CN1651395B - Borneol fatly acid ester derivative and preparation containing said derivative - Google Patents
Borneol fatly acid ester derivative and preparation containing said derivative Download PDFInfo
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- CN1651395B CN1651395B CN 200410087683 CN200410087683A CN1651395B CN 1651395 B CN1651395 B CN 1651395B CN 200410087683 CN200410087683 CN 200410087683 CN 200410087683 A CN200410087683 A CN 200410087683A CN 1651395 B CN1651395 B CN 1651395B
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- borneol
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- acid ester
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- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229940116229 borneol Drugs 0.000 title claims abstract description 78
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 title claims abstract description 78
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 title claims abstract description 76
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000002148 esters Chemical class 0.000 title claims description 27
- 239000002253 acid Substances 0.000 title claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- -1 oleic acid acyl chlorides Chemical class 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 11
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 11
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 11
- 239000005642 Oleic acid Substances 0.000 claims description 11
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 11
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 8
- MBMBGCFOFBJSGT-KUBAVDMBSA-N docosahexaenoic acid Natural products CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- DVSZKTAMJJTWFG-UHFFFAOYSA-N docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCCC=CC=CC=CC=CC=CC=CC(O)=O DVSZKTAMJJTWFG-UHFFFAOYSA-N 0.000 claims description 5
- RNHWYOLIEJIAMV-UHFFFAOYSA-N 1-chlorotetradecane Chemical compound CCCCCCCCCCCCCCCl RNHWYOLIEJIAMV-UHFFFAOYSA-N 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
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- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 3
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 3
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- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种含冰片和脂肪酸的衍生物及其含有该衍生物的制剂，该类衍生物是由冰片与脂肪酸经酯化反应而得到的。其结构通式如图所示。所述冰片包括异冰片，有天然的与合成的两大类，所述的脂肪酸为C5～C30的直链或支链脂肪酸或R＝C4～C29。可促进药物的吸收，作为口服、外用、注射制剂的辅料，提高药物的生物利用度，特别是提高药物的透皮吸收和提高药物穿透血脑屏障、黏膜，是一很好的脑靶向辅料。 The invention discloses a derivative containing borneol and fatty acid and a preparation containing the derivative. The derivative is obtained by esterifying borneol and fatty acid. Its structural general formula is shown in the figure. The borneol includes isoborneol, which has two types: natural and synthetic. The fatty acid is C 5 -C 30 straight chain or branched chain fatty acid or R=C 4 -C 29 . It can promote the absorption of drugs, and as an auxiliary material for oral, external, and injection preparations, it can improve the bioavailability of drugs, especially improve the transdermal absorption of drugs and improve the penetration of drugs through the blood-brain barrier and mucous membranes. It is a good brain targeting Accessories.
Description
Technical field:
The present invention relates to medical technical field, exactly is to disclose derivative (borneol fatly acid ester derivative) that a class contains borneol and lipid acid and the preparation that contains this derivative.
Background technology:
Borneol can divide natural Broneolum Syntheticum and synthetic borneol two big classes.Natural Broneolum Syntheticum is the processed goods of brain savoury herb Borneolum Syntheticum resin, because of resource scarcity, now many uses with camphor, turpentine wet goods as the synthetic product of raw material (the new medical college in Jiangsu volume. " Chinese medicine voluminous dictionary " Shanghai People's Press, 1977 951.) structure of borneol is as follows:
Borneol suffering, hardship are slightly cold.The thoughts of returning home, spleen, lung channel.Has the inducing resuscitation of having one's ideas straightened out, clearing away heat to and alleviating pain.Be used for the pyreticosis coma, convulsion is fainted, the apoplexy coma due to blocking of the respiratory system, the obstruction of the circulation of vital energy is fainted cruelly, middle evil stupor, hot eyes, aphtha, swelling and pain in the throat, duct is suppurated.Borneol has multiple pharmacological effect: 1, to the effect of central nervous system: borneol or its isomer (isocamphol), synthetic borneol 250mg/kg abdominal injection, and the mouse hot plate method can be licked the sufficient time by significant prolongation; 200mg/kg abdominal injection significant prolongation vetanarcol induced mice length of one's sleep.2, anti-inflammatory action: 5% borneol or isocamphol emulsion are coated with ear and 2% crotons are coated with the inflammatory reaction of ear mixture induced mice restraining effect is arranged, and wherein the isocamphol effect is remarkable.3, anti-microbial effect: borneol, isocamphol and synthetic borneol are to streptococcus aureus, beta hemolytic streptococcus, Streptococcus viridans, streptococcus pneumoniae and intestinal bacteria etc. all have obvious anti-microbial effect in vitro, and three's anti-microbial effect is similar, lower concentration is antibacterial, the high density sterilization.4, antifertility action: 5, with the interaction of other drug. recently, with borneol be used for the brain target, (Chen Yanming, Wang Ning give birth to influence " new Chinese medicine and clinical pharmacology " 2003,14 (2) .-96-99s of borneol to P-glycoprotein to absorption enhancer; Zhao protects and wins short Blood Brain Barrier (BBB) opening of Liu Qi moral borneol and open comparison " new Chinese medicine and clinical pharmacology " 2002,13 (5) .-287-288 of pathologic; Wang Ningsheng thanks solely, and the beam beauty treatment waits the .CT dynamic scan to observe the influence " new Chinese medicine and clinical pharmacology " of borneol to the effect of rabbit hemato encephalic barrier, 1992,3 (4): 28; Chen Tiefeng, the woods dawn, Chen Luxi, etc. borneol promotes the absorption " Acta Pharmacologica Sinica " of Tetramethylpyrazine, 1993,4 (4): 42.).
