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Organic acid menthol derivative and transdermal drug delivery preparation having the same

A menthol enanthate and drug delivery technology, which is applied in the field of menthol ester derivatives, can solve the problems of single drug, unimproved volatility, production and storage barriers of percutaneous absorption preparations, etc., and achieve wide application prospects, Enhanced through ability, easy to save the effect

Active Publication Date: 2013-05-29
SHENYANG PHARMA UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] (1) Only a preliminary irritation evaluation has been made, and no reports on potential toxicity in vivo have been seen, and its safety needs further evaluation
[0010] (2) The boiling point of MET is close to that of menthol, and its volatility has not been improved, which will bring obstacles to the production and storage of percutaneous absorption preparations
The shortcoming of this method is: (1) smear its concentration of menthyl ester on rat skin surface and can't quantify accurately
(2) This patent does not prepare any transdermal preparations containing menthol derivatives, and the use of solution system screening has certain deficiencies in the screening science
(3) The selected screening model drug is single, without considering the selectivity of different drug properties to accelerators

Method used

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  • Organic acid menthol derivative and transdermal drug delivery preparation having the same
  • Organic acid menthol derivative and transdermal drug delivery preparation having the same
  • Organic acid menthol derivative and transdermal drug delivery preparation having the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Take 12g (0.2mol) of acetic acid, add 17.85g (0.15mol) of thionyl chloride, mix and react at 60°C for 3 hours, add 20ml of menthol tetrahydrofuran solution containing 15.6g (0.1mol), and continue the reaction for 3 hours. The reaction solution was adjusted to pH 6-7 with NaOH solution, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and anhydrous Na 2 SO 4 Dry overnight, evaporate the solvent, perform column chromatography (silica gel is 200-300 mesh), use petroleum ether and ethyl acetate (15:1) as the eluent, and evaporate the eluent to obtain 18.64 g of a colorless liquid. Rate: 94%. product of 1 HNMR and MS data are as follows: 1 HNMR (CDCl 3 ), δ: 0.71 (3H, d, J = 7.0Hz, Me-2-isopropyl), 0.83 (3H, d, J = 2.2Hz, Me-2-isopropyl), 0.85 (3H, d, J = 1.6Hz , Me-5), 0.96~1.05(3H, m), 1.33~1.45(2H, m), 1.73~1.83(2H, m), 1.91~1.92(2H, m), 1.96(3H, s, Me- ester), 4.68 (1...

Embodiment 2

[0041] Take 14.8g (0.2mol) of propionic acid, add 17.85g (0.15mol) of thionyl chloride, mix and react at 60°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.6g (0.1mol) of menthol, and continue the reaction for 3 hours, the reaction solution was adjusted to pH 6-7 with NaOH solution, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, anhydrous Na 2 SO 4 Dry overnight, evaporate the solvent, perform column chromatography (silica gel is 200-300 mesh), use petroleum ether and ethyl acetate (15:1) as the eluent, and evaporate the eluent to obtain 19.32 g of a colorless liquid. Rate: 91.4%. product of 1 HNMR and MS data are as follows: 1 HNMR (CDCl 3 ), δ: 0.76 (3H, d, J = 7.0Hz, Me-2-isopropyl), 0.89 (3H, d, J = 2.2Hz, Me-2-isopropyl), 0.91 (3H, d, J = 1.6Hz , Me-5), 0.99~1.04(2H, m), 1.07~1.11(1H, m), 1.14(3H, t, J=7.6Hz, Me-ester), 1.33~2.00(6H, m), 2.30 (2H, q...

Embodiment 3

[0043] Take 17.6g (0.2mol) of butyric acid, add 17.85g (0.15mol) of thionyl chloride, mix and react at 60°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.6g (0.1mol) of menthol, and continue the reaction for 3 hours, the reaction solution was adjusted to pH 6-7 with NaOH solution, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, anhydrous Na 2 SO 4 Dry overnight, evaporate the solvent, and perform column chromatography (silica gel is 200-300 mesh), using petroleum ether and ethyl acetate (15:1) as the eluent, and evaporate the eluent to obtain 20.91 g of a colorless liquid. For: 92.4%. product of 1 HNMR and MS data are as follows: 1 HNMR (CDCl 3 ), δ: 0.76 (3H, d, J = 6.9Hz, Me-2-isopropyl), 0.89 (3H, d, J = 2.2Hz, Me-2-isopropyl), 0.91 (3H, d, J = 1.6Hz , Me-5), 0.97~1.11(6H, m), 1.13~1.15(2H, m), 1.59~1.69(4H, m), 1.83~1.87(1H, m), 1.92~1.98(1H, m) , 2.2...

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Abstract

The invention discloses the menthol derivate for organic acid andTDDS preparation which includes the derivate. The preparation (comprising patch agent, Bab agent, emulsion inhibitor, ointment agent, gelling agent, etc.) can increase the TD absorptivity of medicine. The derivate is obtained through esterification reaction of menthol and acid. The invention adopts a first method that: acyl chlorideis prepared through the reaction of acid and sulphoxides chloride, and then the ulphoxides chloride is reacted with menthol to prepare the derivate. The invention provides a second method that: menthol is directly reacted with water to prepare the derivate by taking DCC as the catalyst; and the invention also has a third method that: the menthol and paratoluenesulfonic acid are filled in dehydrated lactic acid to prepare lactic acid menthol ester. The compound is reinforcing agent which can promote medicine absorbing and articulately increase the TD medicine absorbing. The invention is the good TDDS accelerating agent.

Description

technical field [0001] The present invention relates to 17 kinds of menthol ester derivatives, including fatty acid menthyl ester and pharmaceutical excipient menthyl acid menthyl ester: B, C, D, E, Hexa, Hepta, Octyne, Nonyl, Decane, Laurel, Nutmeg, Palm, Hard Menthyl fatty acid and lactic acid, oleic acid, salicylic acid, menthyl cinnamate, its preparation method and transdermal administration preparation (patch, cataplasm, emulsion, cream, gel, ointment, liniments, sprays, etc.). Background technique: [0002] Menthol is the main component of peppermint oil, it is colorless acicular or prismatic crystal or white crystalline powder, there are four pairs of optical isomers, its safety is called GRAS (Generally Regarded as Safe by the FDA) compound, this compound has It has the advantages of strong penetration-enhancing activity, low toxicity, small irritation, and both hydrophilic and lipophilic drugs. It has become one of the hot spots in the research of percutaneous abso...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/013C07C67/08A61K9/70A61K47/14
Inventor 方亮赵利刚徐勇男何忠贵
Owner SHENYANG PHARMA UNIVERSITY
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