CN110934875A - 5-fluorouracil methotrexate double-drug preparation and preparation method thereof - Google Patents
5-fluorouracil methotrexate double-drug preparation and preparation method thereof Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a 5-fluorouracil-methotrexate dual-drug preparation and a preparation method thereof, wherein the preparation comprises a nano micelle formed by 5-fluorouracil and methotrexate through hydrogen bond action. The particle size distribution of the invention is between 100-200nm, the invention has better drug slow release and targeting characteristics, and cytotoxicity tests prove that the invention has stronger tumor inhibition effect compared with the pure dual-drug use of methotrexate and 5-fluorouracil, and has the characteristics of strong targeting, low toxicity, synergistic effect and the like.
Description
Technical Field
The invention belongs to the technical field of antitumor drugs, and particularly relates to a 5-fluorouracil methotrexate dual-drug preparation and a preparation method thereof.
Background
5-Fluorouracil (5-Fluorouracil, 5-FU), Mr 130.08, uracil fluoride, which is a white or off-white crystalline powder, sparingly soluble in water, sparingly soluble in ethanol, hardly soluble in chloroform, soluble in dilute hydrochloric acid or sodium hydroxide solution. 5-FU was synthesized by Heidelberger in 1957, and as a pyrimidine-based broad-spectrum antitumor drug, it can inhibit thymidylate synthase in tumor cells. The 5-FU mechanism of action is: inhibits deoxythymidylate synthase by its conversion to 5-fluorouracil deoxynucleotide (5F-dUMP) in vivo, prevents the conversion of deoxyuridylate (dUMP) methyl to deoxythymidylate (dTMP), thereby affecting DNA synthesis; on the other hand, the 5-FU can be more firmly combined with enzyme due to the stable C-F bond structure and the enhancement of acidity, and after being taken into cells, the important precursor uracil of tumor nucleic acid is replaced on a molecular level, and the biological macromolecules are fraudulently incorporated to form abnormal RNA to influence the function of the nucleic acid, so that gene mutation is caused. That is, when 5-FU enters the body, it inhibits the synthesis of DNA and RNA of tumor cells, resulting in the death of tumor cells during the proliferation stage.
In the prior art, 5-FU is clinically used for treating various malignant tumors such as digestive tract tumor, breast cancer, ovarian cancer and the like, and obtains remarkable curative effect. However, the long-term administration of 5-FU in large doses can cause significant toxic side effects in patients, such as myelosuppression, short half-life in vivo, and adverse gastrointestinal reactions like nausea and vomiting. In addition, 5-FU is inconvenient to administer, low in oral bioavailability, and very long in clinical intravenous injection time, and brings inconvenience and pain to patients.
Methotrexate (MTX) is a folic acid antimetabolite, can be combined with a folate receptor on the surface of a tumor cell to play a good targeting role, is commonly used for treating various malignant tumors and is also a commonly used antirheumatic drug. MTX has many medical disadvantages, and can increase the toxicity of liver and kidney functions, because the acting part of MTX is the cytoplasm of tumor cells rather than the nucleus, and the synthesis of tumor cell DNA is hindered by inhibiting dihydrofolate reductase, so it also has drug action on normal biological cells, and has large toxic and side effects.
In order to reduce the dosage and reduce side effects, doctors often combine more than two antitumor drugs with different action sites in clinic, for example, the combined administration of 5-fluorouracil and methotrexate is often better than the single administration, and the drug resistance is not easy to generate. However, the clinical effect of the simple combined medication on the toxic and side effect reduction of the medicine is limited, and the medicine cannot play a certain sustained release and targeting effect.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a 5-fluorouracil methotrexate dual-drug preparation.
The invention also aims to provide a preparation method of the 5-fluorouracil methotrexate dual-drug preparation.
The technical scheme of the invention is as follows:
a dual-medicine 5-fluorouracil-methotrexate preparation contains nano-micelle formed by 5-fluorouracil and methotrexate through hydrogen bond.
