CN106214850A - A kind of blood fat reducing and the composition of natural products that protects the liver and preparation method thereof - Google Patents
A kind of blood fat reducing and the composition of natural products that protects the liver and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of blood fat reducing and the composition of natural products protected the liver and preparation method thereof, blood fat reducing of the present invention and the composition of natural products protected the liver are by tea polyphenols, olive oil and perilla oil and adjuvant are prepared from, three taste natural product Synergistics, can well treat hyperlipidemia, for the blood fat reducing provided relative to prior art and the compositions protected the liver, use less medical material, play more preferable curative effect, good liver protective effect can also be reached while preferably treatment hyperlipidemia, it is that one has no side effect, curative effect reliable pure natural product compositions.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to a kind of blood fat reducing and the composition of natural products protected the liver and system thereof
Preparation Method.
Background technology
Lipid metabolism or operating make one or more lipids of blood plasma extremely higher than being just frequently referred to hyperlipidemia.Hyperlipidemia is
A kind of systemic disease, refers to T-CHOL in blood (TC) and/or triglyceride (TG) is too high or HDL-C
(HDL-C) too low or low-density lipoprotein cholesterol (LDL) is too high, modern medicine is referred to as dyslipidemia.Lipid is insoluble or micro-
It is dissolved in water, it is necessary to existing with lipoprotein form with protein bound, therefore, hyperlipidemia is also commonly referred to as hyperlipoproteinemia.
The reason of Hyperlipemia is that feed is fatty and cholesterol food too much, has relation with inherited genetic factors etc. simultaneously.
" fat " in blood plasma mainly cholesterol and triglyceride, they and non-singleton, but turned with the form of apolipoprotein
Fortune, apolipoprotein mainly includes Chylomicron (CM), very low density lipoprotein (VLDL) (VLDL), intermediate density lipoprotein (IDL) (IDL), low close
Degree lipoprotein (LDL) and high density lipoprotein (HDL) five kinds.Hyperlipidemia can bring following harm:
1, this disease to the infringement of health be concealment, gradually, Progressive symmetric erythrokeratodermia and general.Its directly infringement is to accelerate whole body
Atherosclerosis, because the vitals of whole body will rely on tremulous pulse blood supply, oxygen supply, once tremulous pulse is blocked by atheromatous plaque,
May result in serious consequence.The renal failure etc. that arteriosclerosis causes, all closely related with hyperlipidemia.Numerous studies data
Showing, hyperlipidemia is apoplexy, coronary heart disease, myocardial infarction, cardiac sudden death independently important risk factor.A large amount of medical science are ground
Study carefully and show: the Therapeutic Method of hyperlipidemia can not be only by drug-layer side, taking good care of of health to be noticed.
2, the concentration of the lipid composition such as hyperlipidemia plasma cholesterol, triglyceride, total fat exceedes arm's length standard.Hyperlipidemia
The main harm of disease is to cause atherosclerosis, and then causes numerous relevant diseases, most common of which one mortality
Disease is exactly coronary heart disease.Serious chylomicronemia may result in acute pancreatitis, is another fatal disease.
3 additionally, hyperlipidemia is also to promote hypertension, impaired glucose tolerance, an important risk factor of diabetes.High
Blood fat disease can also result in fatty liver, liver cirrhosis, cholelithiasis, pancreatitis, retinal hemorrhage, blind, peripheral vascular disease, limping, height
Hyperuricemia.Some constitutional and familial hyperlipemia it may also occur that around tendon shape, nodositas, palm plane and eye socket.
Therefore, reduce blood lipid level and be the important of prevention and treatment cardiovascular and cerebrovascular disease and effective means.
Blood lipid-lowering medicine is wide in variety at present, and effect is different, a certain in its mechanism of action generally interference Regulating Lipid Metabolism
Or several link, as reduced decomposition and the excretion that lipid absorbs or accelerates lipid, the synthesis of interference liver lipoprotein or stop fat
Albumen transmits into blood plasma in liver, increases the speed etc. that lipoprotein is removed from serum.Conventional natural product has Xuezhikang etc..
Western medicine Statins, fibrate are notable to the comparitive study of the symptoms such as hyperlipidemia, but Western medicine is while blood fat reducing at present, meeting
Cause the reactions such as blood glucose rising, nauseating, diarrhoea and liver function injury.And natural product has good effect for reducing blood fat and secondary
Act on less, become the important selection of blood fat reducing.
Applicant applied for two pieces blood fat reducing and the patent protected the liver in 2008, Application No. CN2008103001439,
200810300483.1, this composition of natural products is by crude drug Fructus Ligustri Lucidi or Rhizoma Alismatis and tea polyphenols, olive oil and Fructus Perillae
Oil is prepared from, and while effectively alleviating hyperlipidemia, also has obvious hepatoprotective effect, and inventor is in this two pieces application
On the basis of, blood fat reducing and the composition of natural products that protects the liver are further studied.
Summary of the invention
The technical problem to be solved is to provide a kind of blood fat reducing and the composition of natural products protected the liver and preparation thereof
Method, this composition of natural products has more preferable blood fat reducing and the effect protected the liver, provides this composition of natural products simultaneously
Preparation method.
In order to solve above-mentioned technical problem, the present invention adopts the following technical scheme that:
A kind of blood fat reducing of the present invention and the composition of natural products protected the liver, by the natural product system of following weight portion
Become: tea polyphenols 40～100 parts, olive oil 160～260 parts, perilla oil 160～260 parts.
Preferably, composition of natural products of the present invention is made up of the natural product of following weight portion: tea polyphenols 50
～90 parts, olive oil 170～250 parts, perilla oil 170～250 parts.
