.
Therefore, it is necessary to develop an embolic material having the characteristics of biodegradability, high drug release, good development effect, long development time, uniform embolization of the tip, excellent catheter passability, and the like.
Disclosure of Invention
In order to solve the technical problems, the invention firstly provides a developable in-situ crosslinking embolic composition; the components of the composition comprise a gel solution and a crosslinking promoting solution, wherein the volume ratio of the gel solution to the crosslinking promoting solution is (0.8-2): 1, a step of; the crosslinking promoting solution is 0.05-10wt% of an aqueous solution containing divalent cations.
Further, the components of the gel solution include: sodium alginate, a C6-C18 compound with a cyclic structure and at least 1 polar group, a linear polyalcohol substance and a nonionic developer.
In the application, sodium alginate is a main crosslinking matrix, and a crosslinking structure formed by a molecular chain of the sodium alginate is utilized to wrap a drug and a developer and form an embolism. However, the embolism effect of the gel formed by the gel is poor and the wrapping performance of the gel on the developer is insufficient, so that the water solubility is poor, and the medicine cannot be well released into blood when the medicine is wrapped; the polar group and the cyclic structure of the C6-C18 compound with at least one polar group and the cyclic structure of the compound have intermolecular actions with-OH, -COOH and conjugated structures in sodium alginate, so that the crosslinking degree in a gel system is improved, and the polar group of the compound also improves the dispersibility of the sodium alginate in an aqueous solution and the release of the coated medicine; in addition, a plurality of hydroxyl groups in the linear polyalcohol substance can form hydrogen bonds and crosslinking of molecular chains with the two substances, the elasticity of the embolic particles can be regulated and controlled by the linear structure of the linear polyalcohol substance while the gel effect is further improved, the deformation stress of the gel after phase transition is improved, the embolism effect is enhanced, and the developer is wrapped in the linear polyalcohol substance and the linear polyalcohol substance through the crosslinking structure of the linear polyalcohol substance, so that the development effect and development persistence are ensured.
Further, the volume ratio of the total mass of the sodium alginate to the C6-C18 compound which has a cyclic structure and at least has 1 polar group to the nonionic developer is 0.01-0.5g/mL; preferably 0.015-0.3g/mL.
Further, the non-ionic developing solution includes, but is not limited to, any one of a solution containing iodide ions, iohexol injection, iobiol injection, iodixanol injection, iopamidol injection, iopromide injection.
Further, the concentration of iodide ions in the nonionic developer is 120-400mg/mL.
In one embodiment, the concentration of iodide ions in the non-ionic developer is 350mg/mL.
Further, the mass ratio of the sodium alginate to the C6-C18 compound which has a cyclic structure and has at least 1 polar group is (0.1-5): (0-18). Further regulating, namely adding linear polyalcohol substances into the sodium alginate and the C6-C18 compound which has a cyclic structure and at least has 1 polar group, wherein the mass ratio of the linear polyalcohol substances to the sodium alginate is (0.1-5): (0-18): (0.3-20) so that the crosslinking system plays a better role in slow release after embolism.
The dosage of the two or the three components is further regulated so that the cross-linking system forms proper embolic particle size after shearing by blood, uniform embolism of blood vessels is realized, when the adding amount of the C6-C18 compound with at least one polar group and a ring structure is excessive, the cohesive strength of the material is too high, the proper embolic particle size is formed after shearing by blood, uniform embolism of blood vessels is realized, when the adding amount of the C6-C18 compound with at least one polar group and a ring structure is excessive, the cohesive strength of the material is too high, the shearing action of blood flow on the cross-linking system is difficult, the particle size of embolic particles is too long, when the adding amount of the linear polyol substance is excessive, the re-dissolution time of the freeze-dried powder is influenced, the viscosity of the material is also increased, and the injection difficulty is increased for injection in operation.
Preferably, the mass ratio of the sodium alginate to the C6-C18 compound which has a cyclic structure and has at least 1 polar group is (0.1-3): (0-15).
In a preferred embodiment, the mass ratio of sodium alginate, the C6-C18 compound having a cyclic structure and having at least 1 polar group, and the linear polyol is (0.3-0.7): (0.3-1.5): (0.3-2.1).
