CN101875608B - Carveol ester derivative and percutaneous absorption preparation containing same - Google Patents

Abstract

The invention belongs to the technical field of medicine and discloses a class of carveol ester derivatives and a transdermal preparation containing the derivatives. The general structural formula is as follows. The derivatives include carveol esters of saturated and unsaturated fatty acids, which can be directly formed into esters through the reaction of fatty acids and carveol under the catalysis of p-toluenesulfonic acid, and the used solvent is anhydrous cyclohexane. Carveol ester derivatives can be used as penetration enhancers in external preparations such as patches, cataplasms, ointments, gels, etc., thereby increasing the transdermal absorption of drugs. It has high safety and low irritation, and has good drug penetration ability.

Description

A class of carveol ester derivatives and percutaneous absorption preparations containing the derivatives

technical field

The invention belongs to the technical field of medicine, relates to a class of carverol ester derivatives and transdermal absorption preparations containing the derivatives, in particular to 8 carverol ester derivatives, including saturated and unsaturated fatty acid carverol esters : heptanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid carveyl ester and oleic acid carveyl ester, its preparation method and in transdermal preparation (patch, Babu formulations, ointments, gels, creams, etc.).

Background technique

Most of the terpenoid accelerators are derived from natural products (volatile oils). They have the advantages of strong penetration-promoting activity, low toxicity, low irritation, and penetration-promoting effects on both hydrophilic and lipophilic drugs. They have become domestic and foreign percutaneous absorption accelerators. One of the hotspots of research. However, the volatility of terpenoids including carveol 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. The most commonly used terpene accelerator is l-menthol. Our research group has carried out structural modification on it, prepared 17 derivatives, and screened out a promoter that is less toxic, more efficient, and non-volatile than l-menthol. (LG Zhao, Y Li, L Fang, YN Xu, ZG He. Effect of O-acylmenthol and salt formation on the skinpermeation of diclofenac acid. Drug Dev Ind Pharm, accepted. LG Zhao, LFang, YN Xu, YY Zhao, ZG He. Effect of O-acylmenthol on transdermal delivery of drugs with different lipophilicity. Int J Pharm, 2008, 352: 92-103. LG Zhao, L Fang, YN Xu, S Liu, ZG He, YY Zhao. Transdermal delivery of penetrants with differing lipophilicities using O-acylmenthol derivatives aspenetration enhancers. Eur J Pharm Biopharm, 2008, 69: 199-213.), and applied for a patent (publication number: CN 101157612A). Carveol is a kind of volatile oil substance beneficial to human body (KH Wagner, I Elmadfa. Biological relevance of terpenoids. Overview focusing on mono-, di- and tetraterpenes. Ann Nutr Metab, 2003, 47: 95-106.), while It can also promote the secretion of water and ethanol (BM Magnusson, P Runn, LO Koskinen. Terpene-enhanced transdermal permeation of water and ethanol in humanepidermis. Acta Derm Venereol, 1997, 77: 264-267.), thyrotropin secretion hormone Skin absorption (BM Magnusson, P Runn, K Karlsson, L-OD Koskinen. Terpenes and ethanol enhance the transdermal permeation of tripeptide thyrotropin releasing hormone in human epidermis. Int J Pharm, 1997, 157: 113-121.). According to the research, the inventors found that, compared with menthol, carveol can exert its transdermal penetration-enhancing activity at a relatively low concentration (eg, 0.5%). In order to provide a more ideal accelerator for the development of TDDS, we modified the structure of (-)-carveol and synthesized a series of carveol ester derivatives. So far, there have been no research reports on the synthesis of new accelerators using carveol as a parent at home and abroad.

Contents of the invention

The object of the present invention is to provide eight carverol ester derivatives, including saturated and unsaturated fatty acid carverol esters and a preparation method thereof.

Another object of the present invention is to propose that above-mentioned 8 kinds of carverol ester derivatives are used as transdermal absorption promoters, and preparations for transdermal administration (patch, cataplasm, ointment, gel, cream) wait).

The general structural formula of the carveol ester derivatives provided by the present invention is as follows:

The carveol includes natural or synthetic (.+-.)-carveol, (-)-carveol and (+)-carveol; organic acids include saturated fatty acids and unsaturated fatty acids. The saturated fatty acid is C7-C18 or R=C6-C17 straight-chain fatty acid, and the unsaturated fatty acid is R=(CH ₂ ) ₇ CH=CH(CH ₂ ) ₇ CH ₃ .

The saturated fatty acid is heptanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid; the unsaturated fatty acid is oleic acid.

