CN107353203A - Citronellol aliphatic ester derivatives and its application and preparation method - Google Patents

Abstract

The present invention relates to a kind of citronellol fatty acid ester derivative derivative and the application and preparation method of the derivative thereof. The citronellol fatty acid ester derivative is used as a transdermal absorption penetration enhancer to prepare a transdermal drug delivery preparation. Improve the percutaneous absorption of drugs and increase the cumulative penetration of drugs. The fatty acid ester derivative of citronellol is prepared by reacting with thionyl chloride, and the fatty acid chloride is reacted with citronellol to obtain the fatty acid ester derivative of citronellol. The compound of the present invention can be applied in transdermal drug delivery preparations to enhance the penetration ability of medicines, and can also be used as spices to cover up the bad smell of preparations.

Description

Citronellol fatty acid ester derivative and its application and preparation method

technical field

The invention relates to a derivative and its application and preparation method, in particular to a citronellol fatty acid ester derivative and its application and preparation method.

Background technique

Transdermal drug delivery systems (TDDS) are a new class of preparations in which drugs are absorbed through the skin and enter the systemic circulation to produce curative effects. Once TDDS appeared, it attracted the attention of the medical community due to its long-lasting, constant and controllable blood drug concentration, avoiding the hepatic first-pass effect, convenient administration, and high patient compliance. The skin is a natural barrier that prevents the entry of foreign substances into the body and the loss of body water. The skin is composed of epidermis, dermis and subcutaneous tissue. The epidermis can be divided into stratum corneum and active epidermis. The stratum corneum is the main barrier for drug transdermal absorption. After transdermal administration of most drugs, the permeation rate is far below the therapeutic requirements. Therefore, in order to develop more drugs into TDDS, finding ways to increase drug permeation is a top priority in TDDS research. The chemical penetration enhancing method using a penetration enhancer is the oldest method, but it is the simplest, safe, cheap and practical method. Most of the terpenoid penetration enhancers are derived from natural products (volatile oils), which have the advantages of strong penetration-enhancing activity, low toxicity, low irritation, and penetration-enhancing effects on both hydrophilic and lipophilic drugs. However, the volatility of terpineols, including terpineol, will hinder the production and storage of percutaneous absorption preparations. Because it is volatile, it will cause unstable content in the formulation, and lead to poor reproducibility between batches. Commonly used terpenoid penetration enhancers such as l-menthol, α-terpineol, citronellol, etc., the applicant of l-menthol has carried out structural modification, prepared 17 kinds of derivatives, and screened out Compared with l-menthol, it is less toxic, efficient and non-volatile penetration enhancer (Ligang Zhao, Liang Fang, Yongnan Xu, et al. Transdermal delivery of penetrants with differing lipophilicities using O-acylmenthol derivatives as penetration enhancers. Eur J Pharm Biopharm, 2008 ,69:199–213; Ligang Zhao, Liang Fang, Yongnan Xu, et al.Effect of O-acylmenthol ontransdermal delivery of drugs with different lipophilicity.Int J Pharm,2008,352:92–103), and applied for a patent ( Patent certificate number: ZL 200710158246.1). α-Terpineol is a volatile oil that is beneficial to the human body, and it can also promote lidocaine (S Mohammadi-Samani, A Jamshidzadeh, HMontaseri, M Rangbar-Zahedani, R Kianrad. The effects of some permeability enhancers on the percutaneous absorption of lidocaine.Pak J Pharm Sci,2010,23:83–88.), curcumin (JY Fang, CF Hung, HC Chiu, JJ Wang, TF Chan.Efficacy and irritancy of enhancers on the in-vitro and in- vivo percutaneous absorption of curcumin.J Pharm Pharmacol,2003,55:593-601), estradiol (D Monti,P Chetoni,S Burgalassi,M Najarro,MF Saettone,Boldrini E.Effect of different terpene-containing essential oils on permeation of estradiol through hairless mouseskin.Int J Pharm,2002,26:237:209-214) and other drugs, is also a relatively common natural penetration enhancer, and the applicant for α-terpineol has carried out Through structural modification, 11 kinds of derivatives were prepared, and a penetration enhancer with lower toxicity, higher efficiency and non-volatility than α-terpineol was screened out, and a patent was applied for (patent certificate number: ZL201510006421.X). Citronellol is structurally similar to α-terpineol, and studies have shown that citronellol also has a significant transdermal penetration-enhancing effect on various drugs (JY Fang, TH TSAI, YY LIN. Transdermal delivery of tea catechins and theophylline enhanced by terpenes : a mechanistic study. Biol Pharm Bull, 2007, 30:343-349; CH Liu, FY Chang, DK Hung. Terpene microemulsions for transdermal curcumin delivery: effects of terpenes and cosurfactants. Colloids Surf BBiointerfaces, 2011, 82: 63-70; RM, Varman, S Singh. Investigation of effects ofterpene skin penetration enhancers on stability and biological activity of lysozyme. AAPS PharmSciTech, 2012, 13:1084-1090), but its boiling point is low, volatile, and its content in the preparation is unstable. The present inventors modified its structure, synthesized a series of fatty acid ester derivatives, and systematically studied its permeation-promoting activity.