Because borneol has stronger volatility, brings difficulty to preparation process, simultaneously also can be after long storage, drug loss is serious, causes drug effect not guarantee, can consider to connect on the borneol molecule lipid groups, the preparation norbornene derivative.Reported norbornene derivative has borneol Portugal (grape) glycuronide (HUEBNER CF, LINK KP.Note on the bornyl ester of bornyl d-glucuronide.J Biol Chem.1950Sep; 186 (1): 393-4.) etc., but do not see derivative pointed among the present invention.
Summary of the invention:
The purpose of this invention is to provide a kind of borneol fatly acid ester derivative, it can reduce the volatility of borneol, and uses it in the preparation, realizes improving the Transdermal absorption of medicine and improves the purpose that medicine penetrates hemato encephalic barrier, mucous membrane.
A kind of derivative that contains borneol and lipid acid---borneol fatly acid ester derivative, its general structure is as follows:
Borneol shown here comprises iso-borneol, and natural and synthetic two big classes are arranged.Said lipid acid is C
5～C
30Straight or branched lipid acid (or R=C
4～C
29), comprise saturated or unsaturated fatty acids, as caproic acid, sad, certain herbaceous plants with big flowers is sour, lauric acid, tetradecanoic acid, palmitinic acid, stearic acid, trimethylacetic acid, (Asia) oleic acid, linolenic acid, docosahexenoic acid (DHA) etc.In order to prepare borneol fatly acid ester derivative, can be by reacting with borneol behind the preparation fat acyl chloride.In order to improve speed of response and degree, can in reaction solution, add conventional catalyzer, as pyridine, DMAP, triethylamine, salt of wormwood.Used solvent is for removing the organic solvent that anhydrates, as chloroform, methylene dichloride, benzene,toluene,xylene, ethers, ester class, acetone, alkanes, hexanaphthene, dioxane.In addition, borneol fatly acid ester derivative can also by with lipid acid and borneol mixed dissolution behind organic solvent, add the catalyzer of dewatering agent and routine, as EDCI, DCC, NHS, also can add pyridine, DMAP, triethylamine, salt of wormwood.Also can be by the preparation acid anhydrides, as valeric anhydride, at solid acid catalyst, solid super acid catalyst S
2O
8 2-/ ZRO
2Act on borneol and carry out esterification, preparation borneol derivative of fatty acid.Prepared borneol derivative of fatty acid can be used in injection, oral preparation and the external application agent, as liposome, emulsion, nanoparticle, emulsifiable paste, eye drops etc., absorbs with brain target, Transdermal absorption or the mucous membrane that improves medicine, improves bioavailability of medicament.Also can utilize the low volatility of derivative to be used for containing the preparation of borneol as the borneol substitute, as SUXIAO JIUXIN WAN, XINGNAOJING ZHUSHEYE.
Description of drawings:
Fig. 1 is the residual counting rate meter of different derivatives sample under 50 ℃ of conditions.
Fig. 2 is concentration (ug/g) table of Zorubicin in cerebral tissue.
Fig. 3 is cerebral tissue Azo-Blue concentration (ug/g) table.