Carveol ester derivatives can be used in external preparations such as patches, cataplasms, ointments, gels, creams, etc., to improve the percutaneous absorption of drugs and increase the cumulative penetration of drugs; the derivatives can be used as It is used as a substitute for carveol in topical preparations containing carveol.

The preparation method of carveol ester derivatives involved in the present invention is as follows:

Collect organic acids with different chemical structures, and synthesize carveol ester derivatives according to the synthetic route shown below.

The derivative can directly form an ester through the reaction of fatty acid and carveol under the catalysis of p-toluenesulfonic acid, and the used solvent is anhydrous cyclohexane.

8 kinds of carveol ester derivatives synthesized by the present invention can be used as transdermal absorption accelerators to prepare transdermal drug preparations (patch, cataplasm, ointment, gel, cream, etc.), their It is characterized in that it can show a good penetration-enhancing effect at a concentration of 0.5%.

The model drug in the present invention covers the fat-soluble difference of the drug, and a patch containing diclofenac diethylamine, ketoprofen, and indomethacin is prepared, and the penetration-promoting activity of the carverol ester is comprehensively investigated.

Toxicological evaluation proves that the synthetic menthol ester derivatives of the present invention have no irritation, and it can be speculated that carveol ester derivatives have higher safety and lower irritation; and it is generally believed that the volatility and molecular Size is related, and the volatility of substances with large molecules is lower than that of substances with small molecules. Therefore, it is speculated that the volatility of carveol esters may be lower than that of carveol, which provides a theoretical basis for reducing the volatility of carveol.

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

Description of drawings

Figure 1 is a diagram of the in vitro percutaneous cumulative penetration of diclofenac diethylamine promoted by carveol derivatives in patches

Figure 2 is a diagram of the in vitro percutaneous cumulative penetration of indomethacin promoted by carveol derivatives in patches

Fig. 3 is applied to the in vitro percutaneous cumulative permeation figure of ketoprofen promoted by carveol derivatives in the patch

Fig. 4 is the medicine-time curve graph that promotes diclofenac diethylamine applied to carveol derivatives in the patch

Figure 5 is a diagram of the in vitro percutaneous cumulative penetration of flurbiprofen cataplasm when applied to carveol derivatives in patches

Figure 6 is a diagram of the in vitro percutaneous cumulative penetration of diclofenac potassium ointment promoted by carveol derivatives in patches

Figure 7 is a diagram of the in vitro percutaneous cumulative penetration of indomethacin gels promoted by carveol derivatives in patches

Detailed ways

Below in conjunction with example the present invention is described in further detail:

Example 1:

Take 15.6g (0.12mol) of heptanoic acid and 15.2g (0.1mol) of carveol, add an appropriate amount of p-toluenesulfonic acid and cyclohexane, heat and reflux for 30 minutes, wash the reaction solution three times with water, wash three times with saturated saline, and anhydrous _MgSO4 was dried for 2 hours, the solvent was evaporated, and column chromatography (silica gel was 200-300 mesh), using sherwood oil and ethyl acetate (100:1) as eluent, gave 16.6 g of colorless liquid, and the yield was: 58%. The ¹ HNMR and MS data of the product are as follows: ¹ HNMR (CDCl ₃ ), δ: 0.893(t, 3H), 1.204～1.387(br, 7H), 1.563～2.339(m, 14H), 4.717～4.754(m, 2H ), 5.271～5.749(m, 2H); GC-MS m/z: 264.3[M ⁺ ]

Example 2:

Take 17.3g (0.12mol) of octanoic acid and 15.2g (0.1mol) of carveol, add appropriate amount of p-toluenesulfonic acid and cyclohexane, heat and reflux for 30 minutes, wash the reaction solution three times with water, wash three times with saturated saline, and wash with anhydrous MgSO ₄ was dried for 2 hours, the solvent was evaporated, and column chromatography (silica gel was 200-300 mesh), using petroleum ether and ethyl acetate (100:1) as the eluent, gave 18.3 g of a colorless liquid, and the yield was: 62 %. The ¹ HNMR and MS data of the product are as follows: ¹ HNMR (CDCl ₃ ), δ: 0.861(t, 3H), 1.212～1.365(br, 9H), 1.621～2.357(m, 14H), 4.716～4.751(m, 2H ), 5.272～5.753(m, 2H); GC-MS m/z: 278.3[M ⁺ ]

Example 3:

Take 20.6g (0.12mol) of decanoic acid, 15.2g (0.1mol) of carveol, add appropriate amount of p-toluenesulfonic acid and cyclohexane, heat and reflux for 30 minutes, wash the reaction solution three times with water, wash three times with saturated saline, anhydrous _MgSO4 was dried for 2 hours, the solvent was evaporated, and column chromatography (silica gel was 200-300 mesh), using sherwood oil and ethyl acetate (100:1) as eluent, gave 17.8 g of colorless liquid, and the yield was: 55%. The ¹ HNMR and MS data of the product are as follows: ¹ HNMR (CDCl ₃ ), δ: 0.889(t, 3H), 1.198～1.387(br, 13H), 1.596～2.353(m, 14H), 4.721～4.754(m, 2H ), 5.276～5.754(m, 2H); GC-MS m/z: 306.3[M ⁺ ]

Example 4:

Take 24.0g (0.12mol) of lauric acid and 15.2g (0.1mol) of carveol, add an appropriate amount of p-toluenesulfonic acid and cyclohexane, heat and reflux for 30 minutes, wash the reaction solution three times with water, wash three times with saturated saline, and anhydrous _MgSO4 was dried for 2 hours, the solvent was distilled off, and column chromatography (silica gel was 200-300 mesh), using sherwood oil and ethyl acetate (100:1) as the eluent, gave 22.19 g of a colorless liquid, with a yield of: 63%. The ¹ HNMR and MS data of the product are as follows: ¹ HNMR (CDCl ₃ ), δ: 0.902(t, 3H), 1.219～1.1.417(br, 18H), 1.633～2.369(m, 13H), 4.712～4.744(m , 2H), 5.268～5.744(m, 2H0; GC-MS m/z: 334.3[M ⁺ ]

Example 5:

Take 27.4g (0.12mol) of myristic acid and 15.2g (0.1mol) of carveol, add an appropriate amount of p-toluenesulfonic acid and cyclohexane, heat and reflux for 30 minutes, wash the reaction solution three times with water, and wash three times with saturated brine. Water _MgSO4 was dried for 2 hours, the solvent was evaporated, and column chromatography (silica gel was 200-300 mesh), using petroleum ether and ethyl acetate (100:1) as eluent, gave 22.43 g of colorless liquid, and the yield was : 59%. The ¹ HNMR and MS data of the product are as follows: ¹ HNMR (CDCl ₃ ), δ: 0.902(t, 3H), 1.213～1.415(br, 22H), 1.628～2.370(m, 13H), 4.721～4.751(m, 2H ), 5.272～5.755(m, 2H); GC-MS m/z: 362.4[M ⁺ ]

Embodiment 6:

Take 30.7g (0.12mol) of palmitic acid and 15.2g (0.1mol) of carveol, add an appropriate amount of p-toluenesulfonic acid and cyclohexane, heat and reflux for 30 minutes, wash the reaction solution three times with water, wash three times with saturated saline, and anhydrous _MgSO4 was dried for 2 hours, the solvent was evaporated, and column chromatography (silica gel was 200-300 mesh), using sherwood oil and ethyl acetate (100:1) as eluent, gave 24.49 g of colorless liquid, and the yield was: 60%. The ¹ HNMR and MS data of the product are as follows: ¹ HNMR (CDCl ₃ ), δ: 0.886(t, 3H), 1.213～1.1.353(br, 22H), 1.590～2.369(m, 13H), 4.712～4.744(m , 2H), 5.268～5.744(m, 2H); GC-MS m/z: 362.4[M ⁺ ]

Embodiment 7:

Get 34.1g (0.12mol) of stearic acid, 15.2g (0.1mol) of carveol, add appropriate p-toluenesulfonic acid and cyclohexane, heat and reflux for 30 minutes, wash the reaction solution three times with water, and wash three times with saturated saline, without Water _MgSO4 was dried for 2 hours, the solvent was evaporated, and column chromatography (silica gel was 200-300 mesh), using petroleum ether and ethyl acetate (100:1) as eluent, gave 24.87 g of colorless liquid, and the yield was : 57%. The ¹ HNMR and MS data of the product are as follows: ¹ HNMR (CDCl ₃ ), δ: 0.888(t, 3H), 1.216～1.1.357(br, 22H), 1.612～2.364(m, 13H), 4.715～4.747(m , 2H), 5.255～5.754(m, 2H); GC-MS m/z: 418.4[M ⁺ ]

Embodiment 8:

Take 33.8g (0.12mol) of oleic acid and 15.2g (0.1mol) of carveol, add an appropriate amount of p-toluenesulfonic acid and cyclohexane, heat and reflux for 30 minutes, wash the reaction solution three times with water, wash three times with saturated saline, and anhydrous _MgSO4 was dried for 2 hours, the solvent was evaporated, and column chromatography (silica gel was 200-300 mesh), using sherwood oil and ethyl acetate (100:1) as eluent, gave 26.49 g of colorless liquid, and the yield was: 61%. The ¹ HNMR and MS data of the product are as follows: ¹ HNMR (CDCl ₃ ), δ: 0.875(t, 3H), 1.212～1.1.335(br, 20H), 1.626～2.061(m, 18H), 2.312～2.337(m , 1H), 4.715～5.752(m, 6H); GC-MS m/z: 416.4[M ⁺ ]