Contents of the invention

The object of the present invention is to provide a kind of citronellol fatty acid ester derivative with penetrating promoting activity and its application in transdermal administration preparation and its preparation method.

The present invention adopts following technical scheme:

A kind of citronellol fatty acid ester derivative, the general structural formula of this derivative is as follows:

The preferred scheme of derivatives is as follows:

Citronellol is natural or synthetic (±)-citronellol, (+)-citronellol, (-)-citronellol; fatty acids include saturated straight-chain fatty acids and unsaturated straight-chain fatty acids.

The saturated fatty acid is straight chain fatty acid of C ₂ ~C ₁₈ or R=C ₁ ~C ₁₇ , and the R of unsaturated fatty acid is: (CH ₂ ) ₇ CH=CH(CH ₂ ) ₇ CH ₃ .

The saturated fatty acid includes propionic acid, butyric acid, hexanoic acid, heptanoic acid, caprylic acid, capric acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid and octadecanoic acid; the unsaturated fatty acid is oleic acid.

The technical scheme adopted in the application of citronellol fatty acid ester derivative is:

The citronellol fatty acid ester derivative is used as a percutaneous absorption penetration enhancer to prepare a transdermal drug delivery preparation, improve the percutaneous absorption of the drug, and increase the cumulative permeation amount of the drug.

The preferred scheme selected for the application of derivatives is:

The preparations for transdermal administration are respectively: patch, cataplasm, latex, gel, cream, ointment, liniment or spray for external use.

The pharmaceutical ingredients are: diclofenac potassium, indomethacin, ketoprofen, oxybutynin, flurbiprofen, bisoprolol, lidocaine, selegiline or isosorbide dinitrate.

The pressure-sensitive adhesive is silicone pressure-sensitive adhesive, acrylate pressure-sensitive adhesive or polyisobutylene pressure-sensitive adhesive.

The patch is prepared by the following method: after adding diclofenac potassium to the pressure-sensitive adhesive, stir until the medicine is completely dissolved in the pressure-sensitive adhesive solution; after that, add an absorption penetration enhancer (citronellol fatty acid ester derivative or Other conventional penetration enhancers) and glycerin, ethyl acetate and hydroxypropyl cellulose, continue to stir until a uniform solution is formed; then, use an experimental coater to transfer and coat on the release layer, and heat through 30 ° C ~ 100 ° C After drying, the compound backing non-woven fabric is punched and cut into a size of 7×7 cm2 to obtain a diclofenac potassium patch.

The effective amount of the citronellol fatty acid derivative is 0.5%-20% (w/w).

The optimal dosage of citronellol fatty acid derivatives is 3%-10% (w/w).

The preparation method of citronellol fatty acid ester derivative, the technical scheme adopted is:

The invention discloses a method for preparing citronellol fatty acid ester derivatives. The citronellol fatty acid ester derivatives are prepared by preparing fatty acid chlorides and reacting with citronellol to obtain the citronellol fatty acid ester derivatives.

