CN113730646A - High-drug-loading degradable alginic acid sulfate vascular embolization microsphere as well as preparation method and application thereof - Google Patents
High-drug-loading degradable alginic acid sulfate vascular embolization microsphere as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of high drug loading degradable alginic acid sulfate blood vessel embolism microspheres, which comprises the following steps: s01, preparing a water phase; s02, preparing an oil phase; s03, preparing alginic acid sulfate microspheres; s04, preparing the alginate sulfate embolism microsphere loaded with the drug. The invention also discloses the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere obtained by the preparation method of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere and application of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere in preparation of a transcatheter arterial chemoembolization treatment embolization agent. The alginic acid sulfate blood vessel embolism microsphere has better biocompatibility and biodegradability, and degradation products are safe and nontoxic. The preparation method has the advantages of simple and convenient operation, good repeatability, mild conditions and the like, the prepared microsphere has uniform and controllable particle size, and the prepared blood vessel embolism microsphere has better application prospect in the field of tumor interventional therapy.
Description
Technical Field
The invention relates to a high drug loading degradable alginic acid sulfate blood vessel embolism microsphere and a preparation method and application thereof, belonging to the technical field of biomedical materials.
Background
Transcatheter Arterial Chemoembolization (TACE) refers to a technique of injecting embolization material into the supply vessel of a diseased organ through an intra-Arterial catheter in a controlled manner, so as to occlude the vessel and interrupt the blood supply, thereby achieving the purpose of controlling bleeding, treating tumor and vascular diseases and eliminating the diseased organ. TACE is clinically used for treating malignant tumors which are difficult to intervene by conventional therapies (such as operations and chemotherapy). Taking liver cancer as an example, the clinical treatment means is very limited, which is shown in the following: firstly, the operation is the first choice means for treating liver cancer, but because the physiological structure of the liver is complex and the operation is limited, only 10 to 15 percent of patients with primary diagnosis liver cancer have the opportunity to perform the operation in China, and the recurrence rate after the operation is as high as 40 to 70 percent[1]) (ii) a Secondly, liver cancer patients are generally insensitive to traditional radiotherapy and chemotherapy; and the novel targeted therapy (sorafenib and the like) has low sensitivity and is easy to generate drug resistance. The liver is supplied with blood by a dual vascular system of hepatic artery and portal vein, 20% -25% of normal hepatic tissue is supplied with blood from the hepatic artery, the rest is supplied with blood from the portal vein, and 95% -99% of hepatic cancer cells are supplied with blood from the hepatic artery[2]. TACE can selectively block blood supply vessels of liver cancer by using an embolization material, does not influence the blood supply of normal liver tissues, and enables tumors to be starved. Meanwhile, in recent years, a medicine-carrying embolism material (medicine-carrying microsphere) which is concerned can carry chemotherapeutic medicines to go deep into the tumor. The embolism and the chemotherapy are both managed, thereby achieving the purpose of treatment.
Currently, tumor embolizing agents that are on the market include: liquid embolism materials (such as iodized oil) and solid embolism materials (such as gelatin sponge, polyvinyl alcohol particles, conformable microspheres, drug-loaded microspheres, and the like). Wherein, the liquid embolism material has over strong fluidity, the solid particle embolism material has poor vascular conformability, which is easy to cause unstable or insufficient embolism, and the liquid embolism material is gradually replaced by the embolism microsphere with regular shape, uniform particle size, good elasticity and strong conformability. However, in the actual clinical use process, it is found that the traditional microspheres are mostly prepared from materials which are not degradable in vivo (such as polyvinyl alcohol, sodium polyacrylate vinyl alcohol, silicon dioxide and the like), and are easy to embolize excessively, thereby causing: firstly, the tumor is embolized for a long time to generate a strong hypoxia microenvironment to induce angiogenesis and subsequent development of bypass blood vessels, the embolized tumor is restored to blood supply, and the tumor cannot be cured (embolization failure risk); secondly, excessive embolism causes side effects such as liver abscess and pain in some cases, which greatly affects prognosis (side effect risk); and thirdly, the patient loses the chance of secondary treatment (subjective risk) due to excessive embolism caused by insufficient experience, which is highly dependent on the subjective experience and technique of a clinical operator.