Embodiment:
Below in conjunction with example the present invention is done further detailed description
Embodiment 1: borneol laurate (BL)
Get borneol 5g and add the dissolving of 50mL methylene dichloride, press equimolar amount and add lauroyl chloride, after being mixed, add the 0.5ml pyridine, reaction is 5 hours under 30 ℃ of conditions, steams and removes methylene dichloride, add entry 10ml in the gains, 30 ℃ were reacted 0.5 hour, and eliminated unreacted lauroyl chloride, add water 100ml, after being mixed, use dichloromethane extraction, totally three times, each 30ml, combined dichloromethane, go out remaining moisture with anhydrous sodium sulphate, remove methylene dichloride under reduced pressure, product.
IR (KBr compressing tablet) ν/cm
-1: characteristic peak 1735.4 (ester, C=O), 1160.3 (C-O), 1112.8 (C-O).
13C NMR (DMSO-d
6), δ: 172 (ester, C=O).ESI-MS?m/z：337.6[M]
+。Ultimate analysis (%) measured value: C 62.17, N 8.82, and H 3.22; Calculated value: C 62.19, N 8.81, and H 3.22.Prove target compound.
Embodiment 2: borneol myristinate (BM)
Get borneol 5g and add the dissolving of 50mL toluene, press equimolar amount and add myristyl chloride, after being mixed, add 0.3 gram lutidine (DMAP), back flow reaction is 3 hours under 60 ℃ of conditions, steams and removes toluene, add entry 5ml in the gains, 60 ℃ were reacted 0.5 hour, and eliminated unreacted myristyl chloride, add water 100ml, after being mixed, use ethyl acetate extraction, totally three times, each 30ml, combined ethyl acetate extraction liquid, go out remaining moisture with anhydrous sodium sulphate, remove ethyl acetate under reduced pressure, product.
IR (KBr compressing tablet) ν/cm
-1: characteristic peak 1 735.8 (ester, C=O), 1161.1 (C-O), 1113.1 (C-O).
13C NMR (DMSO-d
6), δ: 172 (ester, C=O).ESI-MS?m/z：365.6[M]
+。Ultimate analysis (%) measured value: C 62.17, N 8.82, and H 3.22; Calculated value: C 62.19, N 8.81, and H 3.22.Prove target compound.
Embodiment 3: borneol oleic acid ester (BO)
Get borneol 5g and add the dissolving of 50mL isopropyl ether, add the oleic acid acyl chlorides by 1: 1.1 molar weight, after being mixed, add the 1ml triethylamine, back flow reaction is 7 hours under 40 ℃ of conditions, steams and removes isopropyl ether, add entry 5ml in the gains, 60 ℃ were reacted 0.5 hour, and eliminated unreacted oleic acid acyl chlorides, add water 100ml, after being mixed, use dichloromethane extraction, totally three times, each 30ml, combined dichloromethane extraction liquid, go out remaining moisture with anhydrous sodium sulphate, remove methylene dichloride under reduced pressure, product.
IR (KBr compressing tablet) ν/cm
-1: characteristic peak 1735.6 (ester, C=O), 1160.6 (C-O), 1113.4 (C-O).
13C NMR (DMSO-d
6), δ: 172 (ester, C=O).ESI-MS?m/z：419.7[M]
+。Prove target compound.
Embodiment 4: borneol cetylate (BP)
Get borneol 5g and add the dissolving of 50mL dioxane, add palmitinic acid by 1: 1.5 molar weight, after being mixed, add 1 gram salt of wormwood and 0.3 gram DCC, back flow reaction is 10 hours under 40 ℃ of conditions, steams and removes dioxane, add entry 5ml in the gains, 60 ℃ were reacted 0.5 hour, and eliminated unreacted oleic acid acyl chlorides, add water 100ml, after being mixed, use chloroform extraction, totally three times, each 30ml, combined chloroform extraction liquid, go out remaining moisture with anhydrous sodium sulphate, remove chloroform under reduced pressure, product.
IR (KBr compressing tablet) ν/cm
-1: characteristic peak 1735.5 (ester, C=O), 1160.1 (C-O), 1113.2 (C-O).
13C NMR (DMSO-d
6), δ: 172 (ester, C=O).ESI-MS?m/z：393.7[M]
+。Ultimate analysis (%) measured value: C 62.17, N 8.82, and H 3.22; Calculated value: C 62.19, N 8.81, and H 3.22., prove target compound.
Embodiment 5: borneol docosahexenoic acid ester (BDHA)
Get borneol 5g, NHS, DCC add tetrahydrofuran (THF) 50mL dissolving, add docosahexenoic acid by 1: 1.5 molar weight, logical nitrogen, and after being mixed, stirring reaction 8h under the room temperature.Take out reaction mixture, remove by filter precipitation, filtrate decompression is removed and is desolvated, and adds entry 25ml in the gains, ethyl acetate extraction is used in the jolting that is mixed, and totally three times, each 30ml, the combined ethyl acetate extraction liquid is gone out remaining moisture with anhydrous sodium sulphate, removes ethyl acetate under reduced pressure, product.
