CN110201030A - It is a kind of for treating the composition and preparation method thereof containing cannabidiol of nervous tinnitus - Google Patents
It is a kind of for treating the composition and preparation method thereof containing cannabidiol of nervous tinnitus Download PDFInfo
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Abstract
The present invention relates to a kind of for treating the composition and preparation method thereof containing cannabidiol of nervous tinnitus, belongs to pharmaceutical composition technical field.It is poor to solve the existing curative effect of medication for treating nervous tinnitus, the big problem of side effect, the present invention provides a kind of for treating the composition containing cannabidiol of nervous tinnitus, active drug ingredient cannabidiol, Puerarin, total-tanshinone and phosphoric acid rhizome of chuanxiong piperazine organically combine, play the role of restoring inner ear auditory nerve normal function, its formed with lecithin phospholipid complexes and and soya-bean oil, Tween 80 forms oil phase component, oil phase component and glycerol and water form oil-in-water stable emulsion body under the action of high speed shear and homogeneous, drop average particle size reaches nanoscale.The composition, which is used as auristilla, can fast implement Transdermal absorption, into ear's capillary and directly act on lesion, and being used for treatment nervous tinnitus can be realized low dose, high-drug-effect, the quickly effective, therapeutic effect that has no toxic side effect.
Description
Technical field
The invention belongs to pharmaceutical composition technical field more particularly to a kind of contain hemp for treat nervous tinnitus
Composition of diphenol and preparation method thereof.
Background technique
Nervous tinnitus refers to that generated abnormal sound feels that mostly the cicada cried for high frequency under conditions of without extraneous sound source
Or ear-piercing sharp sound.Nervous tinnitus is divided into phonosensitive tinnitus, peripheral neuropathic tinnitus and central nervous system tinnitus.Sense
Sound tinnitus is derived from cochlea, and obstacle hypoxic-ischemic, which occurs, for cochlea blood microcirculation leads to damaged hair cells on basilar membrane；Week
Nervous tinnitus is enclosed derived from auditory nerve cell damage；Central nervous system tinnitus is impaired derived from auditory nerve maincenter or benumbs.
Modern's chronic stress is big, nervous fatigue, it is angry, flu of getting angry, tympanitis, noise, drink, hypertension,
Diabetes etc. can all lead to the damage of phonosensitive nerve, cause nervous tinnitus.Long-term tinnitus, which can make one to generate, upsets, carries on a shoulder pole
The emotional changes such as the heart, worry, anxiety, depression, influence work and family life, long-term tinnitus also result in hearing further by
Damage, or even deafness is caused, seriously affect the quality of life of patient.
The drug of the treatment nervous tinnitus clinically used at present is mostly to expand blood vessel, trophic nerve, antianxiety, anti-suppression
Based on strongly fragrant Western medicine, although illness can be alleviated to a certain extent, need to take for a long time, generated side effect is larger；?
Have part have dredge few sun, logical ear key, breath tinnitus, tonifying kidney and benefiting sperm Chinese herbal oral medicine be used to treat nervous tinnitus, but
The effective component that these Chinese patent drugs can act on lesion by oral administration, after digestion and absorption is extremely limited, attainable therapeutic effect
It is very little.
Summary of the invention
To solve the problems, such as that the existing curative effect of medication for treating nervous tinnitus is poor, side effect is big, the present invention provides one kind
For treating the composition and preparation method thereof containing cannabidiol of nervous tinnitus.
Technical solution of the present invention:
It is a kind of for treating the composition containing cannabidiol of nervous tinnitus, the component including following mass parts: big
1~5 part of numb diphenol, 1~3 part of Puerarin, 1~3 part of total-tanshinone, 1~2 part of phosphoric acid rhizome of chuanxiong piperazine, 20~80 parts of lecithin, soya-bean oil
30~100 parts, 20~60 parts of Tween 80,1~10 part of poly-D-lysine, 100~800 parts of glycerol and 1~200 part of deionized water.
Further, the component including following mass parts: 3 parts of cannabidiol, 2 parts of Puerarin, 2 parts of total-tanshinone, phosphoric acid
1 part of rhizome of chuanxiong piperazine, 55 parts of lecithin, 70 parts of soya-bean oil, 60 parts of Tween 80,7 parts of poly-D-lysine, 700 parts of glycerol and deionized water 100
Part.
It is a kind of for treating the preparation method of the composition containing cannabidiol of nervous tinnitus, include the following steps:
Step 1: by extracting tetrahydrocannabinol in Chinese fiber crops:
(1) Chinese straw, Chinese sesame slices, Chinese fried dough twist and/or Chinese fiber crops seed high pressure sterilization, cooling, crushed after being dried to 40 mesh are waited for
With；
(2) liquid seed culture medium being accessed after Trichoderma harzianum activation, culture obtains Trichoderma harzianum seed liquor under certain temperature,
It takes sterilized Chinese fiber crops powder and potato dextrose broth to mix by certain solid-liquid ratio, accesses Trichoderma harzianum seed liquor,
Mixing is placed on solid culture certain time under certain temperature and relative humidity, obtains Trichoderma harzianum fermentation culture medium, by gained
Trichoderma harzianum fermentation culture medium high pressure sterilization, it is stand-by after cooling down, sufficiently drying and crush；
(3) MRS culture medium is accessed after bacillus polymyxa activation, shaking table culture obtains bacillus polymyxa under certain temperature
Seed liquor takes sterilized Trichoderma harzianum fermentation culture medium and nutrient broth medium to mix by certain solid-liquid ratio, and access is mostly viscous
Bacillus seed liquor, mixing are placed on solid culture certain time under certain temperature and relative humidity, obtain more viscous gemma bars
Bacterium fermentation culture medium sufficiently washs gained bacillus polymyxa fermentation culture medium high pressure sterilization with 95% ethyl alcohol after cooling, from
The heart collects supernatant, and centrifugation is sufficiently washed with 95% ethyl alcohol, and supernatant is collected by centrifugation, and it is stand-by to merge gained supernatant；
(4) gained supernatant is concentrated under reduced pressure, using macroporous absorbent resin as chromatography media, by certain macroporous absorbent resin with
The solid-liquid ratio of the volume of the concentrated liquid adds the supernatant after concentration into macroporous absorbent resin, absorption is completed under certain temperature, with 45
~55% ethanol elution removes polar impurity, then uses 80~95% ethanol elution cannabidiol, collects rich in cannabidiol
Eluent, be concentrated under reduced pressure to give cannabidiol concentrate；Gained cannabidiol concentrate is further purified with silica gel column chromatography,
Using petroleum ether as mobile phase, isocratic elution is carried out with certain flow rate of mobile phase, collects the eluent for being rich in cannabidiol, is depressurized dense
Contracting obtains cannabidiol refined solution, and the cannabidiol refined solution is dried in vacuo, white cannabidiol solid is obtained；
Step 2: preparation phospholipid complexes:
Cannabidiol, Puerarin, total-tanshinone, ligustrazine phosphat and lecithin are dissolved in dehydrated alcohol respectively, then will
Cannabidiol, Puerarin, total-tanshinone, phosphoric acid rhizome of chuanxiong piperazine and lecithin alcoholic solution mixed, it is equal with the stirring of certain revolving speed
After even, certain time is handled to mixed solution ultrasonic disperse under certain ultrasonic power, it is dry that acquired solution is then carried out freezing
Dry processing, obtains phospholipid complexes；
Step 3: preparing oil mixes liquid；
Phospholipid complexes obtained by step 1, soybean oil, Tween 80 and poly-D-lysine are subjected to mixing and in certain revolving speed
Under the conditions of high speed shear, mix liquid until being visible by naked eyes solid content in mixed liquor and obtaining oil；
Step 4: preparing the composition containing cannabidiol for treating nervous tinnitus；
Oil made from step 2 is added in glycerol and deionized water to mix in liquid, the high speed shear under certain speed conditions
Certain time, high-pressure homogeneous circular treatment of the gained emulsion through certain pressure, obtain translucent milky for treating nerve
The composition containing cannabidiol of tinnitus.
Further, step 1 (2) the Trichoderma harzianum seed culture condition is 25 DEG C of culture 48h, the Trichoderma harzianum
The mycelial concentration of seed liquor is 200~250g/L；The material of the sterilized Chinese fiber crops powder and potato dextrose broth
Liquor ratio is 1:1, and the access amount of the Trichoderma harzianum seed liquor is sterilized Chinese fiber crops powder and potato dextrose broth
The 5~10% of mixture quality；The temperature of the solid culture is 28 DEG C, relative humidity 92%, and incubation time 5d is described
High pressure sterilization is the 40min that sterilizes in 120 DEG C of autoclaves, described to crush to be crushed to 40 mesh.
Further, step 1 (3) the bacillus polymyxa seed culture condition is 37 DEG C, revolving speed is that 220r/min shakes
For 24 hours, the gemma rate of the bacillus polymyxa seed liquor is 90% or more for bed culture；The sterilized Trichoderma harzianum, which ferments, to be trained
The solid-liquid ratio for supporting object and nutrient broth medium is 1:1, and the dense bacterium of the bacillus polymyxa seed liquor is 106~108CFU/
mL；The condition of the solid culture is 28 DEG C, for 24 hours, the high pressure sterilization is 120 to fermented and cultured under conditions of relative humidity 80%
Sterilize 40min in DEG C autoclave.
Further, step 1 (4) macroporous absorbent resin is DM-130 macroporous absorbent resin, the macroporous absorption tree
Solid-liquid ratio between lipid amount and the volume of the concentrated liquid is 1:5；The adsorption temp is 25 DEG C, big in the cannabidiol concentrate
The content of numb diphenol is 60~70%；The silica gel column chromatography is 200 mesh silica gel column chromatographies, and the flow rate of mobile phase is 10mL/
Min, the cannabidiol solid purity are 98%.
Further, speed of agitator described in step 2 is 200~300rpm, and the ultrasonic power is 100~500W, described
Ultrasonic disperse handles the time as 10~15min.
Further, high speed shear revolving speed described in step 3 is 5000~7000rpm.
Further, high speed shear revolving speed described in step 4 is 10000~13000rpm, and the high speed shear handles the time
Pressure for 5~20min, the high-pressure homogeneous processing is 1500~2200bar, and the number of the high-pressure homogeneous circular treatment is
10~20 times.
Further, provided by the present invention for treat nervous tinnitus the composition containing cannabidiol in effectively at
The mass concentration for dividing cannabidiol is 0.08~2.5%, the mass concentration of Puerarin is 0.08~1.5%, the matter of total-tanshinone
Amount concentration is 0.08~1.5%, the mass concentration of ligustrazine phosphat is 0.08~1.0%, and composition is translucent milky liquid, liquid
Average particle size≤100nm of drop.
It further, is as drop provided by the present invention for the composition containing cannabidiol for treating nervous tinnitus
Ear agent uses, and specific application method: patient takes lateral position, makes the exposure of side ear canal, and 2~3 are instilled into ear canal and drips this hair
The auristilla of bright offer keeps 5~10min of lateral position, while gently pinning tragus to ear with finger after medical fluid enters ear canal
Road direction do one by one put rub by acting and cooperate swallowing act so that medical fluid flows to ear canal depths, daily 2~3 times.
Beneficial effects of the present invention:
Provided by the present invention for treating the composition of nervous tinnitus with cannabidiol, Puerarin, total-tanshinone and phosphorus
Sour rhizome of chuanxiong piperazine is principle active component, and wherein cannabidiol has antioxidation, is a kind of natural neuroprotective agent, can
Oxidative stress is reduced, auditory nerve is repaired, prevents auditory nerve from degenerating, reduce the risk of ischemia injury；In Puerarin expansion
Ear blood vessel adjusts blood fortune, promotes cell metabolism, improves inner ear blood circulation, to facilitate the function of recovery ear cells；Always
Tanshinone can improve microcirculation blood flow velocity, increase cochlear blood flow, expand blood vessel, reduce blood viscosity, promote cell
Aerobic metabolism and energy supply；Phosphoric acid rhizome of chuanxiong piperazine can expand blood vessel, improve inner ear microcirculation, and can penetrate blood-brain barrier, improve
Encephalic blood circulation adjusts cochiear blood flow supply.Effective ingredient used in the present invention mutually organically combines, and plays recovery inner ear
The effect of auditory nerve normal function can fundamentally cure nervous tinnitus.
Effective component of chinese medicine in the present composition and lecithin formed phospholipid complexes and with soya-bean oil, emulsifier tween
80 form oil phase component, and oil phase component and glycerol and water form oil-in-water stable emulsus under the action of high speed shear and homogeneous
Liquid, the average particle size of drop can reach nanoscale, and after instilling ear canal, nanoscale compositions molecule can be fast implemented
Skin absorbs, into ear's capillary, to directly reach inner ear auditory nerve cell, hair cell and sense of hearing mind on basilar membrane
Through maincenter, the effective components such as the cannabidiol being wrapped in lecithin lipid microvesicle can directly be absorbed by cell, play drug effect.This hair
The composition application method of bright offer is simple, and being used for treatment nervous tinnitus can be realized low dose, high-drug-effect, effective
Fastly, the therapeutic effect having no toxic side effect.
When the present invention extracts cannabidiol from Chinese fiber crops, using the pre-treating method of microbial solid fermentation, solid fermentation
The enzyme system that microorganism growth metabolism generates in the process can destroy the physicalchemical structure of Chinese fiber crops surface compact, can significantly improve
The recovery rate and Chinese fiber crops utilization rate of cannabidiol.The preparation method simple process of composition, mild condition, non-environmental-pollution, symbol
Close the requirement of the green safe production of modern pharmaceutical industry.
Specific embodiment
Below with reference to embodiment, the following further describes the technical solution of the present invention, and however, it is not limited to this, all right
Technical solution of the present invention is modified or replaced equivalently, and without departing from the spirit and scope of the technical solution of the present invention, should all be contained
Lid is within the protection scope of the present invention.
Embodiment 1
It present embodiments provides a kind of for treating the composition containing cannabidiol of nervous tinnitus, including following matter
Measure the component of part: 1~5 part of cannabidiol, 1~3 part of Puerarin, 1~3 part of total-tanshinone, 1~2 part of phosphoric acid rhizome of chuanxiong piperazine, lecithin
20~80 parts, 30~100 parts of soya-bean oil, 20~60 parts of Tween 80,1~10 part of poly-D-lysine, 100~800 parts of glycerol and go from
1~200 part of sub- water.
Cannabidiol has antioxidation in the present embodiment, is a kind of natural neuroprotective agent, can reduce oxidation
Stress, it prevents auditory nerve from degenerating, reduces the risk of ischemia injury；Puerarin expands vessels of internal ear, adjusts blood fortune, promotes thin
Born of the same parents' metabolism, improves inner ear blood circulation, to facilitate the function of recovery ear cells；Total-tanshinone can improve microcirculation blood
Flow velocity degree increases cochlear blood flow, expands blood vessel, reduces blood viscosity, promotes cell aerobic metabolism and energy supply；Phosphoric acid
Rhizome of chuanxiong piperazine can expand blood vessel, improve inner ear microcirculation, and can penetrate blood-brain barrier, improve encephalic blood circulation, adjust cochlea blood
Stream supply.These effective ingredients mutually organically combine, and play the role of restoring inner ear auditory nerve normal function, Neng Goucong
Fundamentally cure nervous tinnitus.
Embodiment 2
It present embodiments provides a kind of for treating the composition containing cannabidiol of nervous tinnitus, including following matter
Measure the component of part: 3 parts of cannabidiol, 2 parts of Puerarin, 2 parts of total-tanshinone, 1 part of phosphoric acid rhizome of chuanxiong piperazine, 55 parts of lecithin, soya-bean oil 70
Part, 60 parts of Tween 80,7 parts of poly-D-lysine, 700 parts of glycerol and 100 parts of deionized water.
The mass concentration of cannabidiol is 0.3% in the present embodiment resulting composition, the mass concentration of Puerarin is
0.2%, the mass concentration of total-tanshinone is 0.2%, the mass concentration of ligustrazine phosphat is 0.1%.
Embodiment 3
It present embodiments provides a kind of for treating the composition containing cannabidiol of nervous tinnitus, including following matter
Measure the component of part: 5 parts of cannabidiol, 3 parts of Puerarin, 3 parts of total-tanshinone, 2 parts of phosphoric acid rhizome of chuanxiong piperazine, 20 parts of lecithin, soya-bean oil 30
Part, 20 parts of Tween 80,1 part of poly-D-lysine, 100 parts of glycerol and 16 parts of deionized water.
The mass concentration of cannabidiol is 2.5% in the present embodiment resulting composition, the mass concentration of Puerarin is
1.5%, the mass concentration of total-tanshinone is 1.5%, the mass concentration of ligustrazine phosphat is 1.0%.
Embodiment 4
It present embodiments provides a kind of for treating the composition containing cannabidiol of nervous tinnitus, including following matter
Measure the component of part: 1 part of cannabidiol, 1 part of Puerarin, 1 part of total-tanshinone, 1 part of phosphoric acid rhizome of chuanxiong piperazine, 80 parts of lecithin, soya-bean oil 100
Part, 60 parts of Tween 80,10 parts of poly-D-lysine, 800 parts of glycerol and 200 parts of deionized water.
The mass concentration of cannabidiol is 0.08% in the present embodiment resulting composition, the mass concentration of Puerarin is
0.08%, the mass concentration of total-tanshinone is 0.08%, the mass concentration of ligustrazine phosphat is 0.08%.
Embodiment 5
It present embodiments provides a kind of for treating the composition containing cannabidiol of nervous tinnitus, including following matter
Measure the component of part: 4 parts of cannabidiol, 2 parts of Puerarin, 2 parts of total-tanshinone, 1 part of phosphoric acid rhizome of chuanxiong piperazine, 75 parts of lecithin, soya-bean oil 90
Part, 50 parts of Tween 80,5 parts of poly-D-lysine, 120 parts of glycerol and 51 parts of deionized water.
The mass concentration of cannabidiol is 1.0% in the present embodiment resulting composition, the mass concentration of Puerarin is
0.5%, the mass concentration of total-tanshinone is 0.5%, the mass concentration of ligustrazine phosphat is 0.25%.
Embodiment 6
Present embodiments provide it is a kind of for treating the preparation method of the composition containing cannabidiol of nervous tinnitus,
Include the following steps:
Step 1: preparation phospholipid complexes:
By 1~5 part of cannabidiol, 1~3 part of Puerarin, 1~3 part of total-tanshinone, 1~2 part of ligustrazine phosphat, 20~80
Part lecithin and 100~500 parts of dehydrated alcohols are mixed, speed of agitator be 200~300rpm after mixing evenly, with ultrasonic function
Acquired solution is carried out freeze-drying process, obtains phospholipid complexes by 100~500W of rate ultrasonic disperse 10~15 minutes；
Step 2: preparing oil mixes liquid；
Phospholipid complexes obtained by step 1,30~100 portions of soybean oils, 20~60 parts of Tween 80s and 1~10 part of poly are relied
Propylhomoserin is mixed, high speed shear under the conditions of 5000~7000rpm, is obtained until being visible by naked eyes solid content in mixed liquor
Oil mixes liquid；
Step 3: preparing the composition containing cannabidiol for treating nervous tinnitus；
Oil made from step 2 is added in 100~800 parts of glycerol and 1~200 part of deionized water to mix in liquid, 10000
5~20min of high speed shear under the conditions of~13000rpm, gained emulsion are that the high-pressure homogeneous of 1500~2200bar follows through pressure
Ring is handled 10~20 times, obtains translucent milky for treating the composition containing cannabidiol of nervous tinnitus.
The Puerarin CAS:3681-99-0 that the present embodiment uses is commercially available Puerarin bulk pharmaceutical chemicals, purity 98%；
The ligustrazine phosphat CAS:1124-11-4 that the present embodiment uses is commercially available ligustrazine phosphat bulk pharmaceutical chemicals, purity
98%.
Effective component of chinese medicine in the present composition and lecithin formed phospholipid complexes and with soya-bean oil, emulsifier tween
80 form oil phase component, and oil phase component and glycerol and water form oil-in-water stable emulsus under the action of high speed shear and homogeneous
Liquid, average particle size≤100nm of drop.The effect of poly-D-lysine in the composition is stabilizer, can make oil-in-water
Emulsus auristilla keeps stablizing, while being also preservative, plays bacteriostasis.
After composition manufactured in the present embodiment is instilled ear canal as auristilla, nanoscale compositions molecule can be quickly real
Existing Transdermal absorption, into ear's capillary, to directly reach inner ear auditory nerve cell, hair cell and listen on basilar membrane
Feel nerve center, the effective components such as cannabidiol being wrapped in lecithin lipid microvesicle can directly be absorbed by cell, play drug effect.
Composition application method provided by the invention is simple, and being used for treatment nervous tinnitus can be realized low dose, high-drug-effect, shows
The therapeutic effect that effect is fast, has no toxic side effect.
Embodiment 7
Present embodiments provide it is a kind of for treating the preparation method of the composition containing cannabidiol of nervous tinnitus,
Include the following steps:
Step 1: preparation phospholipid complexes:
By 3 parts of cannabidiols, 2 parts of Puerarins, 2 parts of total-tanshinones, 1 part of ligustrazine phosphat, 55 parts of lecithin and 300 parts of nothings
Water-ethanol is mixed, speed of agitator be 250rpm after mixing evenly, with ultrasonic power 300W ultrasonic disperse 15 minutes, by gained
Solution carries out freeze-drying process, obtains phospholipid complexes；
Step 2: preparing oil mixes liquid；
Phospholipid complexes obtained by step 1,70 portions of soybean oils, 60 parts of Tween 80s and 7 parts of poly-D-lysines are mixed,
High speed shear under the conditions of 6000rpm mixes liquid until being visible by naked eyes solid content in mixed liquor and obtaining oil；
Step 3: preparing the composition containing cannabidiol for treating nervous tinnitus；
Oil made from step 2 is added in 700 parts of glycerol and 100 parts of deionized waters to mix in liquid, under the conditions of 13000rpm
High speed shear 18min, gained emulsion obtain translucent milky use through high-pressure homogeneous circular treatment 16 times that pressure is 2000bar
In the composition containing cannabidiol for the treatment of nervous tinnitus.
The mass concentration of cannabidiol is 0.3% in composition manufactured in the present embodiment, the mass concentration of Puerarin is
0.2%, the mass concentration of total-tanshinone is 0.2%, the mass concentration of ligustrazine phosphat is 0.1%.
Embodiment 8
Present embodiments provide a kind of method that cannabidiol is extracted from Chinese fiber crops, the specific steps are as follows:
Step 1: extracting cannabidiol by Chinese fiber crops:
(1) Chinese straw, leaf, flower and seed are placed in 120 DEG C of autoclaves the 20min that sterilizes, cooling, crushed after being dried to 40
It is stand-by that mesh obtains Chinese fiber crops powder；
(2) access liquid seed culture medium after Trichoderma harzianum activation, 25 DEG C of culture 48h, obtain mycelial concentration for 200~
The Trichoderma harzianum seed liquor of 250g/L；Take sterilized Chinese fiber crops powder 50g, be added potato dextrose broth 50mL and
7mL Trichoderma harzianum seed liquor, in 28 DEG C after mixing, relative humidity cultivates 5d under conditions of being 92%, and gained Trichoderma harzianum is sent out
Ferment culture is placed in 120 DEG C of autoclaves the 40min that sterilizes, cooling, sufficiently dry and to be crushed to 40 mesh stand-by；
(3) bacillus polymyxa activation after access MRS culture medium, 37 DEG C, revolving speed be 220r/min shaking table culture for 24 hours, until
Gemma rate reaches 90% or more, obtains bacillus polymyxa seed liquor, dense bacterium is 106~108CFU/mL；Take sterilized Ha Ci
Nutrient broth medium 50mL is added in trichoderma fermentation culture medium 50g, adds 3mL bacillus polymyxa seed liquor, mixes and in 28
DEG C, gained bacillus polymyxa fermentation culture medium for 24 hours, is placed in 120 DEG C of sterilizings by fermented and cultured under conditions of relative humidity 80%
Sterilize 40min in pot, sufficiently washs gained bacillus polymyxa fermentation culture medium with 95% ethyl alcohol of 2~3 times of volumes after cooling,
Supernatant is collected by centrifugation, centrifugation is sufficiently washed again with 95% ethyl alcohol of 2~3 times of volumes, supernatant is collected by centrifugation, closes
And gained supernatant is stand-by；
(4) gained supernatant is placed in vacuum distillation removing alcohol solvent at 50~70 DEG C, concentrate is obtained, with macropore
Absorption resin DM-130 is chromatography media, and the solid-liquid ratio between macroporous absorbent resin quality and the volume of the concentrated liquid is 1:5, at 25 DEG C
Under the conditions of complete absorption；Most of polar impurities are eluted with 45~55% 5 column volumes of ethanol elution, then with 80~95%
3~5 column volumes of ethanol elution elute cannabidiol, collect the eluent for being rich in cannabidiol, 50~70 DEG C are concentrated under reduced pressure
To cannabidiol concentrate, it is greater than 65% through cannabidiol content in cannabidiol concentrate obtained by efficient liquid phase chromatographic analysis,
And tetrahydrocannabinol is not found；Gained cannabidiol concentrate is further purified with 200 mesh silica gel column chromatographies, with petroleum ether
Isocratic elution is carried out for mobile phase, flow rate of mobile phase 10mL/min collects the eluent for being rich in cannabidiol, is concentrated under reduced pressure
To cannabidiol refined solution, 50 DEG C of cannabidiol refined solution vacuum drying are obtained into white cannabidiol solid, gained hemp two
Phenol solid purity is 98%.
Trichoderma harzianum in the present embodiment for fermentation is purchased from China Committee for Culture Collection of Microorganisms's commonly micro- life
Object center, deposit number CGMCC No.12165: bacillus polymyxa is purchased from Chinese agriculture Microbiological Culture Collection administrative center,
Deposit number is ACCC No.10122.
Trichoderma harzianum liquid seed culture medium formula in the present embodiment are as follows: potato 200g/L, sucrose 10g/L, glucose
10g/L, peptone 1g/L, anhydrous sodium acetate 2g/L, epsom salt 6g/L, pH6.5.
Potato dextrose broth formula in the present embodiment are as follows: potato 200g/L, sucrose 10g/L, glucose
10g/L, pH6.5.
Bacillus polymyxa liquid seed culture medium formula in the present embodiment are as follows: peptone 10g/L, beef extract powder 8g/L,
Yeast extract 4g/L, glucose 20g/L, dipotassium hydrogen phosphate 2g/L, citric acid hydrogen diamine 2g/L, sodium acetate 5g/L, magnesium sulfate
0.2g/L, manganese sulfate 0.04g/L, pH6.5.
Nutrient broth medium formula in the present embodiment are as follows: beef extract 3g/L, peptone 5g/L, NaCl5g/L, pH6.5.
Embodiment 9
A kind of method that alcohol extracting method extracts total-tanshinone from Radix Salviae Miltiorrhizae is present embodiments provided, is included the following steps:
Raw material Radix Salviae Miltiorrhizae, which cleans up, is placed in 65 DEG C of vacuum ovens dry 15h, and the Radix Salviae Miltiorrhizae after abundant drying is crushed
To 80 mesh；The petroleum ether of 10 times of volumes is added into gained Danshen Root, is filtered to remove filtrate after refluxing extraction 2h, filter residue is put
Enter dry 30min in 65 DEG C of vacuum ovens to obtain the Danshen Root of degreasing with solvent flashing, be added into gained mixed-powder
60% ethanol solution of 20 times of volumes carries out assisted extraction, ultrasonic power 2000W, when extraction using ultrasonic wave extraction instrument
Between be 90min, continue under room temperature to impregnate 3h stand-by；Gained total-tanshinone crude extract is concentrated under reduced pressure, pH value makes after being adjusted to neutrality
It is adsorbed by macroreticular resin DM-130 chromatographic column, is adjusted to neutrality with 15% acetone pH value and as the 1st eluting solvent
It is eluted；20% acetone pH value is adjusted to neutrality and is eluted as the 2nd eluting solvent, evaporating containing tanshinone is collected
Point；Gained fraction is concentrated under reduced pressure, is spray-dried, total-tanshinone after purification is obtained, purity is 95~98%.
Comparative example 1
This comparative example provides a kind of composition -0 without cannabidiol, and preparation method includes the following steps:
Step 1: preparation phospholipid complexes:
2 parts of Puerarins, 2 parts of total-tanshinones, 1 part of ligustrazine phosphat, 55 parts of lecithin and 300 parts of dehydrated alcohols are mixed
It closes, after mixing evenly, with ultrasonic power 300W ultrasonic disperse 15 minutes, acquired solution is freezed for 250rpm for speed of agitator
It is dried, obtains phospholipid complexes；
Step 2: preparing oil mixes liquid；
Phospholipid complexes obtained by step 1,70 portions of soybean oils, 60 parts of Tween 80s and 7 parts of poly-D-lysines are mixed,
High speed shear under the conditions of 6000rpm mixes liquid until being visible by naked eyes solid content in mixed liquor and obtaining oil；
Step 3: preparation is free of the composition -0 of cannabidiol；
Oil made from step 2 is added in 700 parts of glycerol and 103 parts of deionized waters to mix in liquid, under the conditions of 13000rpm
High speed shear 18min, gained emulsion are obtained through high-pressure homogeneous circular treatment 16 times that pressure is 2000bar without hemp two
The composition -0 of phenol.
The mass concentration of Puerarin is 0.2% in the composition -0 of this comparative example preparation, the mass concentration of total-tanshinone is
0.2%, the mass concentration of ligustrazine phosphat is 0.1%.
Comparative example 2
This comparative example provides a kind of composition -1 for containing only cannabidiol, and preparation method includes the following steps:
Step 1: preparation phospholipid complexes:
3 parts of cannabidiols, 55 parts of lecithin and 300 parts of dehydrated alcohols are mixed, speed of agitator is 250rpm stirring
After uniformly, with ultrasonic power 300W ultrasonic disperse 15 minutes, acquired solution is subjected to freeze-drying process, it is compound to obtain phosphatide
Body；
Step 2: preparing oil mixes liquid；
Phospholipid complexes obtained by step 1,70 portions of soybean oils, 60 parts of Tween 80s and 7 parts of poly-D-lysines are mixed,
High speed shear under the conditions of 6000rpm mixes liquid until being visible by naked eyes solid content in mixed liquor and obtaining oil；
Step 3: preparing composition -1；
Oil made from step 2 is added in 700 parts of glycerol and 105 parts of deionized waters to mix in liquid, under the conditions of 13000rpm
High speed shear 18min, gained emulsion obtain composition -1 through high-pressure homogeneous circular treatment 16 times that pressure is 2000bar.
The mass concentration of cannabidiol is 0.3% in the composition -1 of this comparative example preparation.
Drug effect verification test:
(1) rabbit blood flow of inner ear variation experiment
25 rabbit are randomly divided into 5 groups, every group 5, are respectively as follows:
(1) group, normal rabbits group, do not apply any drug or physiological saline；
(2) group, model group:, blood flow impaired in normal rabbits the ear portion endotoxin injection (LPS) production inner ear auditory cell
It is slack-off, there are the Rabbits Models of microcirculation disorder, does not apply any drug or physiological saline；
(3) group, control group: physiological saline 3 is added dropwise into Rabbits Models ear canal and drips, once in the morning and once at night；
(4) group, oral western medicine group: to Rabbits Models stomach-filling Nimodipine 3mg/ times, once in the morning and once at night；
(5) group, drop apply composition group: composition 2 prepared by embodiment 7 is added dropwise into Rabbits Models ear canal and drips, it is early daily
Evening is each primary；
120h with laser Doppler flowmetry measures house after 2h and administration after 0.5h, administration before administration, after administration
Rabbit inner ear microcirculation blood perfusion amount, data result are average ± standard deviation expression, and the results are shown in Table 1:
Table 1
Drop applies the inner ear microcirculation blood perfusion amount of composition group rabbit upon administration it can be seen from data in table 1
0.5h has just obtained significantly being promoted, and improves 280% with preceding ratio is administered, the comparison of 2h microcirculation blood flow groundwater increment is normal after administration
Rabbit group has restored 86%, and the microcirculation blood flow groundwater increment of 120h rabbit has just replied normal level after administration.And oral west
The microcirculation blood flow groundwater increment of 0.5h is promoted with before administration than only the inner ear microcirculation blood perfusion amount of medicine group rabbit upon administration
92%, 2h microcirculation blood flow groundwater increment comparison normal rabbits group has restored 56% after administration, and the micro- of 120h rabbit follows after administration
Ring blood perfusion amount can not still restore normal level.
Oral western medicine group and drop apply composition group can to the comparison of the promotion situation of rabbit inner ear microcirculation blood perfusion amount
Sufficiently to confirm, composition prepared by embodiment 7 can improve the microcirculation blood flow perfusion of Rabbits Models inner ear in a short time
Amount, after this illustrates that composition provided by the invention instills ear canal, nanoscale compositions molecule can fast implement Transdermal absorption, into
Entering ear's capillary, the effective components such as cannabidiol being wrapped in lecithin lipid microvesicle can directly be absorbed by cell, thus
Lesion is sufficiently acted on, drug effect can be given full play in a short time.
Just because of composition prepared by the present invention can fast implement Transdermal absorption and directly act on lesion, therefore can
Realize the therapeutic effect of low dosage, high-drug-effect.The mass concentration of cannabidiol is 0.3%, Pueraria lobota in composition prepared by embodiment 7
The mass concentration of root element is 0.2%, the mass concentration of total-tanshinone is 0.2%, the mass concentration of ligustrazine phosphat is 0.1%,
The content of effective component of the present invention can further decrease the cost of material of drug well below oral medicine.
Due to present composition energy fast lifting inner ear microcirculation blood flow, Oxygen supplied level is improved, promote cell has
Oxygen metabolism and energy supply, being capable of fast quick-recovery inner ear auditory nerve cell, hair cell and auditory nerve maincenter on basilar membrane
Normal function, prevent auditory nerve from degenerating, reduce ischemia injury, fundamentally cure nervous tinnitus.
(2) clinical test
It chooses according to medical history, routine inspection, endoscopy of ear, pure tone test and acoustic impedance inspection, is diagnosed as nerve ear
The patient of ring 500, wherein male patient 235, female patient 265, average age 48 years old, max age 66 years old, minimum
Age 27 years old, the course of disease was at -3 years 6 months.
All patients are divided equally into 4 groups at random, 7 groups of embodiment, 1 group of comparative example, 2 groups of comparative example and western medicine group；Each group
Patient the age, the state of an illness, in terms of be statistically analyzed no significant difference, be comparable.Wherein, embodiment
Drop applies drop ear prepared by embodiment 7, comparative example 1 and comparative example 2 respectively as follows for 2 groups of 7 groups, 1 group of comparative example and comparative example
Agent:
Patient takes lateral position, makes the exposure of side ear canal, and 2~3 drop auristilla provided by the invention are instilled into ear canal, when
After medical fluid enters ear canal, 5~10min of lateral position is kept, while with finger gently pinning tragus and does one to ear canal direction and being put by one
Rub by acting and cooperate swallowing act so that medical fluid flows to ear canal depths, daily 2~3 times.
Western medicine group takes orally nimodipine tablet by package insert requirement.
Efficacy assessment standard:
Effective: tinnitus symptom disappears substantially, and hearing returns to normal or without obvious dysaudia, and symptom maintains 2 months
Above without recurrence；
Effective: tinnitus symptom is relieved, or is only broken out once in a while under quiet environment；
Invalid: clinical symptoms grade sign is substantially without change.
Total effective rate=(effective number of cases+effective number of cases)/total inspection number of cases × 100%.Treatment results are shown in Table 2,
Table 2
| Group | Case load | Effective number of cases | Obvious effective rate | Effective number of cases | It is efficient | Invalid number of cases | Total effective rate |
| 7 groups of embodiment | 125 | 121 | 96.8% | 4 | 3.2% | 0 | 100% |
| 1 group of comparative example | 125 | 55 | 44% | 60 | 48% | 10 | 92% |
| 2 groups of comparative example | 125 | 42 | 33.6% | 30 | 24% | 53 | 57.6% |
| Western medicine group | 125 | 71 | 56.8% | 37 | 29.6% | 17 | 86.4% |
The group containing cannabidiol for being used to treat nervous tinnitus that it can be seen from data in table 2 prepared by embodiment 7
100% can be reached by closing object total effective rate, and obvious effective rate reaches 96.8%.And the combination without cannabidiol prepared by comparative example 1
Although the total effective rate of object can reach 92%, its obvious effective rate is only 44%, and efficient is 48%；Comparative example 2 is made simultaneously
The total effective rate of the standby composition containing only cannabidiol is only 57.6%, obvious effective rate 33.6%, and effective percentage is 24%, low
In the numerical value of comparative example 1.
By above-mentioned data comparison result it is found that 1 group of the comparative example effect for lacking cannabidiol, 48% in 92% total effective rate
There are the symptoms broken out once in a while under quiet environment, and 2 groups of comparative example lack Puerarin, total-tanshinone and phosphoric acid rhizome of chuanxiong piperazine, always have
Efficiency is only 57.6%；This explanation only has 7 groups of having cannabidiol, Puerarin, total-tanshinone and phosphoric acid rhizome of chuanxiong piperazine of embodiment
Machine combines, and can both improve inner ear microcirculation, increases cochlear blood flow, improves the confession of auditory nerve by improving amount of blood supply
Oxygen situation, and auditory nerve can be repaired, it prevents auditory nerve from degenerating, reduces the risk of ischemia injury.At the same time, of the invention
Composition can play the role of protecting auditory nerve cell for a long time while curing nervous tinnitus, prevent it because of ischemic
Anoxic and cause to damage, effectively prevent the recurrence of nervous tinnitus.
It can be seen that composition curative effect provided by the invention from the comparison of 7 groups of embodiment and oral western medicine control group
It is substantially better than Western medicine, and safe and free of toxic and side effects.
Claims (10)
1. a kind of for treating the composition containing cannabidiol of nervous tinnitus, which is characterized in that including following mass parts
Component: 1~5 part of cannabidiol, 1~3 part of Puerarin, 1~3 part of total-tanshinone, 1~2 part of phosphoric acid rhizome of chuanxiong piperazine, lecithin 20~
80 parts, 30~100 parts of soya-bean oil, 20~60 parts of Tween 80,1~10 part of poly-D-lysine, 100~800 parts of glycerol and deionized water 1
~200 parts.
2. a kind of for treating the composition containing cannabidiol of nervous tinnitus according to claim 1, feature exists
In the component including following mass parts: 3 parts of cannabidiol, 2 parts of Puerarin, 2 parts of total-tanshinone, 1 part of phosphoric acid rhizome of chuanxiong piperazine, lecithin
55 parts of rouge, 70 parts of soya-bean oil, 60 parts of Tween 80,7 parts of poly-D-lysine, 700 parts of glycerol and 100 parts of deionized water.
3. a kind of as claimed in claim 1 or 2 for treating the preparation side of the composition containing cannabidiol of nervous tinnitus
Method, which comprises the steps of:
Step 1: by extracting tetrahydrocannabinol in Chinese fiber crops:
(1) Chinese straw, Chinese sesame slices, Chinese fried dough twist and/or Chinese fiber crops seed high pressure sterilization, cooling, crushed after being dried is stand-by to 40 mesh；
(2) liquid seed culture medium is accessed after Trichoderma harzianum activation, culture obtains Trichoderma harzianum seed liquor under certain temperature, by one
Determining solid-liquid ratio takes sterilized Chinese fiber crops powder and potato dextrose broth to mix, and accesses Trichoderma harzianum seed liquor, mixes
It is placed on solid culture certain time under certain temperature and relative humidity, obtains Trichoderma harzianum fermentation culture medium, gained is breathed out into thatch
Trichoderma fermentation culture medium high pressure sterilization, it is stand-by after cooling down, sufficiently drying and crush；
(3) MRS culture medium is accessed after bacillus polymyxa activation, shaking table culture obtains bacillus polymyxa seed under certain temperature
Liquid takes sterilized Trichoderma harzianum fermentation culture medium and nutrient broth medium to mix by certain solid-liquid ratio, accesses more viscous gemma
Bacillus seed liquor, mixing are placed on solid culture certain time under certain temperature and relative humidity, obtain bacillus polymyxa hair
Ferment culture sufficiently washs gained bacillus polymyxa fermentation culture medium high pressure sterilization with 95% ethyl alcohol after cooling, centrifugation is received
Collect supernatant, centrifugation is sufficiently washed with 95% ethyl alcohol, supernatant is collected by centrifugation, it is stand-by to merge gained supernatant；
(4) gained supernatant is concentrated under reduced pressure, using macroporous absorbent resin as chromatography media, by certain macroporous absorbent resin and concentration
The solid-liquid ratio of liquid product add the supernatant after concentration into macroporous absorbent resin, completes under certain temperature to adsorb, with 45~
55% ethanol elution removes polar impurity, then uses 80~95% ethanol elution cannabidiol, collects and is rich in cannabidiol
Eluent is concentrated under reduced pressure to give cannabidiol concentrate；Gained cannabidiol concentrate is further purified with silica gel column chromatography, with
Petroleum ether is mobile phase, carries out isocratic elution with certain flow rate of mobile phase, collects the eluent for being rich in cannabidiol, is concentrated under reduced pressure
Cannabidiol refined solution is obtained, the cannabidiol refined solution is dried in vacuo, obtains white cannabidiol solid；
Step 2: preparation phospholipid complexes:
Cannabidiol, Puerarin, total-tanshinone, ligustrazine phosphat and lecithin are dissolved in dehydrated alcohol respectively, then by hemp
Diphenol, Puerarin, total-tanshinone, phosphoric acid rhizome of chuanxiong piperazine and lecithin alcoholic solution mixed, after mixing evenly with certain revolving speed,
Certain time is handled to mixed solution ultrasonic disperse under certain ultrasonic power, then carries out acquired solution at freeze-drying
Reason, obtains phospholipid complexes；
Step 3: preparing oil mixes liquid；
Phospholipid complexes obtained by step 1, soybean oil, Tween 80 and poly-D-lysine are subjected to mixing and in certain speed conditions
Lower high speed shear mixes liquid until being visible by naked eyes solid content in mixed liquor and obtaining oil；
Step 4: preparing the composition containing cannabidiol for treating nervous tinnitus；
Oil made from step 2 is added in glycerol and deionized water to mix in liquid, high speed shear is certain under certain speed conditions
Time, high-pressure homogeneous circular treatment of the gained emulsion through certain pressure, obtain translucent milky for treating nervous tinnitus
The composition containing cannabidiol.
4. a kind of for treating the preparation side of the composition containing cannabidiol of nervous tinnitus according to claim 3
Method, which is characterized in that step 1 (2) the Trichoderma harzianum seed culture condition is 25 DEG C of culture 48h, the Trichoderma harzianum seed
The mycelial concentration of liquid is 200~250g/L；The solid-liquid ratio of the sterilized Chinese fiber crops powder and potato dextrose broth
For 1:1, the access amount of the Trichoderma harzianum seed liquor is that sterilized Chinese fiber crops powder is mixed with potato dextrose broth
Expect the 5~10% of quality；The temperature of the solid culture is 28 DEG C, relative humidity 92%, incubation time 5d, the high pressure
Sterilizing is the 40min that sterilizes in 120 DEG C of autoclaves, described to crush to be crushed to 40 mesh.
5. described a kind of for treating the preparation of the composition containing cannabidiol of nervous tinnitus according to claim 3 or 4
Method, which is characterized in that step 1 (3) the bacillus polymyxa seed culture condition is 37 DEG C, revolving speed is that 220r/min shakes
For 24 hours, the gemma rate of the bacillus polymyxa seed liquor is 90% or more for bed culture；The sterilized Trichoderma harzianum, which ferments, to be trained
The solid-liquid ratio for supporting object and nutrient broth medium is 1:1, and the dense bacterium of the bacillus polymyxa seed liquor is 106~108CFU/
mL；The condition of the solid culture is 28 DEG C, for 24 hours, the high pressure sterilization is 120 to fermented and cultured under conditions of relative humidity 80%
Sterilize 40min in DEG C autoclave.
6. a kind of for treating the preparation side of the composition containing cannabidiol of nervous tinnitus according to claim 5
Method, which is characterized in that step 1 (4) macroporous absorbent resin is DM-130 macroporous absorbent resin, the macroporous absorbent resin
Solid-liquid ratio between quality and the volume of the concentrated liquid is 1:5；The adsorption temp is 25 DEG C, hemp in the cannabidiol concentrate
The content of diphenol is 60~70%；The silica gel column chromatography is 200 mesh silica gel column chromatographies, and the flow rate of mobile phase is 10mL/
Min, the cannabidiol solid purity are 98%.
7. a kind of for treating the preparation side of the composition containing cannabidiol of nervous tinnitus according to claim 6
Method, which is characterized in that speed of agitator described in step 2 is 200~300rpm, and the ultrasonic power is 100~500W, described super
The sound decentralized processing time is 10~15min.
8. a kind of for treating the preparation side of the composition containing cannabidiol of nervous tinnitus according to claim 7
Method, which is characterized in that high speed shear revolving speed described in step 3 is 5000~7000rpm.
9. a kind of for treating the preparation side of the composition containing cannabidiol of nervous tinnitus according to claim 8
Method, which is characterized in that high speed shear revolving speed described in step 4 is 10000~13000rpm, and the high speed shear processing time is 5
~20min, the pressure of the high-pressure homogeneous processing are 1500~2200bar, and the number of the high-pressure homogeneous circular treatment is 10
~20 times.
10. a kind of for treating the preparation side of the composition containing cannabidiol of nervous tinnitus according to claim 9
Method, which is characterized in that the composition is translucent milky liquid, average particle size≤100nm of drop.
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| US20230218542A1 (en) * | 2022-01-12 | 2023-07-13 | Shumin Liu | Medicament for treating hypertension |
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