Embodiment 9:

Diclofenac diethylamine 12 parts Acrylic pressure sensitive adhesive 80 parts

Carveol Laurate 1 part Ethyl Acetate 7 parts

Add diclofenac diethylamine and acrylate pressure-sensitive adhesive into a small beaker, and stir magnetically until the drug dissolves. Then add the transdermal absorption promoter and other ingredients, continue to stir until it becomes a uniform solution, apply it on the anti-adhesive layer with an experimental coater, dry it at 30-100°C, and then cover it with PVC or non-woven fabrics. The backing material is compounded, punched into a certain size and specification, and then produced into a diclofenac diethylamine patch.

In vitro skin test:

Anesthetize a male rat of about 180 g with 20% urethane, cut off the abdominal hair, and then carefully remove the remaining hair with an electric shaver. Rinse well and store at -30°C for later use.

The transdermal absorption test was carried out in a horizontal double-chamber diffusion cell, the temperature of the water bath was 32°C, the transdermal area was 0.95cm ² , the volume of the receiving cell was 3.0ml, and the receiving solution was phosphate buffer (pH 7.4). Paste the patch on the stratum corneum of the skin, fix it on the receiving pool, take 2ml samples at 2h, 4h, 6h, 8h, 10h, and 12h, and add 2ml of blank receiving solution. The sample was analyzed by high performance liquid chromatography, and the 12-hour cumulative permeation amount of the patch was measured to be 607 μg/cm ² .

Example 10:

Diclofenac diethylamine 12 parts Acrylic pressure sensitive adhesive 80 parts

Carveol oleate 1 part Ethyl acetate 7 parts

The preparation method and in vitro transdermal test method are the same as in Example 9.

The 12-hour cumulative permeation amount of this patch was 724 μg/cm ² .

Example 11:

Diclofenac diethylamine 12 parts Acrylic pressure sensitive adhesive 80 parts

Carveol caprylate 1 part Ethyl acetate 7 parts

The preparation method and in vitro transdermal test method are the same as in Example 9.

The 12-hour cumulative permeation amount of this patch was 473 μg/cm ² .

Example 12:

Indomethacin 5 parts Acrylic pressure sensitive adhesive 85 parts

Carveol decanoate 0.5 parts Ethyl acetate 9.5 parts

The preparation method and in vitro transdermal test method are the same as in Example 9.

The 12-hour cumulative permeation amount of this patch was 328 μg/cm ² .

Example 13:

Ketoprofen 8 parts Acrylic pressure sensitive adhesive 85 parts

Carveol stearate 0.5 parts Ethyl acetate 6.5 parts

The preparation method and in vitro transdermal test method are the same as in Example 9.

The 12-hour cumulative permeation amount of this patch was 411 μg/cm ² .

Example 14: Carveol derivatives promote in vivo percutaneous absorption of diclofenac diethylamine patch in rats

Experimental method: 18 male Wistar rats were randomly divided into 3 groups, first anesthetized with ether, cut off the abdominal mouse hair with a pet trimmer, and then carefully removed the short hair with a razor, and took three kinds of diclofenac diethyl ether with an area of ^10cm2 The amine patches were pasted on the skin surface of the abdomen (control group, carveol group, and carveol derivatives group), and the patches were removed 24 hours after administration. At 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 26h, 30h, and 36h after administration, 250 μL of blood was collected and placed in a test tube coated with heparin and centrifuged at 10,000 rpm for 10 min.

Plasma sample processing: Take 50 μL of plasma, add 10 μL of reference substance solution, 100 μL of acetonitrile, vortex for 5 minutes, and centrifuge at low temperature for 5 minutes, take the supernatant, and measure the plasma drug concentration by HPLC.

The preparation method and prescription of the patch are the same as in Example 9.

The results showed that the transdermal penetration-enhancing activity of carveol derivatives was still effective in vivo.

