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Vitamin B that can self-assemble into nanoparticles 12 Derivatives and preparation methods and applications

A technology of nanoparticles and vitamins, applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve problems such as affecting drug activity, failing to meet therapeutic requirements, and limited receptors.

Active Publication Date: 2020-10-27
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method of chemically modifying polypeptide and protein drugs also has deficiencies: one is that the polypeptide and protein drugs are chemically modified and combined with vitamin B 12 Linked, will affect the drug activity; the second is the vitamin B on the intestinal membrane 12 -IF complex has limited receptors, while receptors bind vitamin B 12 vitamin B in plasma 12 Concentration regulation, therefore, vitamin B 12 The dosage of protein or peptide drugs often does not meet the treatment requirements

Method used

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  • Vitamin B that can self-assemble into nanoparticles <sub>12</sub> Derivatives and preparation methods and applications
  • Vitamin B that can self-assemble into nanoparticles <sub>12</sub> Derivatives and preparation methods and applications
  • Vitamin B that can self-assemble into nanoparticles <sub>12</sub> Derivatives and preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1 Vitamin B 12 The synthesis and purification preparation of -OP (flow process such as figure 1 shown)

[0091] (1) Vitamin B 12 -Carbonyl-putrescine (vitamin B 12 -OD) synthesis

[0092] Take 0.2mg of vitamin B 12 Dissolve in 5ml DMSO (dimethyl sulfoxide) and add vitamin B 12 8 times the molar amount of CDT. CDT and vitamin B 12 React in an ultrasonic water bath, the ultrasonic power is 70w, the temperature of the water bath is kept between 30°C and 33°C, and the reaction is carried out for half an hour to obtain the intermediate product of ester imidazole, and then 4 times the volume of ethyl acetate is added to stop the reaction. Transfer the reaction solution to a centrifuge tube, centrifuge at 8000r / min for 5min, remove the supernatant, then add 5ml DMSO to dissolve the centrifuged precipitate, and quickly add 300μl DIEA (N,N-diisopropylethylamine) and 600μl putrescine. The ultrasonic water bath assisted the reaction, the ultrasonic power was 70w, ...

Embodiment 2

[0106] Embodiment 2 vitamin B 12 -Self-assembly of OP and its embedding of peptide drugs

[0107] Prepare 1ml nano system to embed 6-KTP, a glucagon-like peptide derivative (Wang Congfeng, Zou Xin, Ran Yanhong, etc. Fermentation, purification and identification of genetically recombinant GLP-1 derivative (6KTP) [EB / OL]. Beijing: China Science and Technology Papers Online [2012-05-14].) as an example:

[0108] (1) Add 200 μl of ethanol with a volume fraction of 50% and 50 μl of 6-KTP / hexafluoroisopropanol solution with a concentration of 20 mg / ml into the EP tube, and gently mix them up and down;

[0109] (2) Take 40 μl of Boc-FF (Boc-Phe-Phe-OH, BACHEM) / hexafluoroisopropanol solution with a concentration of 100 mg / ml, and VB with a concentration of 1 mg / ml 12 -OP (the VB that embodiment 1 prepares 12 -OP) / hexafluoroisopropanol solution 10 μl, mix well, add to the EP tube in step (1), and gently invert up and down to mix;

[0110] (3) Take out 300 μl of the mixed solution i...

Embodiment 3

[0114] Example 3 Nanoparticles Encapsulation Efficiency and Drug Loading Capacity of Polypeptide Drugs

[0115] Adopt the ultrafiltration centrifuge tube of 30KD filter membrane to filter the nano-solution (the nano-solution that embodiment 2 prepares) loaded with medicine, free 6-KTP can not be intercepted by filter membrane and thereby centrifuges in the filtrate from solution, adsorbs or embeds in The 6-KTP on the nanocarrier will be retained by the filter membrane. The content of 6-KTP in the filtrate was determined by high performance liquid chromatography.

[0116] Encapsulation efficiency EE% of nanoparticles=[(W1-W2) / W1]*100%;

[0117] Drug loading DL% of nanoparticles=[(W1-W2) / W]*100%;

[0118] Where W1: the total amount of 6-KTP, W2: the content of 6-KTP not encapsulated in the nanocarrier,

[0119] W: weight of nanoparticles encapsulated with 6-KTP.

[0120] Chromatographic column: 300Extend-C18 analytical column (specification: 4.6mm×250mm, 5μm)

[0121] Mobil...

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Abstract

The invention discloses a vitamin B12 derivative capable of being self-assembled into nanoparticles, a preparation method and an application. The vitamin B12 derivative capable of being self-assembled into the nanoparticles is shown as formula I. Carboxyl groups of Boc-phenylalanine dipeptide are activated and coupled by a phosphoric acid onium salt coupling agent or a carbodiimide coupling agent, an active intermediate product is formed, then vitamin B12-carbonyl-putrescine is added, and the vitamin B12 derivative capable of being self-assembled into the nanoparticles is obtained. The vitamin B12 derivative can be self-assembled into the nanoparticles with a drug, thereby being capable of carrying multiple drug molecules to penetrate intestinal mucosa in an active transport manner to enter portal circulation and guaranteeing the treatment effect under the administration dosage.

Description

technical field [0001] The invention belongs to the field of nano drug carriers, in particular to a vitamin B that can be self-assembled to form nanoparticles 12 Derivatives and their preparation methods and applications. Background technique [0002] Peptide protein biopharmaceuticals currently account for an increasing share of the drug market. Common ones include monoclonal antibodies for the treatment of cancer and autoimmune diseases, anti-hepatitis A and B vaccines, diabetes therapeutics insulin and incretins, and Drugs such as human growth hormone for the treatment of hormone deficiencies, etc. However, the wider application of such drugs is limited by their own properties, such as: low stability, high molecular weight and hydrophilicity make it difficult to pass through biomembranes, resulting in low bioavailability and so on. Peptide and protein drugs are currently mainly administered through drug injection. However, due to the pain, the patient's compliance is l...

Claims

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Application Information

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IPC IPC(8): C07H23/00C07H1/00A61K47/26
CPCA61K47/26C07H1/00C07H23/00
Inventor 李弘剑陈美云张忠民冉艳红刘天祥李万维杨晓苹
Owner JINAN UNIVERSITY
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