Further, the C6-C18 compound having a cyclic structure and having at least 1 polar group is selected from at least one of including, but not limited to, N-ethyl-5-methyl-2- (1-methylethyl) cyclohexanecarboxamide, 2, 4-dimethyl-5- (phosphonooxymethyl) pyridin-3-ol, pyridine-3-carboxamide, 3- ((4-amino-2-methyl-5-pyrimidinyl) methyl) -5- (2-hydroxyethyl) -4-methylthiazole chloride, 2,3,5, 6-tetrahydroxy-2-hexenoic acid-4-lactone.
Preferably, the C6-C18 compound having a cyclic structure and having at least 1 polar group is any one of 2,3,5, 6-tetrahydroxy-2-hexenoic acid-4-lactone, 2, 4-dimethyl-5- (phosphonooxymethyl) pyridin-3-ol, and pyridine-3-carboxamide.
In a preferred embodiment, the C6-C18 compound having a cyclic structure and having at least 1 polar group is pyridine-3-carboxamide.
Further, the linear polyol substance includes, but is not limited to, one or a combination of several of polyester polyol, polyether polyol, polyolefin polyol and polyethylene glycol, preferably polyethylene glycol.
Preferably, the average molecular weight of the polyethylene glycol is 1500-20000, including but not limited to at least one of PEG1500, PEG2000, PEG4000, PEG6000, PEG8000, PEG10000, PEG 20000.
Further preferably, the polyethylene glycol is at least one selected from the group consisting of PEG1500, PEG2000, and PEG4000.
Further, the preparation method of the gel solution comprises the following steps:
s1, dissolving sodium alginate and a C6-C18 compound which has a cyclic structure and at least has 1 polar group in water, and then filtering, freeze-drying and sterilizing by irradiation;
s2, dissolving the product in the S1 into a nonionic developer.
Further, when linear polyol is added, the gel solution is prepared by the following steps:
s1, dissolving sodium alginate, a C6-C18 compound with a cyclic structure and at least 1 polar group and a linear polyol substance in water, and then filtering, freeze-drying and irradiation sterilizing;
s2, dissolving the product in the S1 into a nonionic developer.
Furthermore, in the preparation method, medicines can be added into the product in the step S1 during redissolution, so that the gel is used for embedding medicines, and embolism and treatment double combination is realized during treatment.
Further, in the step S1, the total amount of sodium alginate and C6-C18 compound having a cyclic structure and having at least 1 polar group is 0.5-10% by weight, preferably 1-3% by weight of water.
Further, in the irradiation sterilization of the step S1, the irradiation dose is 15-45kGy, the molecular weight of sodium alginate is reduced but the embolism effect is not affected after the irradiation treatment, the molecular weight distribution (PDI) value of sodium alginate in the product of the step S1 is also reduced within the acceptable irradiation dose, the pushing force is slightly reduced when the sample is pushed and injected and mixed, the formed gel system is more uniform, however, when the irradiation dose is too high or too low, the reconstitution time of the product of the step S1 in the step S2 and the viscosity, the operation, the gel formation and the embolism effect after the reconstitution are affected, the operation is not facilitated, and the optimal embolism effect cannot be achieved.
Preferably, the irradiation dose is 25-35kGy.
The invention further provides a using method of the developable in-situ crosslinking embolic composition, which comprises the following steps: and synchronously injecting the gel solution and the crosslinking promoting solution into the catheter.
Further, in the use method, the bolus volumes of the gel solution and the crosslinking promoting solution are 1: (0.3-1).
Further, the injection speed of the gel solution and the crosslinking promoting solution is 0.3-5mL/min.
According to the application, clinical application is combined, when the pushing injection speed of the two is further regulated to be 0.3-3mL/min, the particle size of the embolism particles is more uniform after blood is sheared, and the uniformity of embolism at the tail end of a catheter is higher; the applicant analyzed the cause: the application relates to an in-situ embolism gel, namely an in-situ gel, which is a preparation capable of immediately generating phase transition at a medicine application position after being applied in a solution state and forming non-chemical crosslinking semisolid gel by liquid state transition. The medicine and gel material can be prepared into uniform and suspension emulsion thick liquid or semisolid gel. The gel has good tissue compatibility and long retention time at the administration position; meanwhile, the medicine can be stored, and the medicine is prevented from being influenced by the environment and the like.
