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Fatty acid-modified immunosuppressant mmf and fk506 nano-formulations and their preparation methods and applications

A nano-formulation, fatty acid technology, applied in the directions of non-active ingredients medical preparations, medical preparations containing active ingredients, pharmaceutical formulas, etc., can solve problems such as limited therapeutic effect, achieve reduced toxicity, good biocompatibility, Effect of improving pharmacokinetic properties

Active Publication Date: 2022-05-06
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, MMF and FK506 are mainly prepared into nano-preparations to increase their water solubility, but the above-mentioned single-drug nano-preparations cannot better play the synergistic effect of MMF and FK506, so the therapeutic effect is limited

Method used

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  • Fatty acid-modified immunosuppressant mmf and fk506 nano-formulations and their preparation methods and applications
  • Fatty acid-modified immunosuppressant mmf and fk506 nano-formulations and their preparation methods and applications
  • Fatty acid-modified immunosuppressant mmf and fk506 nano-formulations and their preparation methods and applications

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] The synthesis of embodiment 1 Ac-MMF coupled prodrug, such as figure 1 Shown:

[0088] Add MMF (43.2g, 0.10mmol), glacial acetic acid (6.0mg, 0.10mmol) and DMAP (12.6mg, 0.10mmol) successively into a 100mL round bottom flask, dissolve in 4mL of anhydrous dichloromethane, and then add EDC dropwise quickly (16.6 mg, 0.11 mmol). Stir at 43°C for 6 hours, and observe the reaction by thin-layer chromatography. When the reaction is basically over, cool the reaction solution, wash with 0.1M hydrochloric acid solution, saturated sodium bicarbonate, and saturated brine respectively; dry the organic phase with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure after collecting the filtrate; After chromatographic separation and purification (DCM:MeOH=40:1), the product 1 (20.5 mg, yield 43.0%, [C 25 h 33 NO 8 ] + [M+H] + = 476.2279).

Embodiment 2

[0089] The synthesis of embodiment 2 Hep-MMF coupling prodrug, such as figure 2 Shown:

[0090] MMF (73.6mg, 0.17mmol), n-heptanoic acid (23.4mg, 0.18mmol) and DMAP (20.6mg, 0.17mmol) were successively added to a 100mL round bottom flask, dissolved in 5mL of anhydrous dichloromethane, and then rapidly added dropwise EDC (26.9 mg, 0.17 mmol). Stir at 43°C for 4 hours, and observe the reaction by thin-layer chromatography. When the reaction is basically over, cool the reaction solution, wash with 0.1M hydrochloric acid solution, saturated sodium bicarbonate, and saturated brine respectively; dry the organic phase with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure after collecting the filtrate; Product 2 (37.5 mg, yield 40.5%) was obtained after chromatographic separation and purification (DCM:MeOH=20:1).

[0091] product 2 1 The H NMR nuclear magnetic data is as follows, and the nuclear magnetic spectrum is as follows Figure 27 Shown:

...

Embodiment 3

[0093] The synthesis of embodiment 3 Ste-MMF coupling prodrug, such as image 3 Shown:

[0094] Add MMF (45.1mg, 0.10mmol), stearic acid (31.4mg, 0.11mmol) and DMAP (14.6mg, 0.12mmol) sequentially into a 100mL round bottom flask, dissolve in 5mL of anhydrous dichloromethane, and then add EDC (17.5 mg, 0.11 mmol). Stir at 43°C for 4 hours, and observe the reaction by thin-layer chromatography. When the reaction is basically over, cool the reaction solution, wash with 0.1M hydrochloric acid solution, saturated sodium bicarbonate, and saturated brine respectively; dry the organic phase with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure after collecting the filtrate; Product 3 (36.4 mg, yield 52%) was obtained after chromatographic separation and purification (DCM:MeOH=40:1).

[0095] product 3 1 The H NMR nuclear magnetic data is as follows, and the nuclear magnetic spectrum is as follows Figure 28 Shown:

[0096] 1 H NMR (400MHz, CDCl 3...

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Abstract

The invention discloses a fatty acid coupling prodrug and a preparation method thereof, comprising: under the action of a condensing agent and a catalyst, tacrolimus or mycophenolate mofetil is subjected to an esterification reaction with a saturated or unsaturated fatty acid corresponding to R, The fatty acid-coupled prodrug is obtained. The above-mentioned nano-preparation of the present invention significantly improves the water solubility of MMF and FK506, avoids the use of auxiliary materials such as solubilizers, and further increases the drug loading capacity; at the same time, the saturated or unsaturated fatty acids used for modification are substances required by the human body, and have high biocompatibility Well, it is convenient for clinical transformation and has a good application prospect. More importantly, PEGylated MMF-saturated or unsaturated fatty acid coupled prodrugs and FK506 co-assembled nano-preparations, significantly improved the pharmacokinetic properties of the drug, prolonging its in vivo circulation time, can combine MMF and FK506 At the same time, it is delivered to the target site and exerts its drug effect. Compared with clinical MMF / FK506, it has a better anti-graft rejection effect.

Description

technical field [0001] The invention belongs to the field of immunosuppressive drugs, and in particular relates to synthesis of immunosuppressant MMF, FK506 prodrug, preparation method and application of MMF prodrug and FK506 nano-preparation. Background technique [0002] Tacrolimus (FK506) is the first-choice immunosuppressant after organ transplantation, and long-term use can cause various dose-dependent adverse reactions. Clinically, it is usually used in combination with Mycophenolate mofetil (MMF) to prevent acute rejection after organ transplantation, so as to improve the adverse reactions caused by high dosage. Because the combination of FK506 and MMF can significantly reduce postoperative rejection and organ transplant failure, and effectively improve side effects in vivo, the combination therapy has been included in the "Clinical Practice Guidelines: Liver transplantation (2016 edition)" formulated by the European Society of Liver Diseases, and has become a The mo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/54A61K31/436A61K31/5377A61K9/107A61K9/127A61K9/14A61K47/34A61K47/24A61P37/06
CPCA61K47/542A61K31/436A61K31/5377A61K9/1075A61K9/127A61K9/146A61K47/34A61K47/24A61P37/06A61K2300/00
Inventor 谢海洋王杭祥
Owner ZHEJIANG UNIV
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