It is further preferred that composition of natural products of the present invention is made up of the natural product of following weight portion: tea
Polyphenol 55～85 parts, olive oil 180～240 parts, perilla oil 180～240 parts.
It is further preferred that composition of natural products of the present invention is made up of the natural product of following weight portion:
Tea polyphenols 60～80 parts, olive oil 190～230 parts, perilla oil 190～230 parts.
Further preferred, that the present invention provides composition of natural products, is made up of the natural product of following weight portion: tea
Polyphenol 70 parts, 210 parts of olive oil, perilla oil 215 parts.
The composition of natural products that the present invention provides, described adjuvant is Cera Flava, gelatin, glycerol, purified water, cacao pigment
Element.
Preferably, the composition of natural products that the present invention provides, described adjuvant is calculated as by weight: Cera Flava 6～14 parts,
Gelatin 86～130 parts, glycerol 43～65 parts, Cacao pigment 1.2～1.8 parts, purified water 86～130 parts of compositions.
Further preferably, the composition of natural products that the present invention provides, described adjuvant is calculated as by weight: Cera Flava 10
Part, 108 parts of gelatin, glycerol 54 parts, Cacao pigment 1.5 parts, purified water 108 parts composition.
Present invention also offers the method preparing above-mentioned composition of natural products, by tea polyphenols, olive oil and perilla oil
Add customary adjuvant, make drop pill, powder, capsule, tablet, granule, oral liquid according to common process.
Concrete, present invention also offers the preparation method of above-mentioned composition of natural products, be made up of following steps:
1), time perilla oil, olive oil are heated to 50-90 DEG C, adding the Cera Flava of formula ratio so that it is melted, stirring is all
Even, it is cooled to 25～35 DEG C, obtains oily wax liquid, standby；Tea polyphenols being crossed 100 mesh sieves, adds in above-mentioned oil wax liquid, stirring mixing is all
After even, it is evacuated to-0.06～-0.08MPa, de-bubbled, obtain capsule-core feed liquid；
2), by glycerol and purified water putting into glue tank, when being heated to 50～90 DEG C, add gelatin, Cacao pigment, stir
Mix and boil 1.5-2h, be evacuated to-0.06～-0.08MPa, take off bubble, 100 mesh screen, obtain capsule hide glue gelatin, 55～65
DEG C insulation is standby；
3), at indoor temperature 18～26 DEG C, relative humidity 45～55%, capsule-core feed liquid is transported to the stock chest of pellet press
In；Transport to capsule hide glue gelatin, in the storage glue groove of pellet press, start pellet press and can be prepared by soft capsule.
Preferably, the preparation method of the above-mentioned composition of natural products that the present invention provides, it is made up of following steps:
1), time perilla oil, olive oil are heated to 70-80 DEG C, adding the Cera Flava of formula ratio so that it is melted, stirring is all
Even, it is cooled to 30 DEG C, obtains oily wax liquid, standby；Tea polyphenols is crossed 100 mesh sieves, adds in above-mentioned oil wax liquid, be uniformly mixed
After, it is evacuated to-0.06～-0.08MPa, de-bubbled, obtain capsule-core feed liquid；
2), by glycerol and purified water putting into glue tank, when being heated to 70-80 DEG C, add gelatin, Cacao pigment, stir
Mix and boil 1.5-2h, be evacuated to-0.06～-0.08MPa, take off bubble, 100 mesh screen, obtain capsule hide glue gelatin, 55～65
DEG C insulation is standby；
3), at indoor temperature 18～26 DEG C, relative humidity 45～55%, capsule-core feed liquid is transported to the stock chest of pellet press
In；Transport to capsule hide glue gelatin, in the storage glue groove of pellet press, start pellet press and can be prepared by soft capsule.
Described composition weight number can be unit of weight known to the field of medicaments such as μ g, mg, g, kg.
Tea polyphenols is Catechin in Tea class, flavonoid, phenolic acids and the general name of anthocyan compound, to organic
Lipid metabolism produces important effect, has and significantly suppresses the effect that in blood plasma and liver, cholesterol level rises, has rush
Entering the effect that lipoid substance is discharged from feces, therefore it not only can reduce blood fat, suppresses atherosclerosis, and has guarantor
Liver, the effect of fat-reducing.Olive oil and perilla oil itself all have blood fat reducing hepatoprotective effect, individually have beauty treatment, fall with olive oil
Blood fat etc. act on.The present invention is acted on jointly by above three taste natural products, shows the effect of significant Synergistic, with existing
Fat-reducing liver-protecting composition of natural products is compared, and the present invention uses less medical material, plays more preferable curative effect, can significantly reduce serum
Middle triglyceride levels, is not result in that body weight increases simultaneously, and safe without toxic side effect is raw materials used few, low cost, technique letter
Single, it is suitable for the big production of industry.
Detailed description of the invention
Embodiment 1
Formula: tea polyphenols 70g, olive oil 210g, perilla oil 215g, Cera Flava 10g, gelatin 108g, glycerol 54g, cocoa
Pigment 1.5g, purified water 108g
Preparation method:
1), time perilla oil, olive oil are heated to 70-80 DEG C, adding the Cera Flava of formula ratio so that it is melted, stirring is all
Even, it is cooled to 30 DEG C, obtains oily wax liquid, standby；Tea polyphenols is crossed 100 mesh sieves, adds in above-mentioned oil wax liquid, be uniformly mixed
After, it is evacuated to-0.06～-0.08MPa, de-bubbled, obtain capsule-core feed liquid；
2), by glycerol and purified water putting into glue tank, when being heated to 70-80 DEG C, add gelatin, Cacao pigment, stir
Mix and boil 1.5h, be evacuated to-0.06～-0.08MPa, take off bubble, 100 mesh screen, obtain capsule hide glue gelatin, at 55～65 DEG C
It is incubated standby；
3), at indoor temperature 18～26 DEG C, relative humidity 45～55%, capsule-core feed liquid is transported to the stock chest of pellet press
In；Transport to capsule hide glue gelatin, in the storage glue groove of pellet press, start pellet press and can be prepared by soft capsule.