The drug-loaded microspheres are used as the latest generation of embolism products, and have remarkable effect in clinical tumor interventional therapy. After the drug-loaded microspheres are retained at tumor sites, cytotoxic or monoclonal antibody chemotherapeutic drugs can be selectively and directly delivered to the focus of infection, the local concentration of the drugs is increased, the drug loss caused by systemic administration is avoided, and the toxic and side effects of normal organs are reduced. Meanwhile, the drug-loaded microspheres can continuously release chemotherapeutic drugs at tumor sites, so as to achieve the effect of slow release and anticancer. Clinical research shows that the medicine carrying microsphere can raise the life quality of liver cancer patient in middle and late stage obviously, prolong life time and reduce toxic side effect[3]. In recent years, with the rapid development of precise medical treatment and medical technology, individualized precise intervention solutions such as multi-combination chemotherapy (multiple chemotherapeutic drug combinations) and multi-mode chemotherapy (development and chemotherapy) are continuously proposed, and the clinical requirements for tumor embolization agents are correspondingly improved. At present, the drug-loaded microsphere products on the market are all non-degradable microspheres, and have the following two core problems: firstly, due to the limitation of raw materials and process, the content of drug-loaded groups is very limited, and the actual requirement of more complex interventional embolotherapy is difficult to meet; ② the medicine release mechanism is elution effect of peripheral solution (such as blood and tissue fluid), however, after tumor blood vessel embolism, blood flow is blocked, tissue fluid is reduced, so that the medicine on the surface of microsphere is difficult to elute, and the medicine in the interior of microsphere is not easy to elute because of the non-existent raw materialThe drug-loaded microsphere can be degraded and can not be released, the exertion of the drug-loaded microsphere drug-releasing function is commonly restricted, and the research and development of the novel drug-loaded embolism microsphere with larger drug-loaded space and degradable drug release is a necessary trend of TACE technical development in the precise medical age.
Therefore, the novel degradable microspheres with high drug loading capacity are developed, so that the bottleneck problem in the implementation process of the conventional TACE technology can be solved, the requirements of the technology in a new medical age can be met, and the further development of the TACE technology is expected to be promoted. However, comprehensive analysis of the existing degradable interventional biomedical materials shows that the degradable materials generally lack drug-carrying groups and are difficult to realize the drug-carrying function, or are difficult to balance the embolism/degradation function, or have potential safety hazards, such as: gelatin sponge (short embolism period due to too fast degradation speed and no drug-loaded group), sodium alginate (no drug-loaded group), polylactic acid (degradation product has strong irritation to tissue), chitosan (hemolysis risk), and the like. In conclusion, the introduction of the novel degradable material rich in the drug-carrying group is crucial to the research and development of novel embolism microspheres, and the dual functions of high drug-carrying and degradation are expected to be realized on the same microsphere product.
[1] Shenfeng, Wumengtao, anti-relapse therapy after hepatoresection [ J ] J.Zhonghua J.J.2005, 85(41):2886-2888.
[2] Interventional therapy of Wangjianhua, interventional therapy of liver cancer interventional therapy of primary liver cancer [ J ] J.Utility Med.2001, 017(004):278- & 280.
[3] Zhaoyi, Wangtianyu, Liujunzhong, etc. the drug-loaded microspheres have value in the treatment of primary liver cancer by hepatic artery chemoembolization [ J ] J. journal of medical Forum, 41(12):5.
Disclosure of Invention
Aiming at the defects of the current vascular embolization agent and the clinical requirements of the TACE technology at the present stage, the invention aims to provide a preparation method of high drug-loading degradable alginic acid sulfate vascular embolization microspheres used in transcatheter arterial embolization treatment.
Meanwhile, the invention provides a high drug loading degradable alginic acid sulfate blood vessel embolism microsphere.