Further, the aqueous solution of divalent cations includes, but is not limited to, any one or a combination of several of calcium chloride, calcium carbonate, calcium lactate, and calcium oxide solutions.
Further, the developable in-situ crosslinking embolic composition is used for interventional embolic treatment of liver cancer and vascular rich operation malignant tumors.
The working principle of the application is as follows: the composition performs ion exchange in the process of injection mixing to realize further crosslinking of gel, and gel particles with different sizes are formed after the crosslinked gel is sheared by flowing blood, so that the embolism effect is achieved; the iodide ions are encapsulated and immobilized in the gel particles, which enhances and prolongs the development effect.
Advantageous effects
1. The application provides a developable in-situ crosslinking embolic composition which exists in a characteristic combination of liquid delivery and solid embolization, the composition is crosslinked in a catheter to generate gel in situ, a catheter wall is not adhered, the trafficability of the catheter is good, and real-time development in operation is safer; the gel is formed by physical crosslinking, so that the use safety is high, the operation is simple and convenient, the storage and preservation period of the freeze-dried gel dry powder is long, and the gel dry powder is re-dissolved during use.
2. The embolic composition optimizes the crosslinking degree of sodium alginate by using a C6-C18 compound with a cyclic structure and at least 1 polar group, further improves the wrapping of iodide ions and medicines by adding linear polyalcohol substances, improves the crosslinking degree by optimizing the types and the relative contents of the components, further increases the wrapping amount and the slow release effect of an iodide ion developer and medicines, and has good development effect and long development duration when being used for embolization; and the freeze-dried powdery substance is simple to redissolve, and the solution is easy to push and inject after redissolution, so that the comprehensive performance is excellent.
3. The embolic composition of the application is crosslinked in situ during use, has excellent passage in a catheter, also has excellent crosslinking degree, can form embolic particles with specific size after blood is sheared, has excellent embolic effect and can realize uniform embolism of the tail end of a blood vessel.
Drawings
Fig. 1: the in vitro simulation device uses an X-ray contrast map of the embolic composition of example 1 before and after embolization;
fig. 2: an enlarged embolic particle map of the composition of example 1 after blood shear injected into the middle artery via a 2.7F microcatheter;
fig. 3: contrast X-ray contrast effect plots for the composition of example 1, 350mg/mL and 300mg/mL iodine, racing and blank catheters;
fig. 4: a DSA apparatus image monitoring lower graph of right renal lower arterial blood vessels of pama minipigs in order from left to right before surgery, during embolization surgery using the embolization composition of example 1, and after surgery;
fig. 5: left and right kidney contrast pictures of Bama miniature pigs after 7 days of embolization operation (embolization part is right renal inferior artery vessel);
fig. 6: chromatograms of iohexol release in the composition of example 1 (PEG-2000) and the composition of comparative example 2 (no PEG);
fig. 7: particle size fractionation of embolic particles after the composition of example 1 was injected into the middle artery via microcatheter bolus via blood shear.
Detailed Description
Examples
Example 1
The present example provides a developable in situ cross-linking embolic composition comprising a gel solution and a cross-linking promoting solution that is an aqueous solution of 0.5wt% calcium chloride;
the preparation method of the gel solution comprises the following steps:
s1, dissolving 0.50g of sodium alginate, 1.50g of pyridine-3-formamide and 1.00g of PEG-2000 in 100g of water, filtering through a 0.45 mu m membrane, freeze-drying (the freeze-drying parameters are shown in Table 2), and sterilizing at an irradiation dose of 25 kGy; obtaining powdery substances;
s2, redissolving 0.15g of the powdery product of S1 into 5mL of nonionic developer (aqueous solution of iohexol with the iodine concentration of 350mg/mL, purchased from Taizhou sea god pharmaceutical Co., ltd.);
the application method of the composition comprises the following steps: the gel solution and the crosslinking promoting solution are synchronously injected into the catheter by using two syringes with the same specification, wherein the volume ratio of the gel solution to the crosslinking promoting solution is 1:1, the injection speed is 2mL/min, and the catheter is in a state that the blood flow of the renal aorta of the human body is 1500mL/min (adopting a 1:1 renal model of the human body).