Usage: oral, every day 2 times, each 3.
Embodiment 2
Formula: tea polyphenols 40g, olive oil 160g, perilla oil 160g, Cera Flava 6g, gelatin 86g, glycerol 43g, cocoa
Element 1.2g, purified water 86g
Preparation method:
1), time perilla oil, olive oil are heated to 70-80 DEG C, adding the Cera Flava of formula ratio so that it is melted, stirring is all
Even, it is cooled to 30 DEG C, obtains oily wax liquid, standby；Tea polyphenols is crossed 100 mesh sieves, adds in above-mentioned oil wax liquid, after being uniformly mixed
Cross colloid mill to grind 1 time, be evacuated to-0.06～-0.08MPa, de-bubbled, obtain capsule-core feed liquid；
2), by glycerol and purified water putting into glue tank, when being heated to 70-80 DEG C, add gelatin, Cacao pigment, stir
Mix and boil 1.5h, be evacuated to-0.06～-0.08MPa, take off bubble, 100 mesh screen, obtain capsule hide glue gelatin, at 55～65 DEG C
It is incubated standby；
3), at indoor temperature 18～26 DEG C, relative humidity 45～55%, capsule-core feed liquid is transported to the stock chest of pellet press
In；Transport to capsule hide glue gelatin, in the storage glue groove of pellet press, start pellet press and can be prepared by soft capsule.
Usage: oral, every day 2 times, each 3.
Embodiment 3
Formula: tea polyphenols 100g, olive oil 260g, perilla oil 260g, Cera Flava 14g, gelatin 130g, glycerol 65g, cocoa
Pigment 1.8g, purified water 130g
Preparation method: be prepared as soft capsule by embodiment 1 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 4
Formula: tea polyphenols 50g, olive oil 170g, perilla oil 170g, Cera Flava 14g, gelatin 120g, glycerol 60g, cocoa
Pigment 1.2g, purified water 110g.
Preparation method:
It is prepared as soft capsule by embodiment 2 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 5
Formula: tea polyphenols 90g, olive oil 260g, perilla oil 250g, Cera Flava 8g, gelatin 120g, glycerol 60g, cocoa
Element 1.2g, purified water 90g
Preparation method:
It is prepared as soft capsule by embodiment 1 preparation method
Usage: oral, every day 2 times, each 3.
Embodiment 6
Formula: tea polyphenols 40g, olive oil 260g, perilla oil 260g, Cera Flava 14g, gelatin 110g, glycerol 60g, cocoa
Pigment 1.8g, purified water 120g
Preparation method:
1), time perilla oil, olive oil are heated to 50 DEG C, add the Cera Flava of formula ratio so that it is melted, stir,
It is cooled to 30 DEG C, obtains oily wax liquid, standby；Tea polyphenols is crossed 100 mesh sieves, adds in above-mentioned oil wax liquid, be uniformly mixed, take out true
Empty to-0.06～-0.08MPa, de-bubbled, obtain capsule-core feed liquid；
2), by glycerol and purified water putting into glue tank, when being heated to 50 DEG C, adding gelatin, Cacao pigment, stirring is endured
2h processed, is evacuated to-0.06～-0.08MPa, takes off bubble, 100 mesh screen, obtains capsule hide glue gelatin, standby 55～65 DEG C of insulations
With；
3), at indoor temperature 18～26 DEG C, relative humidity 45～55%, capsule-core feed liquid is transported to the stock chest of pellet press
In；Transport to capsule hide glue gelatin, in the storage glue groove of pellet press, start pellet press and can be prepared by soft capsule.
Usage: oral, every day 2 times, each 3.
Embodiment 7
Formula: tea polyphenols 100g, olive oil 160g, perilla oil 160g, Cera Flava 10g, gelatin 90g, glycerol 50g, cocoa
Pigment 1.2g, purified water 120g
Preparation method:
1), time perilla oil, olive oil are heated to 90 DEG C, add the Cera Flava of formula ratio so that it is melted, stir,
It is cooled to 35 DEG C, obtains oily wax liquid, standby；Tea polyphenols is crossed 100 mesh sieves, adds in above-mentioned oil wax liquid, be uniformly mixed, take out true
Empty to-0.06～-0.08MPa, de-bubbled, obtain capsule-core feed liquid；
2), by glycerol and purified water putting into glue tank, when being heated to 90 DEG C, adding gelatin, Cacao pigment, stirring is endured
1.5h processed, is evacuated to-0.06～-0.08MPa, takes off bubble, 100 mesh screen, obtains capsule hide glue gelatin, 55～65 DEG C of insulations
Standby；
3), at indoor temperature 18～26 DEG C, relative humidity 45～55%, capsule-core feed liquid is transported to the stock chest of pellet press
In；Transport to capsule hide glue gelatin, in the storage glue groove of pellet press, start pellet press and can be prepared by soft capsule.
Usage: oral, every day 2 times, each 3.