The preparation method of citronellol fatty acid ester derivative, the preferred scheme adopted is:

The citronellol fatty acid ester derivatives react with thionyl chloride to prepare fatty acid esters.

The fatty acid chloride is reacted with citronellol, and the solvent used in the preparation process is a low-toxic organic solvent that removes water.

Citronellol is one of natural or synthetic (±)-citronellol, (+)-citronellol, (-)-citronellol; fatty acid is C ₂ ~ C ₁₈ saturated straight-chain fatty acid or oleic acid One of.

Collect fatty acids with different chemical structures, and synthesize citronellol ester derivatives according to the synthetic route shown below; Compounds 1-11 are all synthesized by the following route:

The above-mentioned 11 kinds of citronellol derivatives synthesized by the present invention can be used as transdermal absorption and penetration enhancer application, and preparation of transdermal administration preparation (patch, cataplasm, latex, cream, gel, ointment, Liniments, sprays, etc.) can also be used in external preparations containing citronellol by utilizing the low volatility of the derivatives as a citronellol substitute.

The compound described in the present invention can be applied in transdermal drug delivery preparations to enhance the penetration ability of drugs, and can also be used as spices to mask the bad smell of preparations, and has wide potential application prospects; the preparation method is suitable for industrial production, safe, Easy to store.

Description of drawings

Figure 1 is a diagram of cumulative penetration of citronellol fatty acid esters in patches to promote transdermal absorption of diclofenac potassium.

Fig. 2 is a diagram of cumulative penetration of citronellol fatty acid esters applied in patches to promote transdermal absorption of indomethacin.

Figure 3 is a diagram of cumulative penetration of citronellol fatty acid esters applied in patches to promote transdermal absorption of ketoprofen.

Fig. 4 is a diagram of the cumulative penetration amount of citronellol fatty acid ester applied in the patch to promote the transdermal absorption of oxybutynin.

Fig. 5 is a diagram of cumulative penetration of citronellol fatty acid esters applied in patches to promote transdermal absorption of influrbiprofen.

Fig. 6 is a diagram of cumulative penetration of bisoprolol promoted by citronellol fatty acid ester applied in the patch.

Fig. 7 is a diagram of cumulative permeation amount of citronellol fatty acid esters applied in patches to promote transdermal absorption of lidocaine.

Fig. 8 is a diagram of cumulative penetration of citronellol fatty acid esters applied in patches to promote transdermal absorption of selegiline.

Fig. 9 is a diagram of cumulative permeation of citronellol fatty acid esters applied in patches to promote transdermal absorption of isosorbide dinitrate.

detailed description

Below in conjunction with accompanying drawing and embodiment the present invention is described in further detail:

Example 1:

Take 14.8g (0.2mol) of propionic acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 60°C for 3 hours, add 20ml of citronellol tetrahydrofuran solution containing 15.4g (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, dried overnight with anhydrous Na ₂ SO ₄ , and the solvent was evaporated. , column chromatography (silica gel is 200～300 meshes), ethyl petroleum ether and ethyl acetate (volume ratio 15:1) are eluent, evaporate eluent, obtain colorless liquid 17.64g, productive rate: 91 %. The 1HNMR and MS data of the product are as follows: ESI-MS m/z: 211.3[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.68(m, 2H),2.2-1.9(m,6H),1.68(s,3H),1.60(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J= 6.5Hz, 3H).

Example 2:

Take 17.6g (0.2mol) of butyric acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 60°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, 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, dried overnight with anhydrous Na ₂ SO ₄ , and the solvent was evaporated. , column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as the eluent, and the eluent was evaporated to obtain 19.91 g of a colorless liquid with a yield of 91.4%. The 1HNMR and MS data of the product are as follows: ESI-MSm/z: 225.3[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.68(m, 2H ),2.2-1.8(m,8H),1.68(s,3H),1.60(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J＝6.5 Hz, 3H).