Example 2
The present example provides a developable in situ cross-linking embolic composition comprising a gel solution and a cross-linking promoting solution that is an aqueous solution of 0.5wt% calcium chloride;
the preparation method of the gel solution comprises the following steps:
s1, dissolving 0.50g of sodium alginate and 1.50g of pyridine-3-carboxamide in 100g of water, filtering through a 0.45 mu m membrane, freeze-drying (drying parameters are consistent with those of example 1), and sterilizing at an irradiation dose of 25 kGy; obtaining powdery substances;
s2, redissolving 0.1g of the powdery product of S1 into 5mL of nonionic developer (aqueous solution of iohexol with the iodine concentration of 350mg/mL, purchased from Taizhou sea god pharmaceutical Co., ltd.);
the application method of the composition comprises the following steps: the gel solution and the crosslinking promoting solution are synchronously injected into the catheter by using two syringes with the same specification, wherein the volume ratio of the gel solution to the crosslinking promoting solution is 1:1, the injection speed is 2mL/min, and the catheter is in a state that the blood flow of the renal aorta of the human body is 1500mL/min (adopting a 1:1 renal model of the human body).
Example 3
The present example provides a developable in situ cross-linking embolic composition comprising a gel solution and a cross-linking promoting solution that is an aqueous solution of 0.5wt% calcium chloride;
the preparation method of the gel solution comprises the following steps:
s1, dissolving 0.60g of sodium alginate and 2.40g of pyridine-3-carboxamide in 100g of water, filtering through a 0.45 mu m membrane, freeze-drying (drying parameters are consistent with those of the example 1), and sterilizing at an irradiation dose of 25 kGy; obtaining powdery substances;
s2, redissolving 0.30g of the powdery product of S1 into 10mL of nonionic developer (aqueous solution of iohexol with the iodine concentration of 350mg/mL, purchased from Taizhou sea god pharmaceutical Co., ltd.);
the application method of the composition comprises the following steps: the gel solution and the crosslinking promoting solution are synchronously injected into the catheter by using two syringes with the same specification, wherein the volume ratio of the gel solution to the crosslinking promoting solution is 1:1, the injection speed is 1mL/min, and the blood flow in the catheter is 2000mL/min (adopting a human body 1:1 kidney model).
Example 4
The present example provides a developable in situ cross-linking embolic composition comprising a gel solution and a cross-linking promoting solution that is an aqueous solution of 0.3wt% calcium chloride;
the preparation method of the gel solution comprises the following steps:
s1, dissolving 0.60g of sodium alginate, 1.80g of pyridine-3-formamide and 1.20g of PEG-2000 in 100g of water, filtering, freeze-drying (drying parameters are the same as those of the embodiment 1), and sterilizing by irradiation; wherein the irradiation sterilization dose is 35kGy; obtaining powdery substances;
s2, redissolving 0.36g of the powdery product of S1 into 10mL of nonionic developer (aqueous solution of iohexol with the iodine concentration of 350mg/mL, purchased from Taizhou sea god pharmaceutical Co., ltd.);
the application method of the composition comprises the following steps: the gel solution and the crosslinking promoting solution are synchronously injected into the catheter by using two syringes with the same specification, wherein the volume ratio of the gel solution to the crosslinking promoting solution is 1:1, the injection speed is 3mL/min, and the catheter is in a state that the blood flow of the renal aorta of the human body is 2000mL/min (adopting a 1:1 renal model of the human body). .