Meanwhile, the invention provides application of the high-drug-loading degradable alginic acid sulfate blood vessel embolism microsphere in preparation of a transcatheter arterial chemoembolization treatment embolization agent.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of high drug-loading degradable alginic acid sulfate blood vessel embolism microspheres comprises the following steps:
s01, preparation of aqueous phase: dissolving alginic acid sulfate in deionized water to prepare a solution of 0.1-1 g/mL, adding a NaOH solution after uniform dissolution to adjust the pH value to 8-14 for later use;
s02, preparation of oil phase: adding 0.1-20% w/v of emulsifier into vegetable oil serving as a solvent, and stirring at 60-90 ℃ until the emulsifier is completely dissolved for later use;
s03, preparing alginic acid sulfate microspheres: adding the prepared water phase into the oil phase at a speed of 0.1-10 mL/min under stirring of a stirring paddle, wherein the stirring speed is 300-800 r/min, adding a cross-linking agent after the water phase is added, and reacting for 2-20 h at 60-90 ℃; sieving the microspheres by using a screen, repeatedly washing the microspheres for 1-5 times by using petroleum ether, ethyl acetate and absolute ethyl alcohol respectively, and drying the microspheres in vacuum to obtain alginic acid sulfate microspheres;
s04, dissolving the drug in pure water, putting the alginic acid sulfate microspheres into a container, adding a drug solution to soak the alginic acid sulfate microspheres in the drug solution, shaking and mixing uniformly from time to time, filtering and collecting the microspheres after complete reaction, and drying in vacuum to obtain the drug-loaded alginic acid sulfate thromboembolic microspheres.
The molecular weight of the alginic acid sulfate is 1 × 104~3×106D。
The emulsifier is one or more of Span60, Span80, Tween60 and Tween 80.
The volume ratio of the oil phase to the water phase is 1: 1-30: 1.
The cross-linking agent is epichlorohydrin; the volume ratio of the cross-linking agent to the water phase is 1: 10-10: 1.
The drug includes a cationic chemotherapeutic drug.
The cationic chemotherapeutic agent comprises irinotecan, epirubicin or doxorubicin hydrochloride. The cationic chemotherapeutic drugs may also include bleomycin, gemcitabine, pirarubicin, cyclophosphamide, camptothecin, vincristine, etc., which are not described in detail herein.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is obtained by the preparation method of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere.
The invention discloses application of high drug-loading degradable alginic acid sulfate vascular embolization microspheres in preparation of a transcatheter arterial chemoembolization treatment embolization agent.
Transcatheter Arterial Chemoembolization is known as Transcatheter Arterial Chemoembolization (TACE).
Compared with the prior art, the invention has the following beneficial effects:
1. the alginic acid sulfate as the microsphere raw material is prepared by carrying out sulfation on hydroxyl in alginic acid molecules.
Alginic acid (SA), also known as alginic acid, is a natural polysaccharide obtained from marine brown algae, is polymerized from mannose and gulose monosaccharide molecules, and is a classical marine-derived biomaterial. The good biocompatibility and biodegradability of SA are approved by the industry, sodium alginate embolization microspheres are available on the market, and the safety and effectiveness of the material in the field of tumor embolization are fully proved. However, due to the limitations of raw materials and process technology at that time, the product has the defects of uncontrollable degradation, lack of drug-carrying groups and the like, and is not suitable for the clinical requirements of TACE technology development at the present stage. The alginic acid sulfate is an alginic acid derivative prepared by a sulfation method, and the development of the embolism microsphere by taking the alginic acid sulfate as a raw material has the following three advantages: firstly, the glycosidic bond structure of the SA is not changed by the raw materials, the excellent biocompatibility and degradability of the SA are reserved, and the main degradation products are mannose and gulose, so that the SA is safe and non-toxic; the alginic acid molecules are rich in hydroxyl, and the adopted sulfation process can achieve higher substitution degree, so that alginic acid sulfate has a large number of sulfonic acid groups which are main drug-carrying groups of the microsphere, and the embolism microsphere has higher drug-carrying capacity; the polysaccharide molecules have side chain structures, which are different from straight-chain polymer materials, and after crosslinking and energy balance, the obtained microspheres have rough surfaces, large specific surface areas and high surface drug-loaded radical density, so that the drug-loaded performance of the product is improved. In conclusion, the alginic acid sulfate is used as a raw material to develop the novel high-drug-loading degradable embolic microsphere, so that the existing bottleneck problem of TACE is solved, and the alginic acid sulfate has important significance for the innovative development of the TACE technology in a new period.
2. The alginic acid sulfate microspheres can control the degradation speed by adjusting the crosslinking degree, thereby balancing the embolism/degradation function. The crosslinking degree in the present invention means the amount of the crosslinking agent and the crosslinking time.