IR (KBr compressing tablet) ν/cm
-1: characteristic peak 1735.0 (ester, C=O), 1160.6 (C-O), 1112.5 (C-O).
13C NMR (DMSO-d
6), δ: 172 (ester, C=O).ESI-MS?m/z：465.7[M]
+。Prove target compound.
Embodiment 6: the volatility of different derivatives
0.5 gram sample is placed 50 ℃ of thermostat containers, take out sample after 60 minutes, weigh, calculate residual rate, the results are shown in accompanying drawing 1.
Annotate: borneol caproic acid derivative (BC), borneol lauric acid derivative (BL), borneol tetradecanoic acid (BM), borneol oleic acid (BO), borneol docosahexenoic acid (BDHA)
Hence one can see that, borneol is carried out structural modification after, its volatility descends greatly, the carbon number of lipid acid was greater than 10 o'clock, the volatility of medicine can be ignored.
Embodiment 7: the preparation of Zorubicin brain targeted liposome and brain target effect
The preparation of liposome:
Prescription is formed: hydrogenated soy phosphatidyl choline (HSPC) 0.5g, and cholesterol (CH) 0.1g, live target adjuvant--borneol laurate (BL) 0.02g, citrate buffer solution (pH4.0), Zorubicin 10mg becomes 10mL altogether.
HSPC, CH, the BL of recipe quantity are added in the dispensing containers, use an amount of dissolve with ethanol under 60 ℃ of conditions, and wave most ethanol film forming, synthermal citrate buffer solution aquation, the preparation blank liposome of adding down.Blank liposome is handled through ultrasonic apparatus, by the whole grain of 0.22 μ m millipore filtration.Liposome behind the whole grain adopts the pH gradient, 60 ℃ of hatching 20min, preparation Evacet.Its mean particle size is the 186nm granularity.
Distribute in the body:
Get Kunming mouse, body weight 18～22g, divide 3 groups: the Zorubicin aqueous solution, conventional liposome group, target liposomes group, press the dosage tail intravenously administrable of 10mg/kg, in different time points sacrificed by decapitation animal, drain blood after, take out cerebral tissue, clean with normal saline flushing, filter paper blots, and weighs.Through tissue homogenate, behind the protein precipitation, adopt the concentration of fluorescence spectrophotometry Zorubicin.The results are shown in accompanying drawing 2.Show that the concentration of target liposomes group Zorubicin in brain significantly improves.Adopt other test also can obtain identical result.
Embodiment 8: the preparation of brain target emulsion and the influence to distributing in the Azo-Blue brain thereof
The preparation of emulsion:
Prescription is formed: borneol myristinate (BM) 0.5g, injection soybean oil 0.5g, soybean lecithin (SPC) 1.0g, glycerine 2.2g become 100ml altogether.
Preparation technology:
1, in dosing apparatus, the borneol myristinate (BM) of recipe quantity is dissolved in the 0.5g injection soybean oil mixes;
2, SPC and the glycerine (anhydrous) with recipe quantity mixes with proper amount of water for injection;
3, with 2) under stirring condition, add 1) in, get colostrum after in the time of 40 ℃, stirring, cross G3 funnel suction filtration, gained liquid is handled through the microjet instrument, crosses the degerming of 0.22um millipore filtration, brain targeting injection emulsion.Mean particle size 212nm.
The mensuration of Azo-Blue in the cerebral tissue:
Mouse after the tail vein injects brain target emulsion 2 hours is injected 2% Azo-Blue by 2ml/kg, puts to death animal respectively at 15,30,60 minutes, takes out cerebral tissue, through tissue homogenate, behind the protein precipitation, adopts the concentration of spectrophotometry Azo-Blue.The results are shown in accompanying drawing 3.Show that brain target emulsion can increase the concentration in the Azo-Blue brain.
Embodiment 9 promotes the Transdermal absorption of diclofenac sodium
The preparation of skin: get the rat feeding 1 day of body weight 180～220g, put to death, cut off rat back or belly wool, take off depilation place skin, after it is rinsed well, peel off fatty tissue tissue under the skin, select intact skin physiological saline wash clean, 4 ℃ of refrigerator short-terms are preserved, and are standby.
Method: get standby skin, blot surface-moisture with cotton, be coated with Borneo camphor oleic acid ester (BO) on whole rat skin surface, subsequently the mouse skin is fixed on diffusion cell and accepts between the pond, stratum corneum is towards giving coyote hole, get diclofenac sodium solution (1%) 5ml and place, accept to be full of in the pond 30% ethanol, in 32 ℃ of water-baths, carry out the Transdermal absorption test to coyote hole.Calculate percutaneous rate, the result shows that BO can greatly improve the Transdermal absorption amount of diclofenac sodium, and its percutaneous rate is by the 93.2 μ g/cm that do not use BO control group (1%AZONE)
2H brings up to 183.1 μ g/cm
2H.
Embodiment 10 replaces the borneol that contains in the SUXIAO JIUXIN WAN with borneol fatly acid ester derivative, said medicine has same effect.
Embodiment 11 replaces the borneol that contains in the XINGNAOJING ZHUSHEYE with borneol fatly acid ester derivative, XINGNAOJING ZHUSHEYE has same effect.As seen the alternative borneol of borneol fatly acid ester derivative is used for containing the preparation of borneol.
Claims (5)
1. the preparation method of borneol fatly acid ester derivative, it is characterized in that: get borneol 5g and add the dissolving of 50mL methylene dichloride, press equimolar amount and add lauroyl chloride, after being mixed, add the 0.5ml pyridine, reaction is 5 hours under 30 ℃ of conditions, steam and remove methylene dichloride, add entry 10ml in the gains, 30 ℃ were reacted 0.5 hour, eliminate unreacted lauroyl chloride, add water 100ml, after being mixed, use dichloromethane extraction, totally three times, each 30ml, combined dichloromethane is gone out remaining moisture with anhydrous sodium sulphate, remove methylene dichloride under reduced pressure, get product borneol laurate.
2. the preparation method of borneol fatly acid ester derivative, it is characterized in that: get borneol 5g and add the dissolving of 50mL toluene, press equimolar amount and add myristyl chloride, after being mixed, add 0.3 gram lutidine (DMAP), back flow reaction is 3 hours under 60 ℃ of conditions, steam and remove toluene, add entry 5ml in the gains, 60 ℃ were reacted 0.5 hour, eliminate unreacted myristyl chloride, add water 100ml, after being mixed, use ethyl acetate extraction, totally three times, each 30ml, the combined ethyl acetate extraction liquid is gone out remaining moisture with anhydrous sodium sulphate, remove ethyl acetate under reduced pressure, get product borneol myristinate.
3. the preparation method of borneol fatly acid ester derivative, it is characterized in that: get borneol 5g and add the dissolving of 50mL isopropyl ether, add the oleic acid acyl chlorides by 1: 1.1 molar weight, after being mixed, add the 1ml triethylamine, back flow reaction is 7 hours under 40 ℃ of conditions, steam and remove isopropyl ether, add entry 5ml in the gains, 60 ℃ were reacted 0.5 hour, eliminate unreacted oleic acid acyl chlorides, add water 100ml, after being mixed, use dichloromethane extraction, totally three times, each 30ml, the combined dichloromethane extraction liquid is gone out remaining moisture with anhydrous sodium sulphate, remove methylene dichloride under reduced pressure, get product borneol oleic acid ester.
4. the preparation method of borneol fatly acid ester derivative, it is characterized in that: get borneol 5g and add the dissolving of 50mL dioxane, add palmitinic acid by 1: 1.5 molar weight, after being mixed, add 1 gram salt of wormwood and 0.3 gram DCC, back flow reaction is 10 hours under 40 ℃ of conditions, steam and remove dioxane, add entry 5ml in the gains, 60 ℃ were reacted 0.5 hour, eliminate unreacted oleic acid acyl chlorides, add water 100ml, after being mixed, use chloroform extraction, totally three times, each 30ml, the combined chloroform extraction liquid is gone out remaining moisture with anhydrous sodium sulphate, remove chloroform under reduced pressure, get product borneol cetylate.
5. the preparation method of borneol fatly acid ester derivative, it is characterized in that: get borneol 5g, NHS, DCC add tetrahydrofuran (THF) 50mL dissolving, add docosahexenoic acid by 1: 1.5 molar weight, logical nitrogen, after being mixed, stirring reaction 8h under the room temperature, take out reaction mixture, remove by filter precipitation, filtrate decompression is removed and is desolvated, and adds entry 25ml in the gains, jolting is mixed, use ethyl acetate extraction, totally three times, each 30ml, the combined ethyl acetate extraction liquid, go out remaining moisture with anhydrous sodium sulphate, remove ethyl acetate under reduced pressure, product borneol docosahexenoic acid ester.
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