Example 5
The present example provides a developable in situ cross-linking embolic composition comprising a gel solution and a cross-linking promoting solution that is an aqueous solution of 0.5wt% calcium chloride;
the preparation method of the gel solution comprises the following steps:
s1, dissolving 0.70g of sodium alginate, 1.40g of pyridine-3-formamide and 2.5g of PEG-2000 in 100g of water, filtering through a 0.45 mu m membrane, freeze-drying and sterilizing at an irradiation dose of 25 kGy; obtaining powdery substances;
s2, redissolving 0.23g of the powdery product of S1 into 5mL of nonionic developer (aqueous solution of iohexol with the iodine concentration of 350mg/mL, purchased from Taizhou sea god pharmaceutical Co., ltd.);
the application method of the composition comprises the following steps: the gel solution and the crosslinking promoting solution are synchronously injected into the catheter by using two syringes with the same specification, wherein the volume ratio of the gel solution to the crosslinking promoting solution is 1:1, the injection speed is 2mL/min, and the catheter is in a state that the blood flow of the renal aorta of the human body is 2000mL/min (adopting a 1:1 renal model of the human body).
Example 6
Substantially identical to example 1, except that: in the preparation method of the gel solution, 0.50g of sodium alginate, 1.500g of pyridine-3-formamide and 1.00g of PEG-2000.
Example 7
Substantially identical to example 1, except that: in the preparation method of the gel solution, sodium alginate 0.30g, pyridine-3-formamide 1.50g and PEG-2000.5 g.
Example 8
Substantially identical to example 1, except that: in the preparation method of the gel solution, 0.50g of sodium alginate, 1.00g of pyridine-3-formamide and 1.50g of PEG-2000.
Example 9
Substantially identical to example 1, except that: in the using method, the radiation dose is 35kGy.
Comparative example 1
Substantially identical to example 1, except that: in the preparation method of the gel solution, 0.50g of sodium alginate, 0.50g of pyridine-3-formamide and 3.0g of PEG-2000.
Comparative example 2
Substantially identical to example 1, except that: the pyridine-3-carboxamide is replaced with 3- ((4-amino-2-methyl-5-pyrimidinyl) methyl) -5- (2-hydroxyethyl) -4-methylthiazole chloride.
Comparative example 3
Substantially identical to example 1, except that: PEG-2000 was replaced with PEG4000.
Comparative example 4
Substantially identical to example 1, except that: the irradiation dose was 45kGy.
The using method of the embolism composition is carried out according to an in-vitro simulation experiment (adopting a human body 1:1 kidney model), and specific information of the device is shown in a test method 3.
The performance test method comprises the following steps:
1. embolic sample performance: the powdery material of the example was dissolved in 5mL of physiological saline, then added into a container containing 5mL of crosslinking-promoting solution, allowed to stand for 6 hours, and the hardness, elasticity and tackiness of the crosslinked sample were analyzed by a TA.XTC texture analyzer (speed: 1mm/s, probe trigger force: 5 gf), and the test results are shown in Table 1;
2. iodine release amount: using one 5mL syringe to absorb the sample solution containing 350mg/mL iodine (calculated by iodine), using the other 5mL syringe to absorb 5mL calcium solution (concentration 0.5 wt%), installing two syringes on a push pump (C24 double track), setting push parameters of the push pump, injecting 3mL/min and 3mL of push quantity (about 1.5mL remained in a calculated conduit and a tee), injecting the sample into a container containing 20mL of injection water through the tee and the conduit, soaking at the constant temperature of 37 ℃ for 30min, filtering to obtain filtrate with the volume of V1, analyzing the concentration of iodine content in the filtrate by using a liquid chromatograph, and calculating the release quantity of iodine according to a formula, wherein the release quantity of iodine is = (A.V1)/(V2.n) ×100%; wherein A: concentration of iodine in filtrate, V1: filtrate volume, V2: the volume of the bolus, n, is the iodine content of the test sample solution.
