CN107198683B - A kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition and its preparation method and application - Google Patents
A kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition and its preparation method and application Download PDFInfo
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- CN107198683B CN107198683B CN201710453014.2A CN201710453014A CN107198683B CN 107198683 B CN107198683 B CN 107198683B CN 201710453014 A CN201710453014 A CN 201710453014A CN 107198683 B CN107198683 B CN 107198683B
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Abstract
A kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition and its preparation method and application, described pharmaceutical composition is made of farnesylacetic acid spiceleaf alcohol ester active constituent and pharmaceutically acceptable carrier, and the farnesylacetic acid spiceleaf alcohol ester active constituent is no more than 2% (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester containing (4E/8E)-farnesylacetic acid spiceleaf alcohol ester and by active constituent total weight；Described pharmaceutical composition has the advantages that toxicity is low, peptic ulcer protective effect is strong, relative bioavailability is high.
Description
Technical field
The present invention relates to a kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical compositions and its preparation method and application.
Background technique
Farnesylacetic acid spiceleaf alcohol ester, that is, gefarnate, trade name favour are reinforced, and shake flourish feeding drug strain formula meeting for Osaka, Japan is raw
The isoprene class compound gastric mucosa protective agent of society's production, is mainly used for acute or chronic gastritis, peptic ulcer, non-ulcerative
Acute gastric mucosal injury caused by dyspeptic treatment and prevention other factors.Its pharmacological action is by before increase endogenous
Mucosa for Protective Effect is played in the generation of column parathyrine.Promote to burst in addition, aminohexose content can be improved in farnesylacetic acid spiceleaf alcohol ester
Ulcer healing；Inhibit neutrophil leucocyte and monocyte infiltration and relevant inflammatory factors release, to mitigate gastric mucosa tissue
The inflammatory reactions such as hyperemia, oedema, erosion.Other than the application in terms of gastric mucosa, there are also pertinent literatures to report method both at home and abroad
Guanidine-acetic acid spiceleaf alcohol ester is in colitis, the application of dry eye treatment.
Farnesylacetic acid spiceleaf alcohol ester is initially isolated by cabbage, and later adami et al. is obtained by synthetic method,
Structural formula is as indicated with 1.Commercially available farnesylacetic acid spiceleaf alcohol ester is the mixture of two kinds of geometric isomers, is (4E/8E)-method respectively
Guanidine-acetic acid spiceleaf alcohol ester [14 trienic acid of (4E, 8E) -5,9,13- trimethyl -4,8,12--(2 ' E) -3 ', 7 '-dimethyl -
2 ', 6 '-octadiene alcohol esters] and (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester [(4Z, 8E) -5,9,13- trimethyl -4,8,12- ten
- 3 ', 7 '-dimethyl -2 ' of four trienic acids-(2 ' E), 6 '-octadiene alcohol esters], the composition ratio Japanese Pharmacopoeia requirement of the two is
70%~80% to 20%~30%, gas chromatography analysis after marketed tablet is extracted, the two proportion is divided as the result is shown
It Wei 70% and 30%.
There are still more as toxicity is higher, Relative biological utilizes in terms for the treatment of disease of digestive system for existing gefarnate drug
Spend low problem.
Summary of the invention
The purpose of the present invention is high, the peptic ulcer protective effects for toxicity existing for gefarnate drug in the prior art
Problem weak, relative bioavailability is low provides the new farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of one kind, its preparation side
Method, purposes and dosage form, to provide the method that a kind of toxicity is low, peptic ulcer protective effect is strong, relative bioavailability is high
Guanidine-acetic acid spiceleaf alcohol ester pharmaceutical composition.
To achieve the goals above, the present invention the following technical schemes are provided:
The present invention provides a kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition, which is characterized in that described pharmaceutical composition
It is made of farnesylacetic acid spiceleaf alcohol ester active constituent and pharmaceutically acceptable carrier, and the farnesylacetic acid geraniol
Ester active constituent is no more than 2% (4Z/8E)-containing (4E/8E)-farnesylacetic acid spiceleaf alcohol ester and by active constituent total weight
Farnesylacetic acid spiceleaf alcohol ester；Preferably, the content of described (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester is 0.1~1%.
(4E/8E)-farnesylacetic acid spiceleaf alcohol ester of the present invention, chemistry entitled [(4E, 8E) -5,9,13- front threes
Base -4,8, -3 ', 7 '-dimethyl -2 ' of 14 trienic acid of 12--(2 ' E), 6 '-octadiene alcohol esters], such as 2 institute of chemical structural formula
Show:
(4Z/8E)-farnesylacetic acid spiceleaf alcohol ester of the present invention, chemistry entitled [(4Z, 8E) -5,9,13- front threes
Base -4,8, -3 ', 7 '-dimethyl -2 ' of 14 trienic acid of 12--(2 ' E), 6 '-octadiene alcohol esters], such as 3 institute of chemical structural formula
Show:
Optionally, above-mentioned pharmaceutical composition, which is characterized in that the farnesylacetic acid spiceleaf alcohol ester active constituent and medicine
The weight percent of acceptable carrier is 1:19~3:7, preferably 1:10~1:4 on.
Optionally, above-mentioned pharmaceutical composition, which is characterized in that the pharmaceutically acceptable carrier include diluent,
One of excipient, adhesive, filler, disintegrating agent, flavouring agent, sweetener or more than one.