Example 15:

Gelatin 1 part Kaolin clay 3.5 parts

Sodium carboxymethylcellulose 2 parts Polyvinylpyrrolidone 0.25 parts

Sodium polyacrylate 2 parts PEG400 10 parts

Propylene Glycol 20 parts Carveol Enanthate 1 part

Flurbiprofen 1 part

Weigh gelatin, CMC-Na, PVPk-30 and sorbitol according to the prescription amount, add appropriate amount of water to soak, and heat to swell in a water bath; take flurbiprofen, kaolin, propylene glycol and carverol enanthate and mix evenly, add In the above swelling solution, after stirring and mixing, add PEG400 solution and stir for several minutes to obtain the cataplasm matrix. Then apply it evenly on the non-woven fabric and cover it with a protective film to obtain a poultice.

The in vitro transdermal test method is the same as that in Example 9, and the 24-hour cumulative permeation amount of the cataplasm is 221 μg/cm ² measured by HPLC method.

Example 16:

Stearic acid 6 parts White petrolatum 6 parts

Polysorbate 8 parts Sorbitan oleate 1.6 parts

Liquid paraffin 9 parts Glycerin 10 parts

Carveol Myristate 1 part Diclofenac Potassium 1 part

Appropriate amount of distilled water

Heat the oil phase (stearic acid, sorbitan oleate, liquid paraffin, white petrolatum, and carveyl myristate) and the water phase (polysorbate, glycerin, and water) at 80°C, and add the oil phase to the water In the phase, stir while adding until it condenses into an emulsion-type matrix.

In vitro test method:

Anesthetize a male rat of about 180 g with 20% urethane, cut off the abdominal hair, and then carefully remove the remaining hair with an electric shaver. Rinse well and store at -30°C for later use.

The thawed isolated mouse skin was rinsed with normal saline and fixed on a vertical diffusion cell with the cuticle facing the donor cell. Add 3 g of ointment to the donor pool, add 7 mL of pH 7.4 phosphate buffer to the acceptor pool, and keep the whole experimental system in a circulating water bath at 32±0.5°C. 3ml of the sample was taken from the body pool, and an equal amount of isothermal pH7.4 phosphate buffer was added to the receiving pool at the same time, and the sample was filtered through a 0.45 μm microporous membrane. The sample was analyzed by high performance liquid chromatography, and the 12-hour cumulative permeation amount of the ointment was 299 μg/cm ² .

Example 17:

Carbomer 971 1 part Indomethacin 1 part

Macrogol 400 8 parts Glycerin 10 parts

Benzalkonium Bromide 1 part Carveol Palmitate 1 part

Triethanolamine 1.35 parts Distilled water Add to 100 parts

Add Carbomer 971 to 60 parts of water to dissolve, then add triethanolamine and stir to obtain a gel matrix. Weigh polyethylene glycol 400, carveol palmitate, glycerin and indomethacin, heat and dissolve in a beaker, then mix the matrix with polyethylene glycol 400, glycerin, indomethacin and other ingredients in the prescription Evenly, add water to 100 parts.

The in vitro transdermal test method is the same as that in Example 14, and the 12-hour cumulative permeation amount of the gel was measured by HPLC method to be 145 μg/cm ² .

Claims (6)

1. A class of carveol ester derivatives, characterized in that: the general structural formula of the derivatives is as follows:                                                  

The carveol is natural or synthetic (.+ -.)-carveol, (-)-carveol and (+)-carveol; R is selected from -(CH ₂ ) ₅ CH ₃ , -(CH ₂ ) ₆ CH ₃ , -(CH ₂ ) ₈ CH ₃ , -(CH ₂ ) ₁₂ CH ₃ , -(CH ₂ ) ₁₄ CH ₃ , -(CH ₂ ) ₁₆ CH ₃ or -(CH ₂ ) ₇ CH=CH(CH ₂ ) ₇ CH ₃ . 2. the application of the carverol ester derivative described in claim 1 in preparation patch, cataplasm, ointment, gel, cream, liniment, spray. 3. The application according to claim 2, characterized in that: the carveol ester derivatives are used as carveol substitutes in external preparations containing carveol. 4. a preparation method of carveol ester derivatives as claimed in claim 1, is characterized in that: described derivative is reacted under the catalysis of p-toluenesulfonic acid by fatty acid and carveol, directly forms ester, used The solvent is anhydrous cyclohexane. 5. The application according to claim 2, characterized in that: the patch is prepared by the following method: the main ingredient and silicone pressure-sensitive adhesive or acrylate pressure-sensitive adhesive or polyisobutylene pressure-sensitive adhesive and perfume After the celitol ester derivatives are fully mixed, they are transferred and coated on the anti-adhesive layer, dried at 30°C-100°C, then compounded with a mounting material including PVC or non-woven fabric, and punched into a certain size and specification, that is, Make a patch. 6. The application according to claim 5, characterized in that: the main ingredient is diclofenac diethylamine, ketoprofen or indomethacin.

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