Embodiment 8
Formula: tea polyphenols 60g, olive oil 230g, perilla oil 190g, Cera Flava 8g, gelatin 86g, glycerol 45g, cocoa
Element 1.4g, purified water 110g
Preparation method:
It is prepared as soft capsule by embodiment 7 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 9
Formula: tea polyphenols 80g, olive oil 190g, perilla oil 230g, Cera Flava 14g, gelatin 95g, glycerol 60g, cocoa
Element 1.4g, purified water 90g
Preparation method:
It is prepared as soft capsule by embodiment 7 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 10
Formula: tea polyphenols 55g, olive oil 180g, perilla oil 240g, Cera Flava 13g, gelatin 115g, glycerol 55g, cocoa
Pigment 1.3g, purified water 110g
Preparation method:
It is prepared as soft capsule by embodiment 6 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 11
Formula: tea polyphenols 85g, olive oil 240g, perilla oil 180g, Cera Flava 7g, gelatin 86g, glycerol 65g, cocoa
Element 1.2g, purified water 110g
Preparation method:
It is prepared as soft capsule by embodiment 7 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 12
Formula: tea polyphenols 55g, olive oil 180g, perilla oil 180g, Cera Flava 7g, gelatin 86g, glycerol 65g, cocoa
Element 1.2g, purified water 110g
Preparation method:
It is prepared as soft capsule by embodiment 7 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 13
Formula: tea polyphenols 85g, olive oil 240g, perilla oil 240g, Cera Flava 13g, gelatin 115g, glycerol 55g, cocoa
Pigment 1.3g, purified water 110g
Preparation method:
It is prepared as soft capsule by embodiment 6 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 14
Formula: tea polyphenols 60g, olive oil 190g, perilla oil 190g, Cera Flava 13g, gelatin 115g, glycerol 55g, cocoa
Pigment 1.3g, purified water 110g
Preparation method:
It is prepared as soft capsule by embodiment 6 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 15
Formula: tea polyphenols 80g, olive oil 230g, perilla oil 230g, Cera Flava 13g, gelatin 115g, glycerol 55g, cocoa
Pigment 1.3g, purified water 110g
Preparation method:
It is prepared as soft capsule by embodiment 6 preparation method.
Usage: oral, every day 2 times, each 3.
Embodiment 16
Formula: tea polyphenols 60g, olive oil 190g, perilla oil 190g
The preparation method of drop pill:
Take gelatin 86g, glycerol 43g, water 86g mix homogeneously, in 60～70 DEG C of heating in water bath 1 hour, add tea while hot many
Phenol stirs, and is cooled to 65 DEG C, obtains rubber cement, standby 65 DEG C of insulations, by olive oil and perilla oil in 60～70 DEG C of water-baths
After preheating, being stirred continuously lower addition 50ml water, stirring 0.5h carries out emulsifying, and emulsion is being stirred continuously lower addition rubber cement
In, stir and carry out emulsifying in 4 hours, by dosing pump pill dripping machine dripping, 13～15 DEG C of liquid Paraffin make condensed fluid, constant pressure and dry, system
Obtain drop pill.
Usage: oral, every day 2 times, each 3.
Embodiment 17
Prescription: tea polyphenols 80g, olive oil 230g, perilla oil 230g
Preparation method:
1) take gelatin 86g, soak after 0.5h with water 60g, dissolve in 60～70 DEG C of water-baths gelatin solution is standby, by tea
Polyphenol, olive oil and perilla oil add in gelatin solution, add 50 DEG C of distilled water to 100mL, stirring, then add after stirring
Enter the 60%Na of 200mL 50 DEG C2SO4Solution, mixing, keep mixed liquor at 50 DEG C, under stirring, add the 72% of 35～45 DEG C
Na2SO4Solution 500mL, is cooled to 32～35 DEG C naturally, is placed on rapid cooling in ice-water bath and, to less than 10 DEG C, is stirred continuously, and adds
37%HCHO solution 8mL, after stirring 20min, is adjusted to pH 9.0 with 20%NaOH, continues stirring 1h, centrifugal, divides and takes microcapsule, water
It is washed till neutral formaldehydeless, lyophilization, obtain dry microcapsule.
2) in step 1) gained microcapsule adds the starch of 2 times, pelletize, obtain the granule of the present invention.
Usage: oral, every day 2 times, each 1 bag.
Embodiment 18
Formula: tea polyphenols 60g, olive oil 230g, perilla oil 190g
Preparation method:
Prepare microcapsule by embodiment 13 step 1 method, add the starch of 1 times, tabletting, obtain the tablet of the present invention.
Usage: oral, every day 2 times, each 3.
Embodiment 19
Formula: tea polyphenols 80g, olive oil 190g, perilla oil 230g, gelatin 86g, water 130g
Preparation method:
Prepare microcapsule by embodiment 13 step 1 method, load capsule, obtain the capsule of the present invention.
Usage: oral, every day 2 times, each 3.
Embodiment 20
Prescription: tea polyphenols 55g, olive oil 240g, perilla oil 180g, gelatin 86g, water 130g.
Preparation method:
Prepare microcapsule by embodiment 13 step 1 method, add the pure water of 3 times and the sweeting agent of 0.2 times, mixing,
Perfusion, gland, sterilizing, obtain oral liquid.
Usage: oral, every day 2 times, each 1 bottle.
Embodiment 21
Formula: tea polyphenols 85g, olive oil 180g, perilla oil 240g, gelatin 90g, water 130g.
Preparation method:
Preparing microcapsule by embodiment 13 step 1 method, be dried, pulverize, fineness reaches below 1mm, hybrid packed i.e.
Obtain powder.
Usage: oral, every day 2 times, each 1 bag.
