Docetaxel-oleic acid prodrug as well as nanostructure lipid carrier and application thereof

A technology of nano-structured lipids and nano-lipid carriers, which is applied in the application of oral drug delivery. In the field of nano-structured lipid carriers, it can solve the problems of low drug loading and limit clinical applications, and achieve good physical stability and stability. Good sex, improve the effect of oral bioavailability

Active Publication Date: 2016-05-04
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the nanostructured lipid carrier loaded with docetaxel has the problem of low drug loading (5%, w / w), which limits its clinical application

Method used

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  • Docetaxel-oleic acid prodrug as well as nanostructure lipid carrier and application thereof
  • Docetaxel-oleic acid prodrug as well as nanostructure lipid carrier and application thereof
  • Docetaxel-oleic acid prodrug as well as nanostructure lipid carrier and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Synthesis of docetaxel-oleic acid prodrug.

[0033] Oleic acid (OA) was dissolved in a small amount of dichloromethane, under the catalysis of dicyclohexylcarboimide (DCC) and 4-dimethylaminopyridine (DMAP), N 2 Under the protection of ice bath for 2h, then with docetaxel at 25℃N 2 The reaction was carried out for 24 hours under protection, and the white powdery prodrug was obtained by separation and purification. The reaction formula is as follows:

[0034]

[0035] Determination by NMR 1 H-NMR hydrogen spectrum is determined the structure of prodrug in embodiment 1, and the solvent of selection is CDCl 3 , the result is as figure 1 . 1.158ppm, 1.783ppm, 5.229ppm, 8.131ppm are docetaxel H 7’–9’ ,H 14 ,H 20 ,H 25,29 characteristic peaks. 0.886ppm, 1.271ppm, 1.290ppm, 1.334ppm, 1.657ppm, 2.041ppm, 2.372ppm, 5.368ppm are oleic acid-CH 3 , CH 3 - (CH 2 ) 5 -CH 2 -, CH 3 -(CH 2 ) 5 - CH 2 -, -CH 2 - (CH 2 ) 3 -CH 2 -, - CH 2 -CH 2 CH 2...

Embodiment 2

[0039] Stability of docetaxel-oleic acid prodrug

[0040] Docetaxel-oleic acid prodrug and docetaxel were added to rat plasma respectively, placed in a shaker at 37°C, and the drug was measured at 0h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h, 96h, 120h content changes. The result is as Figure 4 shown. In rat plasma, the docetaxel-oleic acid prodrug was more stable than docetaxel.

Embodiment 3

[0042] Preparation of nanostructured lipid carriers based on core-match mechanism by emulsification ultrasonic method

[0043] The preparation process is as follows: a certain amount of glyceryl monostearate (6.7mg), oleic acid (3.3mg), docetaxel-oleic acid prodrug (8mg), PLV 2000 (3mg), dissolved in an appropriate amount of ethanol, heated to 80°C, and dissolved evenly under magnetic stirring. Will F 68 (10mg) was dissolved in 10mL water, heated to 80°C, and dissolved evenly under magnetic stirring. The above ethanol solution was quickly added to the aqueous solution, and magnetic stirring was maintained for 5 min in a water bath at 80°C. The above solution was ultrasonically treated (200W, 5min), and rapidly cooled in an ice bath to obtain a light blue opalescent liquid preparation. The docetaxel-oleic acid prodrug in the above method is replaced by docetaxel, coumarin-6 and DiR respectively, and other conditions remain unchanged, and the preparation contains docetaxel, c...

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Abstract

The invention relates to preparation of a docetaxel-oleic acid prodrug and application of a nanostructure lipid carrier based on a core-match mechanism to drug delivery. The prodrug takes docetaxel as a parent drug and oleic acid as an aliphatic chain and is linked by a fat key. The nanostructure lipid carrier based on the core-match mechanism takes glycerol monostearate as solid lipid, the oleic acid as liquid lipid, Poloxamer 188 or sodium deoxycholate as a surface active agent and PLV2000 or PLV5000 as a modified material and encapsulates the docetaxel-oleic acid prodrug. The drug loading capacity of the nanostructure lipid carrier prepared is about 23 percent, and the drug loading capacity is obviously improved compared with that (5 percent) of the nanostructure lipid carrier encapsulating the docetaxel; the nanostructure lipid carrier is better in colloidal stability and more excellent in slow controlled release effect. A pharmacokinetic experiment can prove that the nanostructure lipid carrier based on the core-match mechanism can obviously improve the oral bioavailability of the docetaxel, and the docetaxel-oleic acid prodrug is good in stability, high in safety, suitable for oral administration and wider in market application prospect.

Description

technical field [0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, including docetaxel-oleic acid prodrug (DTX-OA) and nanostructured lipid carrier (NLC) based on the core-match mechanism, and its oral administration application in medicine. Background technique [0002] Docetaxel (DTX) is an anticancer drug widely used clinically. However, due to the extremely low water solubility, the commercially available preparations contain a large amount of Tween 80 and ethanol as solubilizers, which are prone to toxic and side effects, thereby limiting its clinical application. At the same time, injection administration inevitably faces many disadvantages, such as susceptibility to infection, low patient compliance, and large side effects. Compared with injection administration, oral administration has the characteristics of convenience, economy, and higher patient compliance. However, due to the extremely low water sol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14A61K31/337A61K9/127A61K47/48A61K47/10A61K47/12A61K47/14A61P35/00
CPCA61K9/1271A61K31/337C07B2200/07C07D305/14
Inventor 何仲贵孙进孙丙军罗聪李琳
Owner SHENYANG PHARMA UNIVERSITY
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