Application of pegylated retinoic acid and self-assembly micelle thereof in drug delivery

Abstract

The invention relates to application of amphipathic pegylated retinoic acid and a self-assembly micelle thereof in drug delivery. An amphipathic prodrug block takes polyethylene glycol as a hydrophilic end and is bonded with hydrophobic retinoic acid through an ester bond, so that an AB type amphipathic prodrug block is obtained. The polymer has effects of potential treatment for leukemia and prolonging the half life of drug, has a higher drug loading rate, and effectively increases gastrointestinal mucosa permeability so as to increase the oral bioavailability. The pegylated prodrug is self-assembled to form the micelle in an aqueous medium, and the micelle can be used as a storage cavern of the indissolvable drug retinoic acid to slowly release retinoic acid. The micelle is good in safety, can be used for oral administration, and has a great market application prospect.

Description

technical field

[0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, and relates to the application of PEGylated retinoic acid and its self-assembled micelles in drug delivery, in particular to the amphiphilic prodrugs of polyethylene glycol retinoic acid with different chain lengths used as drug carriers in drug delivery. application in transit. Background technique

[0002] Nanocarriers are widely used in targeted drug delivery systems because they can improve the efficacy of anticancer drugs and reduce drug side effects. PEGylated nanocarriers can show some unique advantages, such as prolonging the circulation time of nanoparticles; through EPR Effects Increase the accumulation of drugs in tumors; improve drug tolerance and so on. Among many carriers, PEGylated nanomicelles have attracted more attention due to their modifiable chemical structures and self-assembly into core-shell structures in aqueous solution. ...

Examples

Embodiment 1

[0041] Preparation of retinoic acid prodrug blocks with different PEG chain lengths.

[0042] All-trans retinoic acid (ATRA) was dissolved in a small amount of dichloromethane in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylamino Under the catalysis of pyridine (DMAP), keep dark ice bath for 0.5-2h, then mix with polyethylene glycol (PEG) with different chain lengths at 30-40℃N 2 React for 10-12 hours under protection, and obtain a yellow oily pegylated retinoic acid amphiphilic prodrug through separation and purification. The reaction formula is as follows:

[0043]

Embodiment 2

[0045] The mPEG in the reaction formula can be mPEG 500 , mPEG 1000 , mPEG 2000 and mPEG 5000 That is, the selected polyethylene glycol has a molecular weight of 500, 1000, 2000 or 5000. The polyethylene glycol of the present invention is one end methylated modified polyethylene glycol, but it is not limited to the above four substances.

[0046] Determination by NMR 1 HNMR hydrogen spectrum to determine the structure of the block copolymer, the selected solvent is CHCl 3 , the result is as Figure 2 to Figure 5. The mass spectrum of ATRA-PEG500, the proton peak is from 1.1 to 2.3ppm, 5.8 to 7.1ppm is the characteristic peak of retinoic acid, the proton peak between 3.52-3.75ppm is H in PEG, and the proton peak at 3.37-3.38ppm is PEG The terminal methyl group (-CH 3 ) characteristic peaks, that is, mPEG proton peaks from 3.3 to 3.8ppm, and the new peak (a) about 4.2ppm belongs to methylene ( figure 2 ) near the ester bond.

Embodiment 3

[0048] Adopt infrared spectrum to determine the structure of block copolymer in embodiment 2, select KBr to be blank auxiliary material for use, the result is as follows Figure 6 to Figure 9 . ATRA-PEG500, at 3444cm -1 The broad absorption peak of hydroxyl group disappears and a new peak is about 1707cm -1 The emerging peak position is due to the conversion of the carboxy-hydroxyl group of ATRA to the ester bond in ATRA-PEG500, these results indicate the formation of PEGylated retinoic acid.

technical field

[0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, and relates to the application of PEGylated retinoic acid and its self-assembled micelles in drug delivery, in particular to the amphiphilic prodrugs of polyethylene glycol retinoic acid with different chain lengths used as drug carriers in drug delivery. application in transit. Background technique

[0002] Nanocarriers are widely used in targeted drug delivery systems because they can improve the efficacy of anticancer drugs and reduce drug side effects. PEGylated nanocarriers can show some unique advantages, such as prolonging the circulation time of nanoparticles; through EPR Effects Increase the accumulation of drugs in tumors; improve drug tolerance and so on. Among many carriers, PEGylated nanomicelles have attracted more attention due to their modifiable chemical structures and self-assembly into core-shell structures in aqueous solution. ...

Examples

Embodiment 1

[0041] Preparation of retinoic acid prodrug blocks with different PEG chain lengths.

[0042] All-trans retinoic acid (ATRA) was dissolved in a small amount of dichloromethane in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylamino Under the catalysis of pyridine (DMAP), keep dark ice bath for 0.5-2h, then mix with polyethylene glycol (PEG) with different chain lengths at 30-40℃N 2 React for 10-12 hours under protection, and obtain a yellow oily pegylated retinoic acid amphiphilic prodrug through separation and purification. The reaction formula is as follows:

[0043]

Embodiment 2

[0045] The mPEG in the reaction formula can be mPEG 500 , mPEG 1000 , mPEG 2000 and mPEG 5000 That is, the selected polyethylene glycol has a molecular weight of 500, 1000, 2000 or 5000. The polyethylene glycol of the present invention is one end methylated modified polyethylene glycol, but it is not limited to the above four substances.

[0046] Determination by NMR 1 HNMR hydrogen spectrum to determine the structure of the block copolymer, the selected solvent is CHCl 3 , the result is as Figure 2 to Figure 5. The mass spectrum of ATRA-PEG500, the proton peak is from 1.1 to 2.3ppm, 5.8 to 7.1ppm is the characteristic peak of retinoic acid, the proton peak between 3.52-3.75ppm is H in PEG, and the proton peak at 3.37-3.38ppm is PEG The terminal methyl group (-CH 3 ) characteristic peaks, that is, mPEG proton peaks from 3.3 to 3.8ppm, and the new peak (a) about 4.2ppm belongs to methylene ( figure 2 ) near the ester bond.

Embodiment 3

[0048] Adopt infrared spectrum to determine the structure of block copolymer in embodiment 2, select KBr to be blank auxiliary material for use, the result is as follows Figure 6 to Figure 9 . ATRA-PEG500, at 3444cm -1 The broad absorption peak of hydroxyl group disappears and a new peak is about 1707cm -1 The emerging peak position is due to the conversion of the carboxy-hydroxyl group of ATRA to the ester bond in ATRA-PEG500, these results indicate the formation of PEGylated retinoic acid.

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