Comparative example 22 positive controls sample 1CN101234160B embodiment 1
Formula: Rhizoma Alismatis 2000g, tea polyphenols 20g, olive oil 250g, perilla oil 250g
Preparation method:
Taking Rhizoma Alismatis, pulverize, add 8 times amount ethanol extraction 3 times, 2 hours for the first time, 1 hour for the second time, 1 is little for the third time
Time, filtering, merging filtrate, filtrate reduced in volume becomes extractum (extracting liquid volume: concentrated solution volume=75: 1), adds water stirring all
Even, stand, take upper strata grease and i.e. obtain Rhizoma Alismatis extract.By Rhizoma Alismatis extract, tea polyphenols, olive oil, perilla oil and Cera Flava
It is placed in material-compound tank, grinds to obtain oily mixture with the rotating speed of 6000r/min, cross 80～100 mesh sieves, obtain implant.By gelatin
Add transconversion into heat glue at 60～70 DEG C, add plasticizer and pigment, make translucent glue, with gelatin glue as softgel shell, adopt
Preparing soft capsule preparation by die pressing, the sprinkler body temperature in die pressing is 50 DEG C, 18～20 DEG C, shape under the conditions of RH ＜ 30%
Being dried, dynamically air-dry 6～12 hours, clean outside capsule, polishing, room temperature is dried in the air ball 12～16 hours, prepares soft capsule preparation
1000.Oral, every day 2 times, each 3.
Comparative example 23 positive controls sample 2CN101229233B embodiment 1
Formula: Fructus Ligustri Lucidi 2000g, tea polyphenols 20g, olive oil 250g, perilla oil 250g, Cera Flava 1.5g
Preparation method:
Take and pulverize as the Fructus Ligustri Lucidi of coarse powder, with alcohol reflux three times, add 7 times amount ethanol extractions 1.5 little every time
Time, united extraction liquid, filter, 6 times of filtrate reduced in volume to Fructus Ligustri Lucidi weight, add Fructus Ligustri Lucidi weight 15%
Activated carbon, is heated to reflux 5 hours, filters, and filtrate reduced in volume to 60 DEG C relative density is the extractum of 1.10～1.20, adds 8 times
Measure water-soluble scattered extractum, with 20% hydrochloric acid solution regulate to pH1.5, be sufficiently stirred for, stand 24 hours, filter, precipitate wash with water to
PH 7.0, drying under reduced pressure, obtain light brown Fructus Ligustri Lucidi extract.Take light brown Fructus Ligustri Lucidi extract, tea polyphenols, olive oil, Folium Perillae
Seed oil and Cera Flava are placed in material-compound tank, grind to obtain oily mixture with the rotating speed of 6000r/min, cross 80～100 mesh sieves, obtain filling
Thing.Gelatin is added transconversion into heat glue at 60～70 DEG C, adds plasticizer and pigment, make translucent glue, make with gelatin glue
For softgel shell, using die pressing to prepare soft capsule preparation, the sprinkler body temperature in die pressing is 50 DEG C, at 18～20 DEG C, RH ＜ 30%
Under the conditions of sizing be dried, dynamically air-dry 6～12 hours, clean outside capsule, polishing, room temperature is dried in the air ball 12～16 hours, prepares soft
Capsule preparations 1000.Oral, every day 2 times, each 3.
Inventor has carried out pharmacodynamic experiment to blood fat reducing and the composition of natural products that protects the liver, specific as follows:
One, the present invention reduces blood fat function animal experiment
1 materials and methods
1.1 tested material blood fat reducing soft capsules of the present invention, CN101234160B embodiment 1 and CN101229233B embodiment 1
Soft capsule is provided by hall (Guizhou) pharmaceutical Co. Ltd of Tongji University of traditional Chinese medicines group, and sample is tan solid, it is recommended that amount 3.0g/
My god/people, by adult's 60kg weighing machine, it is recommended that measure as 0.05g/kg BW/ days.
The SPF level that 1.2 experimental animals select Zhejiang Province's Experimental Animal Center to provide is healthy, adult, body weight 160～180g, male
Property SD rat 82.Laboratory animal production licence number is SCXK (Zhejiang) 2014-0001, and laboratory animal use credit number is
SYXK (Zhejiang) 2011-01660.
1.3 animal feeding ambient room temperature 20～25 DEG C, relative humidity 40～70%, sub-cage rearing.
1.4 normal feedstuff are provided by Zhejiang Province's Experimental Animal Center.
1.5 model feed base feedstuffs 54.4%, sucrose 20.0%, Adeps Sus domestica 15%, cholesterol 1.2%, sodium cholate
0.2%, casein 8.2%, calcium hydrogen phosphate 0.4%, stone powder 0.6%.
1.6 key instrument Liasys automatic clinical chemistry analyzers, electronic balance etc..
1.7 test method
1.7.1 giving tested material mode per os every day gavage once, gavage amount is 5ml/kg body weight.
1.7.2 dose design sets with the 5 of human body recommended amounts, 10,30 times is basic, normal, high three dosage groups, i.e. present invention fall
Blood fat soft capsule 0.25,0.50,1.50g/kg three dosage groups of body weight, separately set two positive controls, a blank group
With a model control group.
1.7.3 operating procedure
1.7.3.1 sample preparation:
Blank group: salad oil；
Model control group: salad oil；
0.25g/kg body weight group: add salad oil in sample stock solution 5g and mix to 100ml ratio；
0.50g/kg body weight group: add salad oil in sample stock solution 10g and mix to 100ml ratio；
1.50g/kg body weight group: add salad oil in sample stock solution 30g and mix to 100ml ratio；
Positive controls 1: add salad oil in CN101234160B embodiment 1 soft capsule 10g and mix to 100ml ratio；
Positive controls 2: add salad oil in CN101229233B embodiment 1 soft capsule 10g and mix to 100ml ratio；
1.7.3.2 animal packet and observation index
1.7.3.2.1 laundering period rat feeding normal feedstuff is observed 5 days.