3. In vitro simulation experiment: the composition in the examples was subjected to in vitro catheter embolization simulation experiments according to the prescribed bolus amounts and bolus rates by simulating the temperature and conditions at the time of clinical use, wherein the in vitro simulator comprises: the renal artery-renal artery model (according to the 1:1 replication of human blood vessel viscera, PLXG 0000), a pulsation pump (PLAB 2001) and a digital display constant temperature water tank (PLAB 3001) are formed, a 5.0Fr catheter (namely femoral artery) is used for entering a renal aortic cannula before embolism, a 2.7Fr microcatheter is used for inserting a secondary artery, and then embolism is carried out; observing the contrast effect before and after embolism, the embolism effect and the particle size of the embolism particles after being pushed out by a microcatheter and blood shearing; the products of examples 1-10 all achieved embolization and were excellent in intraoperative development; wherein the embolization effect of the product of example 1 is shown in figures 1-3;
4. in vivo simulation experiment: animal experiments were performed using 56kg pama minipigs, the right kidney lower level of the minipigs were subjected to super-selected cannulated embolization under DSA according to the protocol of example 1, real-time embolization under DSA equipment image monitoring (see specifically fig. 4) before, during and after the operation was observed in real time, dissected at 7 days post-operation feeding, double kidney comparison; the left and right kidney conditions (see in particular fig. 5) were observed, wherein the left kidney was seen to be reddish and the right kidney was seen to have obvious symptoms of ischemic necrosis; and after 30min of blood coagulation, the ischemic state of the right kidney lower level is more obvious.
Performance test results:
the test results are shown in Table 1.
TABLE 1
TABLE 2
Claims (11)
1. A developable in situ cross-linked embolic composition, characterized in that the composition is present in combination as a liquid delivery, solid embolization feature, comprising a gel solution and a cross-linking promoting solution in a volume ratio of (0.8-2): 1, a step of;
the crosslinking promoting solution is 0.05-10wt% of an aqueous solution containing divalent cations;
the gel solution comprises the following components: sodium alginate, a C6-C18 compound with a cyclic structure and at least 1 polar group and a nonionic developer.
2. The composition according to claim 1, wherein the mass ratio of sodium alginate, C6-C18 compound having a cyclic structure and having at least 1 polar group is (0.1-3): (0-15).
3. The composition according to claim 2, wherein the total mass ratio of sodium alginate, C6-C18 compound having a cyclic structure and having at least 1 polar group, to the nonionic developer is 0.01 to 0.5g/mL.
4. A composition according to claim 3, wherein the C6-C18 compound having a cyclic structure and bearing at least 1 polar group is selected from N-ethyl-5-methyl
-at least one of 2- (1-methylethyl) cyclohexanecarboxamide, 2, 4-dimethyl-5- (phosphonooxymethyl) pyridin-3-ol, pyridin-3-carboxamide, 3- ((4-amino-2-methyl-5-pyrimidinyl) methyl) -5- (2-hydroxyethyl) -4-methylthiazole chloride, 2,3,5, 6-tetrahydroxy-2-hexenoic acid-4-lactone.
5. The composition of claim 2, wherein the sodium alginate and the C6-C18 compound having a cyclic structure and at least 1 polar group are combined to provide a sustained release effect upon the addition of the linear polyol.
6. The composition of claim 5, wherein the linear polyol is polyethylene glycol having an average molecular weight of 1500-20000.
7. The composition according to claim 5, wherein the mass ratio of sodium alginate, C6-C18 compound having a cyclic structure and having at least 1 polar group, and linear polyol is (0.1-3): (0-15): (0.1-10).
8. A composition according to claim 3, wherein the gel solution is prepared by the process of:
s1, dissolving sodium alginate and a C6-C18 compound which has a cyclic structure and at least has 1 polar group in water, and then filtering, freeze-drying and sterilizing by irradiation;
s2, dissolving the product in the S1 into a nonionic developer.
9. The composition of claim 7, wherein the gel solution is prepared by the process of:
s1, dissolving sodium alginate, a C6-C18 compound with a cyclic structure and at least 1 polar group and a linear polyol substance in water, and then filtering, freeze-drying and irradiation sterilizing;
s2, dissolving the product in the S1 into a nonionic developer;
in the irradiation sterilization, the irradiation dose is 15-45kGy.
10. A method of use of a composition according to any one of claims 1 to 9, characterized in that it comprises in particular: and synchronously injecting the gel solution and the crosslinking promoting solution into the catheter.
11. The method of claim 10, wherein the gel solution and the crosslinking-promoting solution are injected at a rate of 0.3-3mL/min.
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