Example 3:

Take 23.2g (0.2mol) of hexanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 60°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, 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, dried overnight with anhydrous Na ₂ SO ₄ , and the solvent was evaporated. , column chromatography (silica gel is 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) are used as eluents, and the eluents are evaporated to obtain 20.77 g of colorless liquid, and the yield is: 91.4%. The 1HNMR and MS data of the product are as follows: ESI-MSm/z: 253.4[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.68(m, 2H ),2.3-1.8(m,12H),1.68(s,3H),1.60(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J＝6.5 Hz, 3H).

Example 4:

Take 26g (0.2mol) of heptanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix and react at 60°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, 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, dried overnight with anhydrous Na ₂ SO ₄ , and the solvent was evaporated. Column chromatography (silica gel: 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluent, evaporated to obtain 24.41 g of colorless liquid, yield: 91%. The 1HNMR and MS data of the product are as follows: ESI-MSm/z: 267.4[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.68(m, 2H ),2.3-1.8(m,14H),1.68(s,3H),1.60(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J＝6.5 Hz, 3H).

Example 5:

Take 28.8g (0.2mol) of octanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 60°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.6g (0.1mol) of citronellol, 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, dried overnight with anhydrous Na ₂ SO ₄ , and the solvent was evaporated. Column chromatography (silica gel: 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluent, evaporated to obtain 259.4 g of colorless liquid, yield: 90%. The 1HNMR and MS data of the product are as follows: ESI-MSm/z: 281.4[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.68(m, 2H ),2.3-1.8(m,16H),1.68(s,3H),1.60(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J＝6.5 Hz, 3H).

Embodiment 6:

Take 34.4g (0.2mol) of capric acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 60°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, 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, dried overnight with anhydrous Na ₂ SO ₄ , and the solvent was evaporated. , column chromatography (silica gel is 200 ~ 300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as the eluent, and the eluent was evaporated to obtain 30.83 g of a colorless liquid with a yield of 93.5%. The 1HNMR and MS data of the product are as follows: ESI-MSm/z: 309.5[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.68(m, 2H ),2.3-1.8(m,20H),1.68(s,3H),1.60(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J＝6.5 Hz, 3H).

Embodiment 7:

Take 40g (0.2mol) of dodecanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 70°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, 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, dried overnight with anhydrous Na ₂ SO ₄ , and the solvent was evaporated. , column chromatography (silica gel is 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) are used as eluent, and the eluent is evaporated to obtain 30.62 g of colorless liquid, yield: 90.5%. The 1HNMR and MS data of the product are as follows: ESI-MSm/z: 337.5[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.68(m, 2H ),2.3-1.8(m,24H),1.68(s,3H),1.60(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J＝6.5 Hz, 3H).

Embodiment 8:

Take 45.6g (0.2mol) of tetradecanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 70°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, continue React for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, combine the organic layers, wash with saturated brine, dry overnight with anhydrous Na ₂ SO ₄ , evaporate Solvent, column chromatography (silica gel is 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) are used as eluent, and the eluent is evaporated to obtain 32.6 g of colorless liquid, yield: 89% . The 1HNMR and MS data of the product are as follows: ESI-MS m/z: 365.5[M+1]+, 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.66(m, 2H), 2.3-1.8(m, 28H), 1.67(s, 3H), 1.601(s, 3H), 1.7-1.52(m, 3H), 1.4-1.1(m, 3H), 0.91(d, J= 6.5Hz, 3H).

Embodiment 9:

Take 51.2g (0.2mol) of hexadecanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 70°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, continue React for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, combine the organic layers, wash with saturated brine, dry overnight with anhydrous Na ₂ SO ₄ , evaporate Solvent, column chromatography (silica gel: 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluent, evaporated to obtain 34.3 g of white solid, yield: 87%. The 1HNMR and MS data of the product are as follows: ESI-MS m/z: 393.6[M+1]+, 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.66(m, 2H),2.3-1.8(m,32H),1.67(s,3H),1.601(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J= 6.5Hz, 3H).