1.7.3.2.2 the modeling phase is randomly divided into 2 groups by body weight, and 12 rats give normal feedstuff as blank group,
70 are only given model feedstuff carries out modeling.Weigh in weekly 1 time.
After modeling rat gives model feedstuff 2 weeks, blank group and modeling rat non-fasting blood sampling (ophthalmic adjoins), blood sampling
After separate serum as early as possible, measure serum TC, TG, LDL-C, HDL-C level.Select 66 modeling success rats random according to TC level
It is divided into 6 groups, often group 11, if a model control group and basic, normal, high three dosage groups and two positive controls.
1.7.3.2.3, after given the test agent gives packet, three dosage groups and two positive controls per os every day give phase
Answering the given the test agent of dosage, blank group and model control group to give the salad oil of same volume, blank group continues simultaneously
Giving normal feedstuff, model control group, two positive controls and three dosage groups continue to give model feedstuff, and weigh weekly
Body weight once, continuous 30 days, at the end of experiment, took a blood sample (ophthalmic adjoins), separates serum after blood sampling as early as possible, measures serum by non-fasting
TC, TG, LDL-C, HDL-C level.
1.8 data process and use SPSS statistical software to carry out variance analysis, first carry out variance by the program of variance analysis neat
Property inspection, variance is neat, calculates F value, F value < F0.05, conclusion: respectively organize no significant difference between mean；F value >=F0.05, P≤
0.05, add up with the comparative approach two-by-two of mean between multiple experimental grouies and a matched group；To abnormal or heterogeneity of variance
Data carry out the conversion of suitable variable, after meeting normal state or variance requires together, add up by the data after conversion；If becoming
Still it is not up to normal state or the neat purpose of variance after amount conversion, uses rank test instead and add up.
1.9 results judge that modeling rat is compared with blank group, and serum TG raises, serum total cholesterol or low
Density lipoprotein-cholesterol raises, and difference all has significance, it is determined that model is set up.(1) each dosage group compares with model control group,
Arbitrary dosage group serum total cholesterol or low-density lipoprotein cholesterol reduce, and arbitrary dosage group serum triglycerides reduces,
Difference all has significance, the most each dosage group serum High Density Lipoprotein Cholesterol to be not significantly lower than model control group, can determine that
It is positive that this given the test agent reduces blood fat function results of animal.(2) each dosage group compares with model control group, arbitrary dosage group
Serum total cholesterol or low-density lipoprotein cholesterol reduce, and difference all has significance, the most each dosage group serum triglycerides
Being not significantly higher than model control group, each dosage group serum High Density Lipoprotein Cholesterol is not significantly lower than model control group, can sentence
It is positive that this given the test agent fixed reduces cholesterol function results of animal.(3) each dosage group compares with model control group, arbitrary dose
Amount group serum triglycerides reduces, and difference has significance, and the most each dosage group serum total cholesterol and low density lipoprotein, LDL gallbladder are solid
Alcohol is not significantly higher than model control group, and serum High Density Lipoprotein Cholesterol is not significantly lower than model control group, can determine that this is subject to
It is positive that test agent reduces triglyceride function results of animal.
2 experimental results
The model control group rat that affects of experimental rat body weight is opened by 2.1 blood fat reducing soft capsules of the present invention from modeling second week
The body weight begun at the end of experiment is above corresponding blank group, and first week, second week and 4th week upon administration
Its difference has significant (P < 0.05).Dosage group rat low, middle starts the body weight at the end of experiment from modeling second week
It is above corresponding blank group, and low dose group second week upon administration, middle dosage group upon administration first week
Its difference has significant (P < 0.05).The body weight that high dose group rat starts at the end of experiment from modeling second week is the highest
In corresponding blank group, but its difference there are no significant meaning (P > 0.05)；Basic, normal, high dosage group rat is from modeling
The body weight started at the end of extremely testing for one week is compared with corresponding positive controls 1, positive controls 2, and body weight increases less than sun
Property matched group, there was no significant difference ((P > 0.05) (being shown in Table 1).
The impact (g, x scholar s) on rat body weight of table 1. blood fat reducing soft capsule of the present invention
Note: * compares p < 0.05 with blank group.
2.2 blood fat reducing soft capsules of the present invention are to Serum TC, the impact of TG, LDL-C, HDL-C, model comparison before being administered
Group, two positive controls and three dosage group Serum TC, TG, LDL-C (are P=obviously higher than blank group
0.000)；Before being administered model control group, two positive controls and three dosage group rat blood serum HDL-C all with blank group
Close, its difference there are no significant difference (P > 0.05), show this experiment modeling success.Model control group after administration, two
Positive controls and three dosage group Serum TC, LDL-C is obviously higher than blank group (being P=0.000)；It is administered
Rear model control group, two positive controls and three dosage group rat blood serum HDL-C are all close with blank group, its difference
Difference that there are no significant (P > 0.05).It is administered rear three dosage group rat blood serum TG the most substantially to reduce, increases reduction with dosage and become
Gesture is obvious, compares with model control group and all has significant difference (respectively P=0.043, P=0.001, P=0.000)；Middle and high
Dosage group is close with blank group, and there are no significant for its difference (P > 0.05)；Low dose group and positive controls 1, positive right
Close according to group 2, middle and high dosage group TG value is below corresponding positive controls 1, positive controls 2, its difference nonsignificance.
Show blood fat reducing soft capsule of the present invention to have substantially and reduce rat blood serum triglyceride effect, and effect is better than positive controls medicine
Thing (be shown in Table 2, table 3, table 4, table 5).
The impact on Serum TC of table 2 blood fat reducing soft capsule of the present invention
Note: P value 1 compares with blank group, P value 2 compares with model control group.