In a preferred embodiment of the invention, it is a vacuum freeze-dried formulation.
Further preferably, the freeze-drying protective agent is also included.
Still further preferably, the lyoprotectant includes one or both of sorbitol, mannitol, sucrose and dextran.
In a preferred embodiment of the invention, the mass ratio of 5-fluorouracil to methotrexate is 0.8-1.2: 0.8-1.2.
The preparation method of the 5-fluorouracil methotrexate double-drug preparation comprises the following steps:
(1) dissolving methotrexate and 5-fluorouracil in an organic solvent respectively to obtain a 5-fluorouracil solution and a methotrexate solution; mixing the 5-fluorouracil solution and the methotrexate solution, and carrying out ultrasonic treatment at room temperature;
(2) adding a proper amount of deionized water into the material obtained in the step (1) to obtain a dispersion solution of 5-fluorouracil and methotrexate;
(3) placing the dispersion solution in the step (2) in a shaking table at room temperature for reaction for 2-6h, and then dialyzing the material obtained after the reaction to obtain dialysate;
(4) filtering the dialysate through a 0.20-0.25 μm microporous filter membrane to obtain a nano micelle solution;
(5) and adding a proper amount of freeze-drying protective agent into the nano micelle solution for vacuum freeze-drying to obtain the 5-fluorouracil methotrexate dual-drug preparation.
In a preferred embodiment of the present invention, the concentration of 5-fluorouracil in the dispersion solution is 1-5 mg/mL.
In a preferred embodiment of the present invention, the concentration of methotrexate in the dispersion solution is 1 to 5 mg/mL.
In a preferred embodiment of the present invention, the organic solvent includes dimethyl sulfoxide, N-dimethylformamide and tetrahydrofuran.
The invention has the beneficial effects that: the particle size distribution of the invention is between 100-200nm, the invention has better drug slow release and targeting characteristics, and cytotoxicity tests prove that the invention has stronger tumor inhibition effect compared with the pure dual-drug use of methotrexate and 5-fluorouracil, and has the characteristics of strong targeting, low toxicity, synergistic effect and the like.
Drawings
FIG. 1 is a schematic diagram of the hydrogen bonding of 5-fluorouracil methotrexate dug-drug in the example of the present invention.
FIG. 2 is a diagram of particle size distribution and transmission electron microscopy of 5-fluorouracil methotrexate double-drug nanomicelle in the example of the present invention.
FIG. 3 is a nuclear magnetic hydrogen spectrum representation of the hydrogen bonding effect of 5-fluorouracil methotrexate in an embodiment of the invention.
FIG. 4 is an infrared spectrum of the hydrogen bonding of 5-fluorouracil methotrexate in an embodiment of the present invention.
FIG. 5 is a graph showing the release contrast between the 5-fluorouracil methotrexate dual drug formulation and the pure drug in the example of the present invention.
FIG. 6 is a graph comparing the release of 5-fluorouracil and methotrexate drugs in a dual drug formulation of 5-fluorouracil and methotrexate at different pH levels in an example of the present invention.
FIG. 7 is a graph showing the comparison of cytotoxicity of 5-fluorouracil methotrexate dual drug formulation and pure drug against cervical cancer cells in the example of the present invention.
Detailed Description
The technical solution of the present invention will be further illustrated and described below with reference to the accompanying drawings by means of specific embodiments.
