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Carbonic ester polymer vesicle for micromolecule-carrying medicine, and preparation method and application of carbonic ester polymer vesicle

A technology of carbonate polymers and small molecules, which is applied in the direction of drug combinations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., which can solve low bioavailability, kidney toxicity and side effects, and short cycle time and other issues, to achieve enhanced anti-tumor effect, good biocompatibility, and long circulation time

Active Publication Date: 2020-09-29
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The invention discloses a new drug-loaded vesicle, which is a carbonate polymer vesicle loaded with small molecule drugs and its preparation method and application. The bioavailability is not high, and sometimes it will cause kidney side effects and other problems. It can effectively improve the efficacy of the drug. Compared with clinical drugs, it has lower doses, stronger tumor site enrichment, less toxic side effects, and longer cycle time, etc. Advantage

Method used

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  • Carbonic ester polymer vesicle for micromolecule-carrying medicine, and preparation method and application of carbonic ester polymer vesicle
  • Carbonic ester polymer vesicle for micromolecule-carrying medicine, and preparation method and application of carbonic ester polymer vesicle
  • Carbonic ester polymer vesicle for micromolecule-carrying medicine, and preparation method and application of carbonic ester polymer vesicle

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0048] The polymers were prepared according to the prior art.

[0049] In a nitrogen glove box, MeO-PEG-OH (Mn=5.0 kg / mol, 0.50 g, 100 μmol), TMC (1.52 g, 14.55 mmol) and DTC (0.23 g, 1.18 mmol) were successively weighed and dissolved in di In methyl chloride (DCM, 7.0 mL), the catalyst diphenyl phosphate (DPP, DPP / OH molar ratio is 10 / 1) was added with stirring. The airtight reactor was sealed and placed in an oil bath at 40°C under magnetic stirring for 2 days; triethylamine was terminated, precipitated twice in glacial ether, filtered by suction, and dried in vacuum to obtain PEG5k-P (DTC2k-TMC15k).

[0050] The targeted carbonate polymer is GE11-PEG-P (TMC-DTC). In the nitrogen environment of the glove box, the macromolecular initiator NHS-PEG-OH (75 mg, 10 μmol), dithiopentane trimethylene Carbonate (DTC, 20 mg, 0.1 mmol) and trimethylene carbonate (TMC, 230 mg, 2.25 mmol) were fully dissolved in 1.6 mL of dichloromethane (DCM), and then rapidly accelerated DPP ( 25 mg,...

Embodiment 1

[0052] Push 100 μL of PEG5k-P at a concentration of 10 mg / mL into 900 μL of HEPES weakly alkaline buffer (5 mM, pH: 8.0) containing 20 mM calcium acetate at room temperature using a syringe pump at a pumping rate of 25 mL / min (TMC15k-DTC2k) in DMSO solution, and then the two items were mixed using magnetic stirring (280 rpm). After forming empty vesicles, add acid buffer (0.4M HAc / NaAc with pH 4.0) to adjust to acidic conditions (pH 4.5 ), then add 20 μL of PEM with a concentration of 5 mg / mL (dissolved in purified water) of negatively charged small molecule drugs, mix well and shake in a shaker at 37°C for 12 hours to fully cross-link. Then, dialysis (MWCO: 3500) was performed against phosphate PB buffer (10 mM, pH 7.4) for 8 h to remove organic solvents and free small molecule drugs, during which the medium was changed 5 times, thereby obtaining drug-loaded reversibly core-crosslinked vesicles.

[0053] Change the calcium acetate, and keep the rest unchanged, for a comparati...

Embodiment 2

[0076] Example 2 Cross-linked targeting vesicle PEM-GE11-Ps loaded with small molecule pemetrexed disodium and its release in vitro

[0077] First mix and dissolve PEG5k-P(TMC15k-DTC2k) and GE11-PEG7.5k-P(TMC15k-DTC2k) in DMSO (10mg / mL) at a weight ratio of 9:1 and 4:1 to obtain two groups of targeted / non-targeted To the mixed polymer solution, PEG5k-P(TMC15k-DTC2k) was dissolved in DMSO (10mg / mL) to obtain a set of non-targeted mixed polymer solutions.

[0078] With reference to the preparation method of Example 1, add 20 mM Ca(Ac) to three groups of 900 μL at room temperature. 2 In HEPES (5 mM, pH: 8.0) weakly alkaline buffer solution, use a syringe pump to push 100 μL of two groups of targeting / non-targeting mixed polymer solutions with a concentration of 10 mg / mL at a pumping rate of 25 mL / min, One set of non-targeted mixed polymer solutions; then two mixed with magnetic stirring (280 rpm), after the formation of empty vesicles, then add acidic buffer (0.4M HAc / NaAc at pH...

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Abstract

The invention discloses a carbonic ester polymer vesicle for a micromolecule-carrying medicine, and a preparation method and application of the carbonic ester polymer vesicle. The medicine is a hydrophilic negatively-charged micromolecule medicine; a reversible crosslinking biodegradable polymer vesicle with an asymmetric membrane structure is obtained in a way that a polymer is subjected to crosslinking after the polymer is self-assembled; the molecular chain of the polymer includes a hydrophilic chain segment and a hydrophobic chain segment, which are connected in sequence; the hydrophobic chain segment comprises a polycarbonate chain segment and / or polyester chain segment; the vesicle loads the medicine through the compounding of intracavity calcium acetate and medicine, i.e., pemetrexed in an alkaline buffer solution; a membrane is reversible crosslinking biodegradable polycarbonate with good biocompatibility; the dithiolane of a side chain is similar to a human body natural antioxidant, i.e., thioctic acid; and a shell takes PEG (polyethylene glycol) as a background and simultaneously contains a targeting molecule capable of carrying out targeting on cancer cells. The carbonic ester polymer is expected to become a nanometer medicine system which combines the advantages of being simple, stable and multifunctional with the advantage that the hydrophilic micromolecule medicine can be favorably subjected to entrapment into a whole. Under the method, the nanometer medicine system can be used for effectively coating a great quantity of negatively-charged micromolecule medicines.

Description

technical field [0001] The invention belongs to the pharmaceutical technology and relates to the technology of drug-loaded vesicles, in particular to carbonate polymer vesicles loaded with small-molecule drugs and its preparation method and application. Background technique [0002] The small-molecule hydrophilic drug pemetrexed disodium is negatively charged under water-soluble conditions. For the entrapment of pemetrexed, the existing drug-loaded particles have problems such as low drug loading, easy leakage and burst release. At the same time, the particle size of liposome-loaded drugs is larger, and the passive targeting effect is worse than that of polymer vesicle nano-drugs. The existing gradient method mainly loaded with doxorubicin (i.e. citric acid gradient method, pH in <pH out ) cannot effectively load such drugs. Contents of the invention [0003] The invention discloses a new drug-loaded vesicle, which is a carbonate polymer vesicle loaded with small mol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/34A61K47/12A61K47/60A61K47/62A61K47/59A61K47/69A61K31/519A61P35/00A61P35/04
CPCA61K9/1273A61K9/1277A61K47/34A61K47/12A61K47/60A61K47/62A61K47/593A61K47/6915A61K31/519A61P35/00A61P35/04Y02A50/30
Inventor 孟凤华杨靓钟志远
Owner SUZHOU UNIV
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