Example 10:

Take 56.8g (0.2mol) of octadecanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 70°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, continue React for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, combine the organic layers, wash with saturated brine, dry overnight with anhydrous Na ₂ SO ₄ , evaporate Solvent, column chromatography (silica gel: 200-300 mesh), ethyl ether and ethyl acetate (15:1) as eluent, evaporated to obtain 35.9 g of white solid, yield: 85%. The 1HNMR and MS data of the product are as follows: ESI-MS m/z: 421.6[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.66(m, 2H),2.3-1.7(m,36H),1.67(s,3H),1.601(s,3H),1.7-1.52(m,3H),1.4-1.1(m,3H),0.91(d,J= 6.5Hz, 3H).

Example 11:

Take 56.4g (0.2mol) of oleic acid, add 17.85g (0.15mol) of thionyl chloride, mix well and react at 70°C for 3 hours, add 20ml of tetrahydrofuran solution containing 15.4g (0.1mol) of citronellol, 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, dried overnight with anhydrous Na ₂ SO ₄ , and the solvent was evaporated. , column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as the eluent, and the eluent was evaporated to obtain 36.14 g of a yellowish liquid with a yield of 84%. The 1HNMR and MS data of the product are as follows: ESI-MSm/z: 419.6[M+1]+; 1H NMR (500MHz, CDCl ₃ ): δ5.10(t, J=7.5Hz, 1H), 3.66(m, 2H ),2.38(2H,t,J＝7.4Hz),2.3-1.7(m,32H),1.67(s,3H),1.601(s,3H),1.7-1.52(m,3H),1.4-1.1( m, 3H), 0.91 (d, J=6.5Hz, 3H).

Example 12: Citronellol Derivatives Promote Transdermal Absorption of Diclofenac Potassium in Patches

Preparation of skin: Take male rats with a body weight of 180g-220g, inject 1ml of urethane solution with a mass ratio of 25% into the abdominal cavity for anesthesia, cut off the abdominal hair, and kill them. Rinse with saline for 3 times, store in -20°C refrigerator for short term (use within 7 days), and set aside.

Preparation of patch: In a 30ml sample bottle, filled with acrylate pressure sensitive adhesive. After adding diclofenac potassium, stir at 300 rpm until the drug ingredients are completely dissolved in the pressure-sensitive adhesive solution. Then add the absorption penetration enhancer and other ingredients (as shown in Table 1), and continue to stir until a uniform solution is formed. Subsequently, it was transferred and coated on the anti-adhesive layer with an experimental coater, dried at 30°C to 100°C, compounded with a backing non-woven fabric, and punched into a size of ⁷ ×7cm2 to obtain a diclofenac potassium patch.

Table 1

METHODS: The transdermal absorption test used a horizontal double-chamber diffusion cell. The prepared diclofenac potassium patch was applied to the treated skin stratum corneum. The pH 7.4 phosphate buffer solution was used as the receiving solution, and the absorption was determined by HPLC. Calculate the amount of drug in the pool, and calculate the cumulative permeation volume and permeation flux. Wherein the concentration of the penetration enhancer in the diclofenac potassium patch is (0 or 5% citronellol or equimolar concentration with 5% citronellol).

Example 13:

The same method as in Example 12 was used except that indomethacin was used instead of diclofenac potassium.

Table 2

Example 14:

Except replacing diclofenac potassium with ketoprofen, use the same method with embodiment 12.

table 3

Example 15:

Except that oxybutynin was used instead of diclofenac potassium, the same method as in Example 12 was used.

Table 4

Example 16:

Except that flurbiprofen was used instead of diclofenac potassium, the same method as in Example 12 was used.

table 5

Example 17:

Except replacing diclofenac potassium with bisoprolol, use the same method with embodiment 12.

Table 6

Example 18:

Except replacing diclofenac potassium with lidocaine, use the same method with embodiment 12.

Table 7

Example 19:

Except using selegiline instead of diclofenac potassium, the same method as in Example 12 was used.

Table 8

Example 20:

The same method as in Example 12 was used except that diclofenac potassium was replaced with isosorbide dinitrate.

Table 9

Claims (16)

1. a kind of citronellol aliphatic ester derivatives, the general structure of the derivative are as follows：

2. citronellol aliphatic ester derivatives according to claim 1, it is characterised in that：Citronellol is natural or synthetic (±)-citronellol, (+)-citronellol, (-)-citronellol；Aliphatic acid includes saturated straight chain aliphatic acid and unsaturated straight chain fatty acid.

