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A class of maleimide-type prodrugs with bioadhesive effects and their application in oral drug delivery

A maleimide-type, maleimidocaproyloxymethyl technology, applied in the new use field of prodrug preparations, can solve the side effects of heart, liver and kidney, inconvenient administration, and poor patient compliance and other problems to achieve the effect of improving oral bioavailability, increasing residence time, and improving permeability

Active Publication Date: 2021-05-25
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, most anti-tumor drugs are mainly applied to patients by injection. Due to the defects of the injection route itself, such as pain, inconvenient administration and poor patient compliance, it will cause serious heart, liver and kidney side effects.

Method used

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  • A class of maleimide-type prodrugs with bioadhesive effects and their application in oral drug delivery
  • A class of maleimide-type prodrugs with bioadhesive effects and their application in oral drug delivery
  • A class of maleimide-type prodrugs with bioadhesive effects and their application in oral drug delivery

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil

[0039] (a) Dissolve 9.806g (100mmol) of maleic anhydride and 13.118g (100mmol) of 6-aminocaproic acid in 100mL of glacial acetic acid, react at 120°C for 3-4h, remove organic reagents by rotary evaporation, use toluene with water, acetic acid After ethyl ester extraction, the organic layers were combined, anhydrous sodium sulfate was added and stirred to remove water, and column chromatography gave white intermediate (I).

[0040] (b) Dissolve 8.45 g (65 mmol) of 5-fluorouracil in a certain volume of 37% formaldehyde solution, react at 50°C for about 4 hours, and concentrate the reaction solution under reduced pressure to obtain a transparent liquid intermediate (II).

[0041] (c) 11.4g (54mmol) of 6-maleimidocaproic acid, 26.7g (70mmol) of HATU and 14.85mL (135mmol) of N-methylmorpholine were dissolved in 150mL of anhydrous acetonitrile, and the activation. Dissolve (Ⅲ) in acetonitrile and slowly transfe...

Embodiment 2

[0044] Determination of Equilibrium Solubility and Oil-Water Partition Coefficient

[0045] Add excess 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil to water, pH 1.2 PBS and PEG400 aqueous solutions with different contents, vortex for 5min, and then place in a constant temperature shaker at 37°C Shake in the box for 72h to make the dissolution reach equilibrium. The suspension was centrifuged at 12,000 r for 10 min, and the supernatant was filtered. After appropriate dilution, the drug concentration was measured by high performance liquid chromatography, and its equilibrium solubility in different media was calculated. The results are shown in Table 1.

[0046] Table 1

[0047]

[0048] Weigh respectively 5-fluorouracil and 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil in appropriate amount in water-saturated n-octanol (n-octanol-saturated water), respectively Mix it with n-octanol-saturated water (water-saturated n-octanol) in equal volume, shake in a shaker at 37°C fo...

Embodiment 3

[0053] Study on the Stability of 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil

[0054] Weigh an appropriate amount of 1-(6-maleimidocaproyloxymethyl)-5-fluorouracil, add appropriate amount of water to dissolve to prepare a stock solution with a concentration of about 200 μg / ml. Take an appropriate amount of the stock solution, and dilute it with phosphate buffer solution of pH 1.2, 4.5, 6.8 and 7.4 respectively, mix thoroughly, and perform triplicate. Put it in a constant temperature oscillator at 37°C by the classical constant temperature method, take samples at 0, 0.25, 0.5, 1, 2, 4, 8 and 12 hours, pass through a 0.45 μm filter membrane, and inject 10 μL into high performance liquid chromatography.

[0055] Artificial gastric fluid (SGF) and intestinal fluid (SIF) were prepared according to the Chinese Pharmacopoeia 2015 edition. Take an appropriate amount of stock solution, dilute and mix with artificial gastric juice and intestinal juice respectively, and make triplica...

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Abstract

The invention belongs to the technical field of medicine, and relates to the application of a class of maleimide prodrugs targeting mucin in promoting bioadhesion and improving oral drug absorption. The structural formula of the maleimide type prodrug is as shown in (I): wherein, n=2~8; X is O, N; The prodrug compound has high drug loading, good stability, safety and available for oral administration. The maleimide group it carries can specifically bind to the mucin in the mucus layer in the gastrointestinal tract to form a mucin-prodrug complex, prolong the residence time of the drug in the gastrointestinal tract, and improve the adsorption-absorption Concentration gradients across sites facilitate passive diffusion, thereby enhancing oral absorption. The invention is a novel maleimide type prodrug with bioadhesive effect, which is used to improve the oral absorption of drugs.

Description

technical field [0001] The invention belongs to the technical field of new applications of prodrug preparations, and relates to a class of maleimide prodrugs with bioadhesive effect and their application in oral drug delivery. Background technique [0002] Malignant tumors seriously threaten human life and health, and its morbidity and mortality are increasing year by year. At present, most anti-tumor drugs are mainly applied to patients by injection. Due to the defects of the injection route itself, such as pain, inconvenient administration and poor patient compliance, it will cause serious heart, liver and kidney side effects. . Oral administration is a convenient and safe way of administration, which has good patient compliance and avoids the toxic and side effects caused by injection. Oral absorption of drugs is affected by many factors, such as drug solubility, permeability, and first-pass effect in the liver. Therefore, how to improve the bioavailability of antitumor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12A61P35/00
CPCC07D403/12
Inventor 孙进何仲贵刘岩
Owner SHENYANG PHARMA UNIVERSITY
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