Example 1
(1) Dissolving methotrexate and 5-fluorouracil in dimethyl sulfoxide respectively to obtain a 5-fluorouracil solution with the concentration of 20mg/mL and a methotrexate solution with the concentration of 20 mg/mL; mixing 500. mu.L of the 5-fluorouracil solution with 500. mu.L of methotrexate solution, and subjecting to ultrasonication at room temperature for 0.5 h;
(2) adding deionized water with the volume 9 times that of the material obtained in the step (1) to obtain a dispersion solution of 5-fluorouracil and methotrexate, wherein the concentrations of the 5-fluorouracil and the methotrexate are both 1 mg/mL;
(3) placing the dispersion solution obtained in the step (2) in a shaking table at room temperature for 5 hours, and then dialyzing the material obtained after the reaction for 10 hours to remove dimethyl sulfoxide to obtain a dialysate;
(4) filtering the dialysate through a 0.22-micron microporous filter membrane to obtain a nano micelle solution with the average particle size of 140 nm;
(5) and adding 2 wt% of mannitol into the nano micelle solution, and carrying out vacuum freeze drying at the condensation temperature of-80 ℃ under the vacuum degree of 10Pa to obtain the 5-fluorouracil methotrexate double-drug preparation.
Example 2
(1) Dissolving methotrexate and 5-fluorouracil in N, N-dimethylformamide respectively to obtain a 5-fluorouracil solution with the concentration of 20mg/mL and a methotrexate solution with the concentration of 20 mg/mL; mixing 500. mu.L of the 5-fluorouracil solution with 500. mu.L of methotrexate solution, and subjecting to ultrasonication at room temperature for 0.5 h;
(2) adding deionized water with the volume 9 times that of the material obtained in the step (1) to obtain a dispersion solution of 5-fluorouracil and methotrexate, wherein the concentrations of the 5-fluorouracil and the methotrexate are both 1 mg/mL;
(3) placing the dispersion solution obtained in the step (2) in a shaking table at room temperature for reaction for 4 hours, and then dialyzing the material obtained after the reaction for 10 hours to remove N, N-dimethylformamide to obtain dialysate;
(4) filtering the dialysate through a 0.22-micron microporous filter membrane to obtain a nano micelle solution with the average particle size of 158 nm;
(5) and adding 5 wt% of dextran into the nano micelle solution, and carrying out vacuum freeze drying at the condensation temperature of-80 ℃ under the vacuum degree of 10Pa to obtain the 5-fluorouracil methotrexate double-drug preparation.
Example 3
(1) Dissolving methotrexate and tetrahydrofuran in N, N-dimethylformamide respectively to obtain a 5-fluorouracil solution with the concentration of 20mg/mL and a methotrexate solution with the concentration of 20 mg/mL; mixing 500. mu.L of the 5-fluorouracil solution with 500. mu.L of methotrexate solution, and subjecting to ultrasonication at room temperature for 0.5 h;
(2) adding deionized water with the volume 9 times that of the material obtained in the step (1) to obtain a dispersion solution of 5-fluorouracil and methotrexate, wherein the concentrations of the 5-fluorouracil and the methotrexate are both 1 mg/mL;
(3) placing the dispersion solution obtained in the step (2) in a shaking table at room temperature for reaction for 4 hours, and then dialyzing the material obtained after the reaction for 10 hours to remove tetrahydrofuran to obtain a dialysate;
(4) filtering the dialysate through a 0.22-micron microporous filter membrane to obtain a nano micelle solution with the average particle size of 150 nm;
(5) and adding 2 wt% of dextran into the nano micelle solution, and carrying out vacuum freeze drying at the condensation temperature of-80 ℃ under the vacuum degree of 10Pa to obtain the 5-fluorouracil methotrexate double-drug preparation.
Example 4
(1) Dissolving methotrexate and tetrahydrofuran in dimethyl sulfoxide respectively to obtain a 5-fluorouracil solution with the concentration of 20mg/mL and a methotrexate solution with the concentration of 20 mg/mL; mixing 500. mu.L of the 5-fluorouracil solution with 500. mu.L of methotrexate solution, and subjecting to ultrasonication at room temperature for 0.5 h;
(2) adding deionized water with the volume 9 times that of the material obtained in the step (1) to obtain a dispersion solution of 5-fluorouracil and methotrexate, wherein the concentrations of the 5-fluorouracil and the methotrexate are both 1 mg/mL;
(3) placing the dispersion solution obtained in the step (2) in a shaking table at room temperature for 3 hours, and then dialyzing the material obtained after reaction for 10 hours to remove dimethyl sulfoxide to obtain a dialysate;
(4) filtering the dialysate through a 0.22-micron microporous filter membrane to obtain a nano micelle solution with the average particle size of 130 nm;
(5) and adding 5 wt% of mannitol into the nano micelle solution, and carrying out vacuum freeze drying at the condensation temperature of-80 ℃ under the vacuum degree of 10Pa to obtain the 5-fluorouracil methotrexate double-drug preparation.
As shown in fig. 1 to 3, the double-drug nanomicelle with tumor targeting 5-fluorouracil and methotrexate prepared in the above examples 1 and 2 has a spherical shape with a particle size distribution of 100-200nm and an average particle size of about 140nm, and fig. 1 is a schematic diagram of hydrogen bonding of 5-fluorouracil methotrexate double drugs, wherein a is a methotrexate structural formula, B is a 5-fluorouracil structural formula, and C is a double-drug structural diagram. FIG. 2 is a graph of particle size distribution and transmission electron microscopy of 5-fluorouracil methotrexate double-drug nanomicelle, wherein a in FIG. 2 is a graph of particle size distribution and transmission electron microscopy, b is a Zeta potential distribution graph, and the potential of the double-drug nanomicelle is about-15 mV according to the Zeta potential distribution graph. FIG. 3 is an infrared spectrum showing that the absorption peak of the specific infrared characteristic of the double drug shifts to a low wavenumber under the influence of hydrogen bonding. Wherein A is methotrexate single pure drug, B is 5-fluorouracil single pure drug, C is mixture of 5-fluorouracil and methotrexate double pure drug, and D is double drug of 5-fluorouracil methotrexate linked by hydrogen bond.
FIG. 4 is a nuclear magnetic hydrogen spectrum diagram, from which it can be seen that the characteristic peak of the specific nuclear magnetic hydrogen spectrum shifts to a high field under the influence of hydrogen bonding. Wherein A is methotrexate single pure drug, B is 5-fluorouracil single pure drug, and C is 5-fluorouracil methotrexate double drug linked by hydrogen bond.
FIG. 5 shows the release of 5-fluorouracil as a main drug in a 5-fluorouracil-methotrexate dual drug formulation in contrast to pure drugs and dual pure drugs at pH 7.4, wherein A is 5-fluorouracil single drug, B is 5-fluorouracil and methotrexate dual pure drugs, and C is a hydrogen bond-linked dual drug of 5-fluorouracil-methotrexate.
FIG. 6 is a release diagram of a main drug 5-fluorouracil drug of the 5-fluorouracil methotrexate dual-drug preparation in different pH environments: (A) the release curve of 5-fluorouracil drug under the condition of pH 5.5; (B) the release curve of 5-fluorouracil is shown under the condition of pH 7.4.
FIG. 7 is a graph showing the comparison of cytotoxicity of 5-fluorouracil methotrexate dual drug formulation and pure drug against cervical cancer cells in the example of the present invention. A is 5-fluorouracil pure drug, B is methotrexate pure drug, and C is 5-fluorouracil methotrexate double drug preparation. The result of a tumor cytotoxicity test shows that the cytotoxicity of the tumor-targeted 5-fluorouracil and methotrexate dual-drug preparation on cervical cancer cells is 2 times that of a 5-fluorouracil and methotrexate single-drug reagent under the conditions that the 5-fluorouracil is 100 mu g/mL and the culture time is 24 h.
In conclusion, the particle size of the nano micelle of the 5-fluorouracil methotrexate dual-drug preparation is 100-200nm, and the freeze-dried preparation added with the freeze-drying protective agent has good stability and better slow release property; the cytotoxicity test shows that the 5-fluorouracil methotrexate double-drug preparation has stronger tumor inhibition effect.
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, which is defined by the appended claims.