3. citronellol aliphatic ester derivatives according to claim 1, it is characterised in that：R is C₁-C₁₇Straight chained alkyl or Person R is (CH₂)₇CH=CH (CH₂)₇CH₃。

4. citronellol aliphatic ester derivatives according to claim 2, it is characterised in that：Saturated fatty acid include propionic acid, Butyric acid, caproic acid, enanthic acid, octanoic acid, capric acid, lauric acid/dodecanoic acid, tetradecylic acid, hexadecylic acid or stearic acid；Unrighted acid is oleic acid.

5. a kind of application of citronellol aliphatic ester derivatives as described in any one in Claims 1-4, its feature exist In：As percutaneous absorbtion transdermal enhancer application, percutaneous drug administration preparation is prepared, improves the percutaneous absorbtion of medicine, increases the accumulation of medicine Transit dose.

6. the application of citronellol aliphatic ester derivatives according to claim 5, it is characterised in that：Percutaneous drug administration preparation point It is not patch, cataplasm, emulsion agent, gel, cream, ointment, liniment or spray class external preparation.

7. the application of citronellol aliphatic ester derivatives according to claim 6, it is characterised in that：The preparation method of preparation It is as follows：After drug ingedient, pressure sensitive adhesive and citronellol aliphatic ester derivatives are sufficiently mixed with metastatic coating be made in it is anti-sticking On layer, by 30~100 DEG C of dryings, then with the Material cladding of mounting for including PVC or non-woven fabrics, that is, percutaneous dosing system is obtained Agent.

8. the application of citronellol aliphatic ester derivatives according to claim 7, it is characterised in that：Drug ingedient is selected from double The fragrant sour potassium of chlorine, Indomethacin, Ketoprofen, oxybutynin, Flurbiprofen, bisoprolol, lidocaine, selegiline or nitric acid are different One kind in sorb ester.

9. the application of citronellol aliphatic ester derivatives according to claim 7, it is characterised in that：Pressure sensitive adhesive is to be selected from silicon One kind in ketone pressure sensitive adhesive, acrylate pressure-sensitive adhesive or Medical PSA.

10. the application of citronellol aliphatic ester derivatives according to claim 7, it is characterised in that：It will add in pressure sensitive adhesive After entering Diclofenac Potassium, stirring is until medicine is completely dissolved in pressure-sensitive sol solution；Afterwards, add citronellol aliphatic ester derivatives and Glycerine, ethyl acetate and hydroxypropyl cellulose, continue to stir, sticky shape homogeneous solution is clarified until being formed；Then, using experiment With coating machine transfer coated on adherent layer, after 30 DEG C~100 DEG C dryings, combination backing non-woven fabrics, Diclofenac Potassium is produced Patch.

11. the application of citronellol aliphatic ester derivatives according to claim 5, it is characterised in that：Lemongrass polyol fatty acid The effective dose of ester derivant is 0.5%-20% (w/w).

12. the application of citronellol aliphatic ester derivatives according to claim 5, it is characterised in that：Lemongrass polyol fatty acid The optimum amount of ester derivant is 3%-10% (w/w).

A kind of 13. preparation method of citronellol aliphatic ester derivatives, it is characterised in that：Citronellol aliphatic ester derivatives pass through Prepare and obtain citronellol aliphatic ester derivatives after being reacted with citronellol after fat acyl chloride.

14. the preparation method of citronellol aliphatic ester derivatives according to claim 13, it is characterised in that：Lemongrass alcohol ester Fat acid ester derivant prepares fatty acid ester by being reacted with thionyl chloride.

15. the preparation method of citronellol aliphatic ester derivatives according to claim 13, it is characterised in that：Fat acyl chloride Reacted with citronellol, solvent for use is the less toxic organic solvent for removing water in preparation process.

16. the preparation method of citronellol aliphatic ester derivatives according to claim 13, it is characterised in that：Collect different The aliphatic acid of chemical constitution, according to synthetic route as follows, synthesize citronellol ester derivative；Compound 1-11, is adopted Synthesized as follows with route：