The impact on rat blood serum TG of table 3 blood fat reducing soft capsule of the present invention
Note: P value 1 compares with blank group, P value 2 compares with model control group.
The impact on rat blood serum LDL-C of table 4 blood fat reducing soft capsule of the present invention
Note: P value 1 compares with blank group, P value 2 compares with model control group.
The impact on rat blood serum HDL-C of table 5 blood fat reducing soft capsule of the present invention
Note: P value I compares with blank group, P value 2 compares with model control group.
4. conclusion
This test sets 0.25,0.50,1.50g/kg body weight three dosage group, is equivalent to the 5,10,30 of human body recommended amounts
Times, separately set two positive controls, a blank group and a model control group, within continuous one month, per os gavage gives greatly
The tested material of Mus various dose.Test result indicate that: three dosage of 0.25,0.50,1.50g/kg body weight all can significantly reduce greatly
Mus serum triglyceride level (P < 0.05), the positive that middle decrease in dose rat blood serum triglyceride levels is better than Isodose is right
According to group 1 and positive controls 2.Prompting submitted sample has reduction triglyceride function, and effect is better than positive controls 1 and sun
Property matched group 2.
Two, toxicological test
1 sample property and process: blood fat reducing soft capsule of the present invention is provided by Guizhou Tongjitang Pharmaceutical Co., Ltd, sample is
Tan solid.Human body recommended intake is 3.0g/ days, and by 60 kg body weight, human body recommended intake is 0.05g/kg
BW.Sample is configured to the sample liquid of variable concentrations for experiment with salad oil for solvent.
2 laboratory animals and testing conditions: ICR mice is provided by Zhejiang Province's Experimental Animal Center in experiment, SPF level, experiment
Animal productiong credit number is SCXK (Zhejiang) 2014-0001, and laboratory animal uses credit number to be SYXK (Zhejiang) 2014-0008.
Laboratory animal feedstuff is provided by Zhejiang Province's Experimental Animal Center.Detection environmental condition, temperature range 20～25 DEG C, relative humidity model
Enclose 40～70%.
3 experimental techniques:
3.1 chmice acute Oral toxicity tests:
3.1.1 laboratory animal: select healthy, ripe, body weight 18～22g ICR mice 20, each 10 of male and female mice.
3.1.2 dosage and medication: set mono-dosage group of sample stock solution 20.0mL/kg BW by maximum tolerated dose method.Little
After Mus fasting (can't help water) 16 hours, give sample stock solution once by 20mLlkg BW gavage capacity gavage.Gavage is dynamic after 2 hours
Thing ad lib, drinking-water, record animal poisoning manifestations and death condition.
3.1.3 observation index: after gavage, observes the general status of mice, poisoning manifestations and death condition.Observation period is limited to
7 days, record mouse experiment beginning and end of term body weight.
3.2 Salmonella reversion tests:
3.2.1 test strain: select histidine auxotroph Salmonella typhimurium, totally four strains, i.e. TA97a,TA98,
TA100, TA102.Bacterial strain is provided by Shanghai Disease Prevention and Control Centre, tests after Biology identification is qualified.
3.2.2 dosage choice and positive control: test uses flat board incorporation methods.Weigh sample 0.05g, grind with DMSO
Being configured to 10.0mL solution, 0.103Mpa, sterilizing in 20 minutes, with sterilizing DMSO gradient dilution to each dosage during experiment.Use TA100
The non-metabolism activation system of bacterial strain carries out trial test, and bacterium and antibacterial does not occurs significantly increasing when dosage is 5000 μ g/ ware in result
Phenomenon, therefore during formal test, Selection experiment concentration is 8,40,200,1000,5,000 five dosage groups of μ g/ ware, additional blank is right
According to, solvent control and positive controls (sodium azide, fenaminosulf, 2-second phthalein amino chrysanthemum, 1.8-dihydroxyanthraquinone).Every kind of bacterial strain is every
It is parallel that individual test concentrations sets three wares, is adding and is being not added with S9Under the conditions of test, retest is once.
3.2.3 observation index: directly in counting culture medium, returning of each bacterial strain becomes clump count.
3.2.4 result judges: with count culture medium become last time clump count number depending on, as in background growth good condition
Under, tested material group is returned change clump count and is doubled above, and has dose-response relationship or the most a certain test point to have repeatably
And statistically significant positive reaction, i.e. it is believed that this tested material Salmonella reversion test is positive.
3.3 mouse marrow cell micro nuclear test
3.3.1 laboratory animal: select healthy, ripe, the mice of body weight 25～30g 50, male and female half and half.Mice is divided at random
Become 5 groups, often group 10, male and female half and half.
3.3.2 dosage and medication: experiment sets 2.5,5.0,10.0g/kg BW tri-dosage groups weigh sample respectively
5.0,10.0,20.0g, 40mL sample liquid it is configured to respectively with salad oil for solvent.Separately set a negative control group (salad oil)
(ring phosphorus phthalein amine 40mg/kg B W, weighs ring phosphorus phthalein amine 80mg, and adding distilled water, to be dissolved to 40mL standby with a positive controls
With).Mice gives tested material, gavage twice by 20mL/kg BW gavage capacity per os gavage, is spaced 24 hours.Fill in second time
After stomach, 6 hours cervical dislocation put to death animal, take bone marrow of sternum and make bone marrow sheet, and methanol is fixed, and Giemsa dyes.
3.3.3 observation index: 1000 polychromatic erythrocytes of every animal counting during microscopy, calculate micronucleus permillage and
PCE/NCE value.Data SPSS statistical software carries out statistical analysis.