Claims (9)
1. A5-fluorouracil methotrexate dual-drug preparation is characterized in that: including nanomicelles formed by the hydrogen bonding of 5-fluorouracil and methotrexate.
2. The dual-drug formulation of 5-fluorouracil methotrexate as claimed in claim 1, wherein: it is a vacuum freeze-dried preparation.
3. The dual-drug formulation of 5-fluorouracil methotrexate as claimed in claim 2, wherein: also comprises a freeze-drying protective agent.
4. A dual drug formulation of 5-fluorouracil methotrexate as claimed in claim 3, wherein: the freeze-drying protective agent comprises one or two of sorbitol, mannitol, sucrose and dextran.
5. A dual-drug formulation of 5-fluorouracil methotrexate as claimed in any one of claims 1 to 4, wherein: the mass ratio of the 5-fluorouracil to the methotrexate is 0.8-1.2: 0.8-1.2.
6. The method for preparing a 5-fluorouracil methotrexate dual drug formulation as claimed in any one of claims 1 to 5, wherein: the method comprises the following steps:
(1) dissolving methotrexate and 5-fluorouracil in an organic solvent respectively to obtain a 5-fluorouracil solution and a methotrexate solution; mixing the 5-fluorouracil solution and the methotrexate solution, and carrying out ultrasonic treatment at room temperature;
(2) adding a proper amount of deionized water into the material obtained in the step (1) to obtain a dispersion solution of 5-fluorouracil and methotrexate;
(3) placing the dispersion solution in the step (2) in a shaking table at room temperature for reaction for 2-6h, and then dialyzing the material obtained after the reaction to obtain dialysate;
(4) filtering the dialysate through a 0.20-0.25 μm microporous filter membrane to obtain a nano micelle solution;
(5) and adding a proper amount of freeze-drying protective agent into the nano micelle solution for vacuum freeze-drying to obtain the 5-fluorouracil methotrexate dual-drug preparation.
7. The method of claim 6, wherein: the concentration of 5-fluorouracil in the dispersion solution is 1-5 mg/mL.
8. The method of claim 6, wherein: the concentration of methotrexate in the dispersion solution is 1-5 mg/mL.
9. The production method according to any one of claims 6 to 8, characterized in that: the organic solvent includes dimethyl sulfoxide, N-dimethylformamide and tetrahydrofuran.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115300514A (en) * | 2022-08-09 | 2022-11-08 | 常州大学 | Dual-response drug controlled release system with dual-drug sequential delivery function and preparation method and application thereof |
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| CN108014346A (en) * | 2018-01-29 | 2018-05-11 | 厦门大学 | A kind of preparation method of methotrexate (MTX) prodrug and its double targeted nano-particles |
| CN108686226A (en) * | 2018-07-03 | 2018-10-23 | 上海交通大学 | Using base as the Nano medication delivery system of carrier |
| CN110063962A (en) * | 2019-04-24 | 2019-07-30 | 厦门大学 | Double medicine preparations of a kind of clofarabine methotrexate (MTX) and preparation method thereof |
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| CN104352498A (en) * | 2014-10-11 | 2015-02-18 | 厦门市壳聚糖生物科技有限公司 | Tumor targeted mitomycin C and MTX (methotrexate) double-drug preparation and preparation method thereof |
| CN108014346A (en) * | 2018-01-29 | 2018-05-11 | 厦门大学 | A kind of preparation method of methotrexate (MTX) prodrug and its double targeted nano-particles |
| CN108686226A (en) * | 2018-07-03 | 2018-10-23 | 上海交通大学 | Using base as the Nano medication delivery system of carrier |
| CN110063962A (en) * | 2019-04-24 | 2019-07-30 | 厦门大学 | Double medicine preparations of a kind of clofarabine methotrexate (MTX) and preparation method thereof |
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| CN115300514A (en) * | 2022-08-09 | 2022-11-08 | 常州大学 | Dual-response drug controlled release system with dual-drug sequential delivery function and preparation method and application thereof |
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Application publication date: 20200331 |