3. The alginic acid sulfate microspheres of the invention can be biologically degraded, thereby realizing the complete release of the loaded drug. At present, the transition from non-degradable materials to degradable materials with high biocompatibility is an important trend in the field of medical device development. For the embolism microsphere, on the premise of ensuring the embolism function, a certain degradable function can effectively solve the excessive embolism phenomenon of the existing product, reduce the risk of angiogenesis, side effect and the like of the embolism tumor, and improve the overall curative effect of TACE technology. Therefore, the novel metabolizable microspheres capable of comprehensively balancing the embolization/degradation functions are important ways for solving the clinical bottleneck problem of the conventional TACE technology.
The alginic acid sulfate blood vessel embolism microsphere has better biocompatibility and biodegradability, and degradation products are safe and nontoxic. The preparation method has the advantages of simple and convenient operation, good repeatability, mild conditions and the like, the prepared microsphere has uniform and controllable particle size, and the prepared blood vessel embolism microsphere has better application prospect in the field of tumor interventional therapy.
Drawings
FIG. 1 is a photo-mirror image (4X 10) of the alginic acid sulfate microspheres of the present invention;
FIG. 2 is a scanning electron microscope image of the alginic acid sulfate microspheres of the present invention;
FIG. 3 is a photo of the alginic acid sulfate microspheres of the present invention after being placed in plasma (containing degrading enzyme) for 60 days;
FIG. 4 is a drug loading curve chart of irinotecan loaded on the alginic acid sulfate blood vessel embolism microsphere of the present invention;
FIG. 5 is a drug loading curve diagram of epirubicin loaded alginate sulfate blood vessel embolism microsphere of the invention;
FIG. 6 is a drug loading curve diagram of alginic acid sulfate vasoocclusive microspheres loaded with doxorubicin hydrochloride.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below with reference to the accompanying drawings and embodiments. The specific embodiments described herein are merely illustrative of the invention and are not intended to be limiting.
Example 1
A preparation method of high drug-loading degradable alginic acid sulfate blood vessel embolism microspheres comprises the following steps:
(1) preparation of an aqueous phase: adding 3.0g of alginic acid sulfate into 15mL of deionized water, uniformly dissolving, and adjusting the pH to 11.0 by using 2mol/LNaOH solution for later use.
(2) Preparing an oil phase: 4.5g of Span60 was added to 300mL of soybean oil and stirred at 85 ℃ until Span60 was completely dissolved for use.
(3) Preparing alginic acid sulfate microspheres: adding the prepared water phase into the oil phase at the speed of 10mL/min, wherein the stirring speed is 500r/min, adding 9mL of epoxy chloropropane after the water phase is added, and reacting for 4h at 70 ℃; sieving to obtain microspheres, respectively washing with petroleum ether, ethyl acetate and anhydrous ethanol repeatedly for 3 times, and vacuum drying at 50 deg.C to obtain alginic acid sulfate microspheres.
As shown in figure 1, the microspheres of the alginic acid sulfate prepared by the invention are regular in shape and uniform in particle size.
As shown in fig. 2, SEM shows that the alginate sulfate microspheres of the present invention have rough surface, non-smooth structure and large specific surface, which is a prerequisite for high drug loading.
As shown in fig. 3, fig. 3 is a photo photograph of the alginic acid sulfate microspheres of the present invention after being placed in plasma (containing degrading enzyme) for 60 days, and it can be seen that the alginic acid sulfate microspheres are fragmented and have a tendency of fragment degradation, which proves that the microspheres of the present invention are degradable.
(4) Dissolving the drug in pure water, putting the alginic acid sulfate microspheres into a container, adding a drug solution to soak the alginic acid sulfate microspheres in the drug solution, shaking and mixing uniformly from time to time, filtering and collecting the microspheres after complete reaction, and drying in vacuum to obtain the drug-loaded alginic acid sulfate thromboembolic microspheres.
Preferably, the molecular weight of the alginic acid sulfate is 1 × 104~3×106D。
Preferably, the drug comprises a cationic chemotherapeutic drug.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is obtained by the preparation method of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is applied to the preparation of a transcatheter arterial chemoembolization treatment embolic agent.
Example 2
A preparation method of high drug-loading degradable alginic acid sulfate blood vessel embolism microspheres comprises the following steps:
(1) preparation of an aqueous phase: 4.5g of alginic acid sulfate is added into 15mL of deionized water, and after uniform dissolution, the pH value is adjusted to 11.0 by using 2mol/LNaOH solution for later use.