3.4 mouse inbred strain:
3.4.1 laboratory animal: select healthy, mature weight 25～30g male mice 25.Mice is randomly divided into 5 groups, often
Organize 5.
3.4.2 dosage and medication: experiment sets 2.5,5.0, tri-dosage groups of 10.0g/kg BW, weigh sample respectively
5.0,10.0,20.0g, be configured to 40mL sample liquid respectively with salad oil for solvent.Separately set a negative control group (salad oil)
(ametycin 1.Smg/kg BW, weighs ametycin 1.5mg, adds physiological saline solution extremely with a positive controls
20mL is standby).Mice gives tested material by 20mL/kg BW gavage capacity per os gavage, continuous 5 days, every day 1 time.Fill in first
After stomach, the 35th day cervical dislocation puts to death animal, takes the attached kingfisher in both sides, makes suction strainer liquid direct smear, natural drying, and methanol is fixed,
1% eosin stains.
3.4.3 observation index: high power Microscopic observation sperm morphology also counts, every mice counting complete sperm 1000,
Calculate Sperm malformation rate (%).Data SPSS statistical software carries out statistical analysis.
4 experimental results:
4.1 chmice acute Oral toxicity tests: dead mouse situation is shown in Table 1.During experiment, during each mice is showed no substantially
Poison performance, also without dead.Blood fat reducing soft capsule of the present invention is all higher than 20.0mL/kg BW and belongs to nontoxic male and female its mouse oral MTD
Level.
Table 1 blood fat reducing soft capsule Mouse Acute Toxicity death condition
| Sex | Starting weight | Weight (g) eventually | Death condition (death toll/group Mus number) | MTD(mL/kg) |
| Female | 19.6 scholar 0.7 | 26.4 scholar 1.2 | 0/10 | >20.0 |
| Male | 20.2 scholar 0.8 | 28.2 scholar 1.1 | 0/10 | >20.0 |
4.2Ames tests: each bacterial strain return change clump count be shown in Table 2, table 3.From result of the test, variable concentrations tested material exists
Add and be not added with S9Under the conditions of return become bacterium colony close with negative control group, and positive controls return become clump count be above feminine gender
Matched group returns change clump count more than 2 times.Blood fat reducing soft capsule Salmonella reversion test testing result of the present invention is negative.
Table 2 blood fat reducing soft capsule of the present invention Salmonella reversion test result (for the first time)
NaN3 sodium azide Dexon is to dimethylamino benzene diazosulfonic acid sodium (fenaminosulf)
2AAF 2 one acetaminofluorene 1.8HAQ 1.8-dihydroxyanthraquinone
Table 3 blood fat reducing soft capsule of the present invention Salmonella reversion test result (for the second time)
NaN3 sodium azide Dexon is to dimethylamino benzene diazosulfonic acid sodium (fenaminosulf)
2AAF 2 one acetaminofluorene 1.8HAQ 1.8-dihydroxyanthraquinone
4.3 mouse marrow cell micro nuclear tests: male and female each dosage group PCE/NCE ratio is not below negative control group
20%, meet demand of technical standard.Blood fat reducing soft capsule of the present invention is shown in Table 4 to the impact of micronuclei in mice rate.With negative control group
Relatively, male and female each dosage group micronucleus permillage there are no significant difference (P > 0.05)；Positive controls micronuclear rates is then significantly higher than
Negative control group, its difference is very significant (P < 0.01).Show that blood fat reducing soft capsule of the present invention is thin to mouse bone marrow cells
Born of the same parents' micronuclear rates has no and significantly affects, and testing result is negative.
The impact on micronuclei in mice rate of table 4 blood fat reducing soft capsule of the present invention
Compare with negative control group, * P < 0.01
4.4 mouse inbred strain: the impact of Sperm Abnormalities of Mice is shown in Table by blood fat reducing soft capsule of the present invention
5.Compare with negative control group, each dosage group Sperm Abnormalities of Mice there are no significant difference (P > 0.05)；Positive control
Group is then apparently higher than negative control group, and its difference is very significant (P < 0.01).Show blood fat reducing soft capsule of the present invention
Having no Sperm Abnormalities of Mice and significantly affect, testing result is negative.
The impact on Sperm Abnormalities of Mice of table 5 blood fat reducing soft capsule of the present invention
Compare with negative control group, * P < 0.01 note: MMC, ametycin
5, brief summary: blood fat reducing soft capsule its mouse oral acute toxicity maximum tolerated dose (MTD) of the present invention, bisexuality is the most equal
More than 20.0mL/kg BW, judging by acute toxicity grading criteria, this sample belongs to nontoxic level.Blood fat reducing soft capsule of the present invention heredity
Toxicity test: Salmonella reversion test, mouse marrow cell micro nuclear test and mouse inbred strain result are feminine gender, points out at this
Under secondary experiment condition, this sample does not shows mutagenicity.
Although, used general explanation, detailed description of the invention and test, the present invention made detailed retouching
Stating, but on the basis of the present invention, it can be made some amendments or improve, this is aobvious and easy to those skilled in the art
See.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Scope.
Claims (10)
1. a blood fat reducing and the composition of natural products that protects the liver, it is characterised in that be made up of the natural product of following weight portion: tea
Polyphenol 40～100 parts, olive oil 160～260 parts, perilla oil 160～260 parts.
Composition of natural products the most according to claim 1, it is characterised in that by the natural product system of following weight portion
Become: tea polyphenols 50～90 parts, olive oil 170～250 parts, perilla oil 170～250 parts.
Composition of natural products the most according to claim 2, it is characterised in that by the natural product system of following weight portion
Become: tea polyphenols 55～85 parts, olive oil 180～240 parts, perilla oil 180～240 parts.
Composition of natural products the most according to claim 3, it is characