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Drug-loaded vitamin B12 derivative self-assembled nanoparticles and preparation method and application thereof

A technology of nanoparticles and vitamins, which is applied in the direction of drug combinations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., and can solve problems that affect drug activity, limited receptors, and failure to meet treatment requirements, etc.

Active Publication Date: 2017-04-26
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 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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  • Drug-loaded vitamin B12 derivative self-assembled nanoparticles and preparation method and application thereof
  • Drug-loaded vitamin B12 derivative self-assembled nanoparticles and preparation method and application thereof
  • Drug-loaded vitamin B12 derivative self-assembled nanoparticles and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1 Vitamin B 12 The synthesis and purification preparation of -OP (flow process such as figure 1 shown)

[0105] (1) Vitamin B 12 -Carbonyl-putrescine (vitamin B 12 -OD) synthesis

[0106] 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, and the temperature of the water bath is kept between 30°C and 33°C for half an hour to obtain an ester-based imidazole intermediate product, and then add 4 times the volume of ethyl acetate 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, and the temperature of the water...

Embodiment 2

[0120] Embodiment 2 vitamin B 12 -Self-assembly of OP and its embedding of peptide drugs

[0121] 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:

[0122] (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 invert up and down to mix;

[0123] (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;

[0124] (3) Take out 300 μl of the mixed solut...

Embodiment 3

[0128] Example 3 Nanoparticles Encapsulation Efficiency and Drug Loading Capacity of Polypeptide Drugs

[0129] 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.

[0130] Encapsulation efficiency EE% of nanoparticles=[(W1-W2) / W1]*100%;

[0131] Drug loading DL% of nanoparticles=[(W1-W2) / W]*100%;

[0132] Where W1: the total amount of 6-KTP, W2: the content of 6-KTP not encapsulated in the nanocarrier,

[0133] W: weight of nanoparticles encapsulated with 6-KTP.

[0134] Chromatographic column: 300Extend-C18 analytical column (specification: 4.6mm×250mm, 5μm)

[0135] Mobil...

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Abstract

The invention discloses drug-loaded vitamin B12 derivative self-assembled nanoparticles and a preparation method and application thereof. A drug and phenylalanine dipeptide are dissolved in hexafluoroisopropanol respectively to obtain a solution A and a solution B; a vitamin B12 derivative shown in the formula I is dissolved in hexafluoroisopropanol to obtain a solution C; an organic solvent or a solution thereof is mixed with the solution A evenly to obtain a solution D; the solution B and the solution C are mixed evenly, then added into the solution D and mixed evenly to obtain a solution E; the solution E is mixed evenly with water, and then PEG 200 is added into the solution to be mixed evenly to obtain a solution F; freeze drying is conducted, water is added for resuspending, and the drug-loaded vitamin B12 derivative self-assembled nanoparticles are obtained. The nanoparticles contain vitamin B12 so that a plurality of drug molecules can pass through an intestinal mucosa by the means of active transportation to enter portal circulation, and it is ensured that the administration dosage achieves treating effects. The formula is shown in the description.

Description

technical field [0001] The invention belongs to the field of nano drug carriers, in particular to a drug-loaded vitamin B 12 Derivative self-assembled nanoparticles, preparation method and application. 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 low in this way of ad...

Claims

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Application Information

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IPC IPC(8): A61K38/26A61K9/51A61K47/18A61K47/26A61P3/10
CPCA61K9/5123A61K38/26
Inventor 李弘剑冉艳红刘天祥陈美云李万维杨晓苹
Owner JINAN UNIVERSITY
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