(2) Preparing an oil phase: 4.5g of Span60 and 0.5g of Tween60 are added into 300mL of soybean oil, and the mixture is stirred at 85 ℃ until the emulsifier is completely dissolved for later use.
(3) Preparing alginic acid sulfate microspheres: adding the prepared water phase into the oil phase at the speed of 10mL/min, wherein the stirring speed is 500r/min, adding 18mL of epoxy chloropropane after the water phase is added, and reacting for 4h at 85 ℃; sieving to obtain microspheres, respectively washing with petroleum ether, ethyl acetate and anhydrous ethanol repeatedly for 3 times, and vacuum drying at 50 deg.C to obtain alginic acid sulfate microspheres.
(4) Dissolving the drug in pure water, putting the alginic acid sulfate microspheres into a container, adding a drug solution to soak the alginic acid sulfate microspheres in the drug solution, shaking and mixing uniformly from time to time, filtering and collecting the microspheres after complete reaction, and drying in vacuum to obtain the drug-loaded alginic acid sulfate thromboembolic microspheres.
Preferably, the molecular weight of the alginic acid sulfate is 1 × 104~3×106D。
Preferably, the drug comprises a cationic chemotherapeutic drug.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is obtained by the preparation method of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is applied to the preparation of a transcatheter arterial chemoembolization treatment embolic agent.
Example 3
A preparation method of high drug-loading degradable alginic acid sulfate blood vessel embolism microspheres comprises the following steps:
(1) preparation of an aqueous phase: adding 1.5g of alginic acid sulfate into 15mL of deionized water, uniformly dissolving, and adjusting the pH to 8.0 by using 2mol/LNaOH solution for later use.
(2) Preparing an oil phase: 0.3g of Span80 is added into 300mL of sunflower seed oil, and the mixture is stirred at 60 ℃ until the emulsifier is completely dissolved for later use.
(3) Preparing alginic acid sulfate microspheres: adding the prepared water phase into the oil phase at the speed of 0.1mL/min, wherein the stirring speed is 300r/min, adding 1.5mL of epoxy chloropropane after the water phase is added, and reacting for 2h at 60 ℃; sieving to obtain microspheres, respectively washing with petroleum ether, ethyl acetate and anhydrous ethanol repeatedly for 1 time, and vacuum drying at 60 deg.C to obtain alginic acid sulfate microspheres.
(4) Dissolving the drug in pure water, putting the alginic acid sulfate microspheres into a container, adding a drug solution to soak the alginic acid sulfate microspheres in the drug solution, shaking and mixing uniformly from time to time, filtering and collecting the microspheres after complete reaction, and drying in vacuum to obtain the drug-loaded alginic acid sulfate thromboembolic microspheres.
Preferably, the molecular weight of the alginic acid sulfate is 1 × 104~3×106D。
Preferably, the drug comprises a cationic chemotherapeutic drug.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is obtained by the preparation method of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is applied to the preparation of a transcatheter arterial chemoembolization treatment embolic agent.
Example 4
A preparation method of high drug-loading degradable alginic acid sulfate blood vessel embolism microspheres comprises the following steps:
(1) preparation of an aqueous phase: adding 15g of alginic acid sulfate into 15mL of deionized water, uniformly dissolving, and adjusting the pH to 14.0 by using 2mol/LNaOH solution for later use.
(2) Preparing an oil phase: 3g of Tween60 is added into 15mL of corn oil, and the mixture is stirred at 90 ℃ until the emulsifier is completely dissolved for later use.
(3) Preparing alginic acid sulfate microspheres: adding the prepared water phase into the oil phase at the speed of 5mL/min, wherein the stirring speed is 800r/min, adding 150mL of epoxy chloropropane after the water phase is added, and reacting for 20h at 90 ℃; sieving to obtain microspheres, respectively washing with petroleum ether, ethyl acetate and anhydrous ethanol repeatedly for 5 times, and vacuum drying at 45 deg.C to obtain alginic acid sulfate microspheres.
(4) Dissolving the drug in pure water, putting the alginic acid sulfate microspheres into a container, adding a drug solution to soak the alginic acid sulfate microspheres in the drug solution, shaking and mixing uniformly from time to time, filtering and collecting the microspheres after complete reaction, and drying in vacuum to obtain the drug-loaded alginic acid sulfate thromboembolic microspheres.
Preferably, the molecular weight of the alginic acid sulfate is 1 × 104~3×106D。
Preferably, the drug comprises a cationic chemotherapeutic drug.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is obtained by the preparation method of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is applied to the preparation of a transcatheter arterial chemoembolization treatment embolic agent.
Example 5
A preparation method of high drug-loading degradable alginic acid sulfate blood vessel embolism microspheres comprises the following steps:
(1) preparation of an aqueous phase: adding 3g of alginic acid sulfate into 10mL of deionized water, uniformly dissolving, and adjusting the pH to 10.0 by using 2mol/LNaOH solution for later use.
(2) Preparing an oil phase: 10g of Tween80 is added into 300mL of corn oil, and the mixture is stirred at 75 ℃ until the emulsifier is completely dissolved for later use.
(3) Preparing alginic acid sulfate microspheres: adding the prepared water phase into the oil phase at the speed of 3mL/min, wherein the stirring speed is 600r/min, adding 1.0mL of epoxy chloropropane after the water phase is added, and reacting for 10h at 80 ℃; sieving to obtain microspheres, respectively washing with petroleum ether, ethyl acetate and anhydrous ethanol repeatedly for 2 times, and vacuum drying at 55 deg.C to obtain alginic acid sulfate microspheres.
(4) Dissolving the drug in pure water, putting the alginic acid sulfate microspheres into a container, adding a drug solution to soak the alginic acid sulfate microspheres in the drug solution, shaking and mixing uniformly from time to time, filtering and collecting the microspheres after complete reaction, and drying in vacuum to obtain the drug-loaded alginic acid sulfate thromboembolic microspheres.
Preferably, the molecular weight of the alginic acid sulfate is 1 × 104~3×106D。
Preferably, the drug comprises a cationic chemotherapeutic drug.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is obtained by the preparation method of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere.
The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere is applied to the preparation of a transcatheter arterial chemoembolization treatment embolic agent.
Example 6
As shown in fig. 4, 10mg of irinotecan was dissolved in 2.0mL of pure water, and 0.25g of the alginic acid sulfate vasoocclusive microspheres synthesized in example 2 was accurately weighed and placed in a 20mL vial, and 2mL of the irinotecan solution was added to soak the microspheres in the irinotecan solution, followed by mixing by shaking. And (3) periodically sampling 20 mu L at 5, 10, 20, 40 and 60min by using a micro-syringe, adding 5.0mL of pure water for dilution, measuring the absorbance at 370nm, substituting the absorbance into a standard curve equation, and calculating the concentration of the drug contained in the sample so as to calculate the drug loading rate of the microspheres on the irinotecan: drug loading is (drug content of pre-drug loading solution-drug content of post-drug loading solution)/weight of microsphere. The drug loading rate of irinotecan loaded by the microspheres is 553 mg/g of microspheres, which is more than 5 times of the data (110 mg/g of microspheres) in the patent (CN 108236732A method for synthesizing the polyvinyl alcohol embolism microspheres loaded with irinotecan serving as a chemotherapeutic drug).
Example 7
As shown in fig. 5, 10mg of epirubicin is dissolved in 2.0mL of pure water, 0.25g of the microsphere-type embolic agent synthesized in example 2 is accurately weighed and placed in a 20mL vial, 2mL of the epirubicin solution is added, and the microspheres are soaked in the epirubicin solution and are mixed by shaking occasionally. And (3) sampling 20 mu L at fixed time by using a micro-syringe at 5 th, 10 th, 20 th, 40 th and 60 th min, adding 5.0mL of pure water for dilution, measuring absorbance at 485nm, substituting the absorbance into a standard curve equation, and calculating the concentration of the drug contained in the sample so as to calculate the drug loading rate of the microspheres to the epirubicin: drug loading is (drug content of pre-drug loading solution-drug content of post-drug loading solution)/weight of microsphere. The drug loading rate of the microsphere loaded epirubicin is 140 mg/g microsphere, which is more than 3 times of the data (38 mg/g microsphere) in the patent (CN 108236736A is the patent (CN 108236732A a method for synthesizing the polyvinyl alcohol embolism microsphere capable of loading the chemotherapeutic irinotecan).
Example 8
As shown in fig. 6, 10mg of doxorubicin hydrochloride was dissolved in 2.0mL of pure water, and the microsphere-type suppository synthesized in example 2 was accurately weighed out to 0.25g, and placed in a 20mL vial, and 2mL of the above doxorubicin hydrochloride solution was added to soak the microspheres in the doxorubicin hydrochloride solution, followed by shaking occasionally and mixing. And (3) sampling 20 mu L of the microspheres at fixed time in 5 th, 10 th, 20 th, 40 th and 60 th min by using a micro-syringe, adding the samples into 5.0mL of pure water for dilution, measuring absorbance at 485nm, substituting the absorbance into a standard curve equation, and calculating the concentration of the drug contained in the samples so as to calculate the drug loading rate of the microspheres on the doxorubicin hydrochloride: drug loading is (drug content of pre-drug loading solution-drug content of post-drug loading solution)/weight of microsphere. The drug loading of doxorubicin hydrochloride on the microspheres was determined to be 281mg per gram of microspheres.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (9)
1. A preparation method of high drug-loading degradable alginic acid sulfate blood vessel embolism microspheres is characterized in that: the method comprises the following steps:
s01, preparation of aqueous phase: dissolving alginic acid sulfate in deionized water to prepare a solution of 0.1-1 g/mL, adding a NaOH solution after uniform dissolution to adjust the pH value to 8-14 for later use;
s02, preparation of oil phase: adding 0.1-20% w/v of emulsifier into vegetable oil serving as a solvent, and stirring at 60-90 ℃ until the emulsifier is completely dissolved for later use;
s03, preparing alginic acid sulfate microspheres: adding the prepared water phase into the oil phase at a speed of 0.1-10 mL/min under stirring of a stirring paddle, wherein the stirring speed is 300-800 r/min, adding a cross-linking agent after the water phase is added, and reacting for 2-20 h at 60-90 ℃; sieving the microspheres by using a screen, repeatedly washing the microspheres for 1-5 times by using petroleum ether, ethyl acetate and absolute ethyl alcohol respectively, and drying the microspheres in vacuum to obtain alginic acid sulfate microspheres;
s04, dissolving the drug in pure water, putting the alginic acid sulfate microspheres into a container, adding a drug solution to soak the alginic acid sulfate microspheres in the drug solution, shaking and mixing uniformly from time to time, filtering and collecting the microspheres after complete reaction, and drying in vacuum to obtain the drug-loaded alginic acid sulfate thromboembolic microspheres.
2. The preparation method of the high drug loading degradable alginic acid sulfate blood vessel embolism microsphere according to claim 1, characterized in that: the molecular weight of the alginic acid sulfate is 1 × 104~3×106D。
3. The preparation method of the high drug loading degradable alginic acid sulfate blood vessel embolism microsphere according to claim 1, characterized in that: the emulsifier is one or more of Span60, Span80, Tween60 and Tween 80.
4. The preparation method of the high drug loading degradable alginic acid sulfate blood vessel embolism microsphere according to claim 1, characterized in that: the volume ratio of the oil phase to the water phase is 1: 1-30: 1.
5. The preparation method of the high drug loading degradable alginic acid sulfate blood vessel embolism microsphere according to claim 1 or 4, characterized in that: the cross-linking agent is epichlorohydrin; the volume ratio of the cross-linking agent to the water phase is 1: 10-10: 1.
6. The preparation method of the high drug loading degradable alginic acid sulfate blood vessel embolism microsphere according to claim 1, characterized in that: the drug includes a cationic chemotherapeutic drug.
7. The preparation method of the high drug loading degradable alginic acid sulfate blood vessel embolism microsphere according to claim 6, characterized in that: the cationic chemotherapeutic drug comprises irinotecan, epirubicin, doxorubicin hydrochloride, bleomycin, gemcitabine, pirarubicin, cyclophosphamide, camptothecin or vincristine.
8. The high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere obtained by the preparation method of the high drug-loading degradable alginic acid sulfate blood vessel embolism microsphere according to any one of claims 1 to 7.
9. The use of the high drug loading degradable alginic acid sulfate blood vessel embolism microsphere in the preparation of transcatheter arterial chemoembolization therapeutic embolization agent according to claim 8.
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