Optionally, above-mentioned pharmaceutical composition, which is characterized in that described pharmaceutical composition include starch, microcrystalline cellulose,
One of magnesium stearate, Almasilate, calcium monohydrogen phosphate, vegetable oil, beeswax, gelatin polyethylene glycol, glycerol or more than one.
Optionally, the dosage form of above-mentioned pharmaceutical composition includes granula, pulvis, tablet, capsule, syrup, suppository, injection
Agent, emulsion, tincture, suspension, solution form oral or non-oral administration dosage form.
Preferably, the dosage form includes tablet, capsule, dripping pill.
The present invention also provides the methods for preparing above-mentioned pharmaceutical composition, which is characterized in that including farnesylacetic acid is fragrant
The step of leaf-alcohol ester active constituent is mixed with pharmaceutically acceptable carrier, the wherein preparation process of farnesylacetic acid spiceleaf alcohol ester
It is middle to use L-Aspartic acid as catalyst.
Optionally, above-mentioned method, which comprises the following steps:
(1) using trans- nerolidol and ortho-acetate as raw material, L-Aspartic acid is catalyst, is reset through Claisen anti-
It should obtain farnesylacetic acid ester；
(2) farnesylacetic acid ester hydrolysis, crystallization, acidification are obtained into farnesylacetic acid；
(3) farnesylacetic acid and geraniol are condensed to yield farnesylacetic acid spiceleaf alcohol ester active constituent；
(4) farnesylacetic acid spiceleaf alcohol ester active constituent and pharmaceutically acceptable carrier are mixed to prepare the medicine group
Close object.
Optionally, above-mentioned method, which comprises the following steps:
(1) using trans- nerolidol and ortho-acetate as raw material, L-Aspartic acid is catalyst, at 90~150 DEG C into
Row reaction, is cooled to 60~90 DEG C of vacuum distillations, is warming up to 90~130 DEG C of vacuum distillations, obtains farnesylacetic acid ester；
(2) farnesylacetic acid ester is mixed with alkali and hydrolysis occurs, reaction solution is extracted with organic solvent (preferably petroleum ether)
It takes, adjusts reaction solution pH to 3~4, organic solvent extraction merges organic phase, adds alkali, be concentrated, organic solvent (preferably acetic acid second is added
Ester), filtering, filter cake adds water and adjusts pH to 3~4, and organic solvent (preferably petroleum ether) extraction merges organic phase, saturated salt solution
Washing, dry farnesylacetic acid；
(3) by farnesylacetic acid, geraniol, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC-
HCl), reaction solution is used water, saturated common salt water washing by 4-dimethylaminopyridine (DMAP) hybrid reaction respectively, dry, crosses silicon
Glue is concentrated, vacuum distillation, crosses silica gel, dry, and the farnesylacetic acid spiceleaf alcohol ester active constituent is made；
(4) farnesylacetic acid spiceleaf alcohol ester active constituent and pharmaceutically acceptable carrier are mixed to prepare the medicine group
Close object.
Optionally, the synthetic route of above-mentioned preparation method is as shown in Figure 8:
The present invention also provides above-mentioned pharmaceutical compositions to treat or prevent the purposes in disease of digestive system drug in preparation.
The present invention also provides above-mentioned pharmaceutical compositions to treat or prevent the purposes in disease of digestive system.
Optionally, the disease of digestive system includes acute and chronic gastritis mucosa injury；Optionally, the disease of digestive system packet
Include acute or chronic gastritis, peptic ulcer, non-ulcer dyspepsia.
The application method of pharmaceutical composition of the present invention is not particularly limited, such as can be applied by oral way
For needing the patient of this treatment.
Pharmaceutically acceptable carrier of the present invention refers to the carrier of pharmaceutical field routine, including various excipient and dilute
Release agent.The term refers to medicament carriers some in this way: themselves be not necessary active constituent, and do not have after applying it is excessive
Toxicity.Suitable carrier is well known to those of ordinary skill in the art.In Remington's Pharmaceutical
Discussing fully about pharmaceutically acceptable excipient can be found in Sciences (Mack Pub.Co., N.J.1991).?
The upper acceptable carrier of combination of traditional Chinese medicine may include liquid, such as water, salt water, glycerol and ethyl alcohol.In addition, may be used also in these carriers
With there are complementary substances, such as: adhesive such as starch, sucrose, cellulose derivative, gelatin, polyethylene glycol, gathers dextrin
Vinylpyrrolidone etc.；Filler for example lactose, microcrystalline cellulose, calcium dihydrogen phosphate, calcium monohydrogen phosphate, calcium sulfate, calcium silicates carbonic acid
Magnesium, Almasilate, Hydrotalcite, superfine silica gel powder etc.；Disintegrating agent for example sodium carboxymethyl starch, crospovidone, carboxymethyl cellulose,
Calcium carbonate, sodium bicarbonate etc.；Furthermore it is also possible to be added in the composition other adjuvants for example flavouring agent, sweetener, wetting agent,
Emulsifier, pH buffer substance etc..
Beneficial effects of the present invention:
The specific farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the present invention, farnesylacetic acid is fragrant in described pharmaceutical composition
It is no more than 2% by weight of active ingredient (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester in leaf-alcohol ester active constituent, there is toxicity
Advantage low, peptic ulcer protective effect is strong, relative bioavailability is high.
When the content of (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester is 0.1%~1.0%, with (4Z/8E)-farnesyl- second
Compared when sour leaf-alcohol ester content is less than 0.1%, the toxicity of described pharmaceutical composition is lower, peptic ulcer protective effect more
By force, relative bioavailability is higher, has unexpected technical effect.
Detailed description of the invention
Fig. 1 is the protective effect photo that farnesylacetic acid spiceleaf alcohol ester causes rat acute mucosal lesion to dehydrated alcohol,
Wherein: A is normal group；B is model group；C is (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester treatment group；D is gefarnate treatment group；
E is farnesylacetic acid spiceleaf alcohol ester medicine composite for curing group of the present invention；F is Lansoprazole control group.
Fig. 2 is that farnesylacetic acid spiceleaf alcohol ester causes rat acute mucosal lesion ulcer area than statistics column dehydrated alcohol
Shape figure, in which: Model is model group；4Z is (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester treatment group；Gefarnate is lucky method
Ester treatment group, 4E are farnesylacetic acid spiceleaf alcohol ester medicine composite for curing group of the invention；Lansoprazole is Lan Suola
Azoles randomized controlled treatment group, * indicate p < 0.05 compared with model group.
Fig. 3 is that farnesylacetic acid spiceleaf alcohol ester causes rat acute mucosal lesion ulcer inhibition rate statistics column to dehydrated alcohol
Shape figure, in which: 4Z is (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester treatment group；Gefarnate is gefarnate treatment group, and 4E is this
The farnesylacetic acid spiceleaf alcohol ester medicine composite for curing group of invention；Lansoprazole is Lansoprazole randomized controlled treatment group.* table
Show compared with model group, p < 0.05.
Fig. 4 is that rat stomach tissue pathologies change schemes under light microscopic, in which: A is normal group；B is model group；C is (4Z/
8E)-farnesylacetic acid spiceleaf alcohol ester treatment group；D is gefarnate treatment group；E is farnesylacetic acid spiceleaf alcohol ester medicine of the invention
Compositions treatment group；F is Lansoprazole randomized controlled treatment group.
Fig. 5 is cylindricality of the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition to rat gastric ulcer inhibiting rate of different purity
Figure, in which: ordinate is inhibiting rate, and abscissa is the farnesylacetic acid of different content (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester
Spiceleaf alcohol ester pharmaceutical composition.
Fig. 6 is influence cylindricality of the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of different purity to rat gastric ulcer area
Figure, in which: ordinate is gastric ulcer area ratio, and abscissa is the method for different content (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester
Guanidine-acetic acid spiceleaf alcohol ester pharmaceutical composition.
Fig. 7 is drug concentration versus time curve after farnesylacetic acid spiceleaf alcohol ester gastric infusion, in which: 4E is this
The farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition group of invention；Gefarnate is gefarnate group；4Z is (4Z/8E)-farnesyl- second
Sour leaf-alcohol ester treatment group.
Fig. 8 is the synthetic route chart of (4E/8E)-farnesylacetic acid spiceleaf alcohol ester, wherein aspartic acid is L- days
Aspartic acid.
Specific embodiment
Detailed description of the preferred embodiments below.It should be understood that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
(1) preparation of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
Farnesylacetic acid spiceleaf alcohol ester in following embodiments in farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition obtained
The content of active constituent detects to obtain by gas chromatography；Geometric configuration is normal by the coupling of gas chromatography and nuclear magnetic resonance
Numerical value is determined.
Embodiment 1
1) synthesis of farnesylacetic acid ethyl ester
Trans- nerolidol 500g (2.25mol), triethly orthoacetate 546g are sequentially added in 2L round-bottomed flask
(3.37mol), L-Aspartic acid 30g (0.22mol), is heated to 120 DEG C and is reacted.TLC (petroleum ether: ethyl acetate=30:
1) reaction process is monitored, until stopping when trans- nerolidol fully reacting.Reaction temperature is set to be down to 80 DEG C, decompression steams in reaction
The coproduct ethanol of generation；Then heat to 120 DEG C, decompression steam unreacted triethly orthoacetate, obtain farnesylacetic acid
Ethyl ester 520g, yield 80%.
2) preparation of farnesylacetic acid
Addition method ethyl 480g (1.6 0mol), sodium hydroxide 70.4g in 5000ml round-bottomed flask
(1.76mol), water 480ml, ethyl alcohol 960ml, are stirred overnight at room temperature, and obtain yellow clear liquid.Stop reaction, with 800ml stone
Oily ether extracts reaction solution 3 times.Then reaction solution concentrated hydrochloric acid tune pH to 3~4 uses 320ml petroleum ether extraction, is extracted twice, close
And petroleum ether layer is washed 3 times, anhydrous sodium sulfate is dry, is evaporated to obtain 404.8g yellow, clear grease, yield 96.1%.
Grease farnesylacetic acid 396g (1.5mol), potassium hydroxide obtained are added in 3000ml round-bottomed flask
82.5g (1.5mol), methanol 1000ml are stirred at room temperature 1h and obtain yellow clear liquid, stop stirring, reaction solution is concentrated into
It is dry, 2000mL ethyl acetate is added, stirs 2h, white solid is precipitated, filters, filter cake 1000mL water dissolves, and uses concentrated hydrochloric acid
PH to 3~4 is adjusted, 1000ml petroleum ether extraction is then used, is extracted twice, merges petroleum ether layer, is washed 1 time with saturated common salt, nothing
Aqueous sodium persulfate is dry, be evaporated 249g is faint yellow, clear grease, i.e. farnesylacetic acid, yield 63%.
3) preparation of farnesylacetic acid spiceleaf alcohol ester active constituent
Farnesylacetic acid 185g (0.7mol) obtained above, geraniol 107g are added in 5000ml round-bottomed flask
(0.71mol), 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl) 151g (0.83mol), DMAP
Reaction is stirred at room temperature in 12.2g (0.1mol) methylene chloride 2000ml, and raw material fully reacting when TLC monitors about 6h stops reaction,
Reaction solution washed once with water, saturated salt solution respectively, dry, cross silica gel, be concentrated to give light yellow, clarification, transparent oily liquid；
The grease removes impurity through vacuum distillation, crosses silica gel again and removes impurity at origin, is evaporated colourless, clarification, transparent, oily
Object farnesylacetic acid spiceleaf alcohol ester active constituent 229g, yield 82%, ((the 4Z/8E)-farnesylacetic acid geraniol of purity 99.5%
Ester content is 0.3%) [gas chromatography: GC-14B gas chromatograph (Japanese Shimadzu), SE-54 column (0.53mm × 30m), column
Temperature: 80 DEG C (5min) 30 DEG C/min-160 DEG C (3min) 30 DEG C/min-260 DEG C 250 DEG C of (20min) injection ports, detector 260
DEG C, nitrogen flow rate 20ml/min].
4) preparation of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
(1) farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition 1
Composition are as follows:
For preparing 1000 farnesylacetic acid spiceleaf alcohol ester medicinal composition tablets, specific preparation method is: will locate
The above-mentioned farnesylacetic acid spiceleaf alcohol ester active constituent just measured is dissolved in dehydrated alcohol, and calcium monohydrogen phosphate is pressed after mixing with Almasilate
Farnesylacetic acid spiceleaf alcohol ester ethanol solution is added according to equal increments method, after mixing well, starch is added to stir evenly, forms sediment with 15%
Softwood is made in slurry, and recipe quantity microcrystalline cellulose, magnesium stearate, talcum powder, pressure are added into particle for granulation, drying, whole grain
Piece is coated with 8% Opadry ethanol solution.
(2) farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition 2
Composition are as follows:
For preparing 1000 farnesylacetic acid spiceleaf alcohol ester medicinal composition soft capsules, specific preparation method is: claiming
The above-mentioned farnesylacetic acid spiceleaf alcohol ester active constituent of recipe quantity is taken to be dissolved in the soybean oil of equivalent, stirring mixes well it,
The soybean oil that remaining recipe quantity is added is uniformly mixed, and three times by colloid mill grinding, vacuum outgas bubble 2 hours spare.Weigh place
The gelatin just measured sufficiently is swollen with the water of recipe quantity 80%.By glycerol and the water of surplus, 70 DEG C are heated to, gelatin solution is added,
Titanium dioxide is added, stirs evenly to melting uniformly within stirring 1.5 hours.Made glue is put into incubator, and temperature is maintained at 80
Film is suppressed between~90 DEG C.Film and content medical fluid are pressed into soft capsule by rotating capsule machine processed automatically, shapes, is whole
Shape, shampooing ball, drying, packaging.
Embodiment 2
1) synthesis of farnesylacetic acid methyl esters
Trans- nerolidol 400g (1.80mol), trimethyl orthoacetate 324g are sequentially added in 2L round-bottomed flask
(2.70mol), L-Aspartic acid 24g (0.18mol), is heated to 100 DEG C and is reacted.TLC (petroleum ether: ethyl acetate=30:
1) reaction process is monitored, until stopping when trans- nerolidol fully reacting.Reaction temperature is set to be down to 70 DEG C, decompression steams in reaction
The coproduct ethanol of generation；Then heat to 100 DEG C, decompression steam unreacted triethly orthoacetate, obtain farnesylacetic acid
Methyl esters 425g, yield 85%.
2) preparation of farnesylacetic acid
Addition method acetic acid methyl ester 50g (0.18mol), sodium hydroxide 7.9g in 250ml round-bottomed flask
(0.20mol), water 50ml, ethyl alcohol 100ml, are stirred overnight at room temperature, and obtain orange clear liquid.Stop reaction, with 100ml petroleum
Ether extracts reaction solution 3 times.Then reaction solution concentrated hydrochloric acid tune pH to 3~4 uses 100ml petroleum ether extraction, is extracted twice, merge
Petroleum ether layer is washed 3 times, and anhydrous sodium sulfate is dry, is evaporated to obtain 45.2g yellow, clear grease, i.e. farnesylacetic acid, is received
Rate 95.2%.
Farnesylacetic acid 26g (0.10mol), potassium hydroxide 5.5g obtained are added in 250ml round-bottomed flask
(0.1mol), methanol 80ml is stirred at room temperature 1h and obtains yellow clear liquid, stop stirring, reaction solution is concentrated to dryness, is added
150mL ethyl acetate stirs 2h, and white solid is precipitated, and filters, and filter cake 80mL water dissolves, and with concentrated hydrochloric acid tune pH to 3~4,
Then 80ml petroleum ether extraction to be used, is extracted twice, petroleum ether layer is merged, is washed 1 time with saturated common salt, anhydrous sodium sulfate is dry,
Be evaporated 15.6g is faint yellow, clear grease, i.e. farnesylacetic acid, yield 60%.
3) preparation of farnesylacetic acid spiceleaf alcohol ester active constituent
Farnesylacetic acid 12.3g (0.05mol) obtained above, geraniol 7.1g are added in 250ml round-bottomed flask
(0.047mol), 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl) 10.1g (0.055mol),
DMAP 1.22g (0.01mol) methylene chloride 100ml, is stirred at room temperature reaction, and raw material fully reacting when TLC monitors about 5h stops
Reaction, reaction solution washed once with water, saturated salt solution respectively, dry, cross silica gel, be concentrated to give light yellow, clarification, clear oil
Liquid；The grease removes impurity through vacuum distillation, crosses silica gel again and removes impurity at origin, is evaporated colourless, clarifies, thoroughly
Bright, grease farnesylacetic acid spiceleaf alcohol ester active constituent 16.6g, yield 83%, ((the 4Z/8E)-farnesyl- second of purity 99.4%
0.5%) sour leaf-alcohol ester content is that gas-chromatography detection method is the same as embodiment 1.
4) preparation of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
Composition are as follows:
(a) farnesylacetic acid spiceleaf alcohol ester active constituent 5mg/ ball
(b) Macrogol 6000 45mg/ ball
For preparing 1000 farnesylacetic acid spiceleaf alcohol ester medicament composition dropping pills, specific preparation method is: will locate
Side's amount Macrogol 6000 is set in aluminum pot, and in being heated to 90 DEG C~100 DEG C in oil bath, after all meltings, recipe quantity is added
Above-mentioned farnesylacetic acid spiceleaf alcohol ester active constituent stirs, and is transferred in reservoir, it is closed and keep the temperature 80 DEG C~
90 DEG C, dropping liquid quantitative valve is adjusted, from top to bottom, instills in 10 DEG C~15 DEG C of methyl-silicone oil, takes out dripping pill, exhaust dripping pill table
Face coolant, it is dry to get.
Farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition in following (two), (three), (five) is prepared by embodiment 1
Farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition 1, wherein the purity of farnesylacetic acid spiceleaf alcohol ester active constituent be 99.5%.
Following (4Z/8E)-farnesylacetic acid spiceleaf alcohol esters: (Zhou Xunrong waits geometric isomer in gefarnate to bibliography
Research, chemical reagent, 2012,34 (3): 266-268) method preparation, purity 99.8%.
Following gefarnates: bibliography (Zhou Xunrong, waits the research of geometric isomer in gefarnate, chemical reagent, and 2012,
34 (3): 266-268) method extract from commercially available tablet (gastric infusion is needed by extracting raw material and removing the auxiliary material of tablet, with
Just dosage is calculated).
Following Lansoprazoles are marketable material medicine.
(2) toxicity test of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
It is fragrant to farnesylacetic acid of the invention respectively by document " pharmacological experimental methodology " (Wei Wei chief editor) recommended method
Leaf-alcohol ester pharmaceutical composition, gefarnate detect acute toxicity, test result by way of oral, intraperitoneal injection, intravenous injection
Show that farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition LD of the invention is administered in Oral Administration in Rats50For 12555mg/kg, (4Z/8E)-
The LD of farnesylacetic acid spiceleaf alcohol ester50For 3826mg/Kg, the LD of gefarnate50For 8455mg/Kg；Rats by intraperitoneal injection administration is originally
The farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition LD of invention50For 7426mg/kg, (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester
LD50For 2522mg/Kg, the LD of gefarnate50For 4688mg/Kg；Farnesylacetic acid spiceleaf of the invention is administered in rat intravenous injection
Alcohol ester pharmaceutical composition LD50For 3894mg/kg, the LD of (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester50For 1498mg/Kg, Ji Fa
The LD of ester50For 2855mg/Kg.Experimental result prompts the toxicity of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention to be lower than
(4Z/8E)-farnesylacetic acid spiceleaf alcohol ester and the two 7:3 scalemic thereof gefarnate.
(3) the peptic ulcer protective effect test of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
(main component is that (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester and (4E/8E)-farnesylacetic acid are fragrant to commercially available gefarnate
Leaf-alcohol ester is mixed in 3:7 ratio) it is used as gastric mucosa protective agent, it can promote ulcer healing, enhance gastric mucosal barrier, expand stomach
Mucous membrane microcirculation improves blood distribution.Pass through document (Hajrezaie M, Salehen N, Karimian H, et
al.Biochanin A Gastroprotective Effects in Ethanol-Induced Gastric Mucosal
Ulceration in Rats.PLoS One, 2015,10 (3): e0121529.) recommend method, induced using dehydrated alcohol
Rat establishes acute gastric ulcer model, oral administration gavage farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention, (4Z/8E)-
Farnesylacetic acid spiceleaf alcohol ester, gefarnate, Lansoprazole are calculated ulcer index and ulcer inhibition rate by software, are contaminated using HE
Color observes gastric tissue morphology, can reflect that drug causes the protective effect of gastric mucosa of rat to dehydrated alcohol.
1 experimental method
1.1 experimental groups and dose design
SD rat is divided into Normal group, model group, positive controls (Lansoprazole 20mg/kg), administration group ((4E/
8E)-farnesylacetic acid spiceleaf alcohol ester 200mg/kg, (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester 200mg/kg, gefarnate
200mg/kg), totally 5 groups, every group animal 8.
1.2 dehydrated alcohols cause rat acute gastric ulcer
SD rat 40 are taken, 180~220g of weight.Daily gastric infusion 1 time, continuous 7 days.Before modeling for 24 hours, rat needs to prohibit
Food can't help water, and after 1h after the last administration, every rat oral gavage dehydrated alcohol 1mL causes acute gastric mucosal lesion.Stomach-filling is anhydrous
10% chloral hydrate anesthesia after ethyl alcohol 1h is taken a blood sample 5mL by abdominal aorta using vacuum venous blood-sampling pipe, stands 4000r/ after 2h
Min be centrifuged 10min, separate serum, be placed in -80 DEG C of refrigerators save it is to be measured.
The measuring and calculating of 1.3 stomach lining ulcer areas and ulcer inhibition rate
It is put to death after rat extracting blood, takes out mouse stomach rapidly, cut off along greater curvature, cleaned in stomach and remained with the physiological saline of pre-cooling
Object is unfolded and gastric tissue is fixed between two pieces of glass plates for taking pictures.Ulcer surface is calculated with Image J image analysis software
Product, and calculate inhibiting rate.Inhibiting rate (%)=(control group ulcer area-administration group ulcer area)/control group ulcer index
X100%.
1.4 rat stomach histopathology histological observations
HE (Haematoxylin andeosin) dyeing is under the action of different dye liquors, by the different material in slice
It dyes different colours and shows, then the various structures in tissue are observed by optical microscopy, it is dye the most conventional
Color can contribute to make diagnosis to gastric ulcer degree.Histopathology operation includes that materials are fixed, dehydration is saturating in gastric tissue
Bright, waxdip embedding, slice dye with patch, dewaxing, HE dyeing, are dehydrated the several steps of transparent and sealing.
1.5 data inputtings and processing are analyzed
As a result it is indicated with mean ± standard error (Mean ± S.E.M.), and is analyzed using 17.0 statistical software of SPSS,
Not comparison in difference one-way analysis of variance (One-way ANOVA) (not assuming that homogeneity of variance Dunnett's T3) between each group.P<
0.05 indicates that difference has statistical significance.
2 experimental results
2.1 farnesylacetic acid spiceleaf alcohol ester pharmaceutical compositions cause the protection of rat acute mucosal lesion to make dehydrated alcohol
With
Dehydrated alcohol causes gastric mucosa damage observation as the result is shown (Fig. 1), and normal group stomach lining finishing is intact, in dark red
Color, mucus is more, no hyperemia, the anomalous variations such as oedema, ulcer and cicatricial tissue hyperplasia.Model group and (4Z/8E)-farnesyl- second
Sour leaf-alcohol ester treatment group gastric mucosa has extensive injuries, and oedema, hyperemia, erosion are in kermesinus, and see and be largely dispersed in bleeding
And bleeding band.Remaining each group blutpunkte and bleeding item have different degrees of reduction, wherein gefarnate and method of the invention
Guanidine-acetic acid spiceleaf alcohol ester medicine composite for curing group compares, the former rotten to the corn situation is more serious, and bleeding band is more；Method of the invention
Guanidine-acetic acid spiceleaf alcohol ester medicine composite for curing group and Lansoprazole control group stomach lining are in kermesinus, for a sheet bleeding,
Most of stomach lining has no inflammatory reaction and damage.
The experimental results showed that farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention is to acute caused by dehydrated alcohol
The protective effect of mucosal lesion be better than (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester and gefarnate, and with positive control drug orchid rope
Draw azoles suitable.
Influence of the 2.2 farnesylacetic acid spiceleaf alcohol ester pharmaceutical compositions to rat gastric ulcer area and ulcer inhibition rate
The ulcer area of experimental rat/itself stomach area result is as shown in Fig. 2, wherein gastric ulcer area damages in model group
Maximum illustrates that dehydrated alcohol causes the success of rat gastric ulcer model.The experimental results showed that farnesylacetic acid spiceleaf alcohol ester of the invention
Pharmaceutical composition and control group Lansoprazole can obviously inhibit dehydrated alcohol ulcerative lesions caused by gastric mucosa tissue, drop
Low ulcer area improves pathomorphism and inflammatory reaction.Gefarnate group inhibits ulcerative lesions effect not obvious enough, and (4Z/
8E)-farnesylacetic acid spiceleaf alcohol ester confrontation dehydrated alcohol causes mucosal lesion substantially to no effect.
Experimental rat ulcer inhibition rate is shown in Fig. 3.The experimental results showed that farnesylacetic acid spiceleaf alcohol ester medicine group of the invention
Object ulcer inhibition rate is closed up to 78.20%, and (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester ulcer inhibition rate is then 35.56%,
Gefarnate ulcer inhibition rate is 37.60%, and farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition ulcer inhibition rate of the invention is obvious,
It is not much different with control group Lansoprazole (ulcer inhibition rate 81.10%).
Rat stomach tissue pathologies change under 2.3 light microscopics
Liver histopathological analysis such as Fig. 4 shows that rat normal gastric mucosa structural integrity, mucous membrane surface foveolae gastricae clearly may be used
See, the close rule of body of gland arrangement in mucous membrane, epithelium, which has no, to fall off, and body of gland has no damage, and lamina propria has no bleeding and inflammatory cell leaching
Profit (0 degree of damage)；Model group and (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester treatment group mucosal lesion are deeper, and area is larger,
Foveolae gastricae structure is destroyed, and oedema and inflammatory infiltration occurs, and a large amount of epithelial cell denaturation fall off, is rotten to the corn, gland structure disorder has
Missing, lamina propria is shown in moderate bleeding (damage of IV degree)；Gefarnate processing group stomach lining is kept than more complete, body of gland degree of injury
Smaller (damage of III degree)；Farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition processing group of the invention to above-mentioned pathology damage have compared with
Be obviously improved effect, stomach lining gastric mucosa minor injury, epithelium, which has no, to fall off, and body of gland has no damage, the rare bleeding of lamina propria and
Cell infiltration (damage of I degree damage-II degree)；Positive group stomach lining minor injury, epithelium, which has no, to fall off, and body of gland has no damage,
Lamina propria has no bleeding and cell infiltration (damage of I degree damage-II degree).
(4) the peptic ulcer protective effect research of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
Pass through document (Hajrezaie M, Salehen N, Karimian H, et al.Biochanin A
Gastroprotective Effects in Ethanol-Induced Gastric Mucosal Ulceration in
Rats.PLoS One, 2015,10 (3): e0121529.) recommend method acute stomach is established using dehydrated alcohol induced rat
Ulcer Models, oral administration gavage farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition calculate ulcer index by software and ulcer inhibit
Rate.
1.1 prepare for reagent product
By embodiment 1 and bibliography (Zhou Xunrong, waits the research of geometric isomer in gefarnate, chemical reagent, 2012,
34 (3): 266-268) farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition, (4E/8E)-farnesylacetic acid spiceleaf prepared by method
Alcohol ester and (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester, being mixed with (4Z/8E)-farnesylacetic acid geraniol ester content is
0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 5%, 10% farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition test sample.
1.2 experiments and detection method are the same as described in (three).
1.3 experimental result
1.3.1 influence result of (the 4Z/8E)-farnesylacetic acid spiceleaf alcohol ester of different purity to rat gastric ulcer inhibiting rate
See Fig. 5.
1.3.2 influence result of (the 4Z/8E)-farnesylacetic acid spiceleaf alcohol ester of different purity to rat gastric ulcer area is shown in
Fig. 6.
From Fig. 5 and Fig. 6: when (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester concentration be less than or equal to 2% and be greater than etc.
When 0.1%, farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention, ulcer inhibition rate is obvious, can obviously inhibit nothing
Water-ethanol ulcerative lesions caused by gastric mucosa tissue reduce ulcer area, improve pathomorphism and inflammatory reaction, have compared with
Consistent unexpected technical effect；But when the concentration of (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester is greater than 2% or small
When 0.1%, farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition is substantially reduced gastric ulcer inhibiting rate, to inhibition dehydrated alcohol pair
Damage aspect effect caused by mucosa tissue is poor.
(5) farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition characteristics of pharmacokinetics is investigated
Farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention, gefarnate, (4Z/8E)-farnesylacetic acid geraniol
There are notable differences for protective effect of the ester to dehydrated alcohol cause gastric mucosa of rat.The present invention establishes superelevation liquid-high resolution mass spectrum connection
With technique study three by the difference after entering in rat body after gastric infusion, the characteristics of pharmacokinetics of three is investigated.
Instrument: Waters Acquity H UPLC, Waters Xevo G2-XS QTof
Chromatographic condition: chromatographic column (Waters BEH C18(2.1mm × 50mm, 1.7 μm of m) columns, 40 DEG C of column temperature)；Mobile phase
(0.1% formic acid water-methanol-acetonitrile (1:54:45) isocratic elution, flow velocity 0.3mLmin-1)；2 μ L of sample volume；Sample injection time
6min。
Mass Spectrometry Conditions: electrospray ionisation source (ESI)；Holotype acquires (Negative mode)；Capillary voltage 2kV, from
120 DEG C of component, 400 DEG C of desolvation temperature, desolventizing gas flow 800Lh-1, taper hole throughput 50Lh-1；Mass spectrometric data
Acquisition and processing software MassLynx V4.1 work station, scanning mode MS mode.
It is linear: standard sample being taken to be configured to the series standard liquid of 20,40,80,200,400,1000,2000ngmL.It takes
100 μ L of blank plasma, is placed in 2mL Ep pipe, sequentially adds 100 μ L of above-mentioned standard liquid, and 400 μ L methanol are added and add 800 μ L
Ethyl acetate, vortex mixed 15min, 10000rmin-1It is centrifuged 10min, upper organic layer is drawn, is dried with nitrogen, residue is added
The dissolution of 100 μ L methanol, 13000rmin-1It is centrifuged the measurement of 10min sample introduction.With mass concentration (c) for abscissa, sample peak area
(y) linear regression is carried out with weighted least-squares method for ordinate, weight coefficient 1/c draws standard curve, obtains (4E/8E)-
Farnesylacetic acid spiceleaf alcohol ester calibration curve equation is Y=256.5086C-11.0039 (r2=0.998 9), Gefarnate mark
Directrix curve equation is Y=224.C-10.0189 (r2=0.997 8), (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester standard curve
Equation is Y=188.4582C-6.8258 (r2=0.998 1) the result shows that, the range of linearity for detecting mass concentration is 20~
2000ngmL, quantitative limit are 20ngmL.
Sample measurement: taking 18 half male and half females of rat, and weight 200-230g is divided into three groups every group 6, fasting before testing
12h, normal water.Rat claims to give stomach-filling solution by common dose conversion stomach-filling after quality, and dosage is 200mg/kg, in filling
Stomach administration after 0.25,0.5,1,2.5,3.5,4.5,6,7.5,9,10.5,12,14,24,30h docking take blood 0.3ml, be placed in liver
In elementization 1.5ml centrifuge tube, 4500r/min is centrifuged 10min, and 100 μ l of plasma sample is taken to be placed in 2mL Ep pipe, and 400 μ L are added
Methanol adds 800 μ L ethyl acetate, vortex mixed 15min, 10000rmin-1It is centrifuged 10min, draws upper organic layer, nitrogen
Air-blowing is dry, and the dissolution of 100 μ L methanol, 13000rmin is added in residue-1It is centrifuged the measurement of 10min sample introduction.
Experimental result: farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention, gefarnate, (4Z/8E)-farnesyl- second
Drug-time curve is as shown in Figure 7 after sour leaf-alcohol ester distinguishes gastric infusion.By pharmacokinetic parameters it is found that after rat oral gavage administration originally
The farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of invention, gefarnate, (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester peak time
About 6 hours, but farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention, gefarnate, (4Z/8E)-farnesylacetic acid
The AUC of spiceleaf alcohol ester0-tRespectively 19126.58 (ngh/ml), 14656.05 (ngh/ml), 8785.62 (ngh/ml).
Illustrate that the relative bioavailability of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention is greater than (4Z/8E)-farnesyl- second
Sour leaf-alcohol ester and gefarnate.
In summary, farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention is protected with toxicity by low, peptic ulcer
The advantage that shield effect is strong, relative bioavailability is high.
It is described the prefered embodiments of the present invention in detail above in conjunction with attached drawing, still, the present invention is not limited to above-mentioned realities
The detail in mode is applied, within the scope of the technical concept of the present invention, a variety of letters can be carried out to technical solution of the present invention
Monotropic type, this simple variant all belong to the scope of protection of the present invention.
Claims (12)
1. a kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition, which is characterized in that described pharmaceutical composition is by farnesylacetic acid
Spiceleaf alcohol ester active constituent and pharmaceutically acceptable carrier composition, and the farnesylacetic acid spiceleaf alcohol ester active constituent by
(4E/8E)-farnesylacetic acid spiceleaf alcohol ester and (the 4Z/8E)-farnesylacetic acid for being 0.1%-2% by active constituent total weight
Spiceleaf alcohol ester composition.
2. pharmaceutical composition according to claim 1, which is characterized in that (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester
Content be 0.1~1%.
3. pharmaceutical composition according to claim 1 or 2, which is characterized in that the farnesylacetic acid spiceleaf alcohol ester activity
Ingredient and the weight percent of pharmaceutically acceptable carrier are 1:19~3:7.
4. pharmaceutical composition according to claim 3, which is characterized in that the farnesylacetic acid spiceleaf alcohol ester active constituent
Weight percent with pharmaceutically acceptable carrier is 1:10~1:4.
5. pharmaceutical composition according to claim 1 or 2, which is characterized in that the pharmaceutically acceptable carrier is selected from
One of diluent, adhesive, disintegrating agent, flavouring agent, sweetener or more than one.
6. pharmaceutical composition according to claim 1 or 2, which is characterized in that the pharmaceutically acceptable carrier is selected from
Starch, microcrystalline cellulose, magnesium stearate, Almasilate, calcium monohydrogen phosphate, vegetable oil, beeswax, gelatin, polyethylene glycol, in glycerol
It is one or more kinds of.
7. pharmaceutical composition according to claim 1 or 2, which is characterized in that the dosage form of described pharmaceutical composition is selected from grain
Agent, pulvis, tablet, capsule, dripping pill, syrup, suppository, injection, emulsion, tincture, suspension, the oral or non-oral of solution are given
Pharmaceutically dosage form.
8. pharmaceutical composition according to claim 7, which is characterized in that the dosage form of described pharmaceutical composition be selected from tablet,
Capsule, dripping pill.
9. the method for preparing pharmaceutical composition of any of claims 1-8, which comprises the following steps:
(1) using trans- nerolidol and ortho-acetate as raw material, L-Aspartic acid is catalyst, is carried out at 90~150 DEG C anti-
It answers, is cooled to 60~90 DEG C of vacuum distillations, be warming up to 90~130 DEG C of vacuum distillations, obtain farnesylacetic acid ester；
(2) farnesylacetic acid ester is mixed with alkali and hydrolysis occurs, reaction solution petroleum ether extraction, tune reaction solution pH to 3~
4, petroleum ether extraction merges organic phase, adds alkali, is concentrated, and ethyl acetate, filtering is added, and filter cake adds water and adjusts pH to 3~4, petroleum
Ether extraction merges organic phase, saturated common salt water washing, dry farnesylacetic acid；
(3) by farnesylacetic acid, geraniol, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride, 4- dimethylamino
Reaction solution is used water, saturated common salt water washing by pyridine hybrid reaction respectively, dry, crosses silica gel, is concentrated, and silicon is crossed in vacuum distillation
Glue, it is dry, the farnesylacetic acid spiceleaf alcohol ester active constituent is made；
(4) farnesylacetic acid spiceleaf alcohol ester active constituent and pharmaceutically acceptable carrier are mixed to prepare the pharmaceutical composition
Object.
10. pharmaceutical composition of any of claims 1-8 treats or prevents in disease of digestive system drug in preparation
Purposes.
11. purposes according to claim 10, which is characterized in that the disease of digestive system is acute and chronic gastritis mucous membrane damage
Wound.
12. purposes according to claim 10, which is characterized in that the disease of digestive system is acute or chronic gastritis, digestion
Property ulcer, non-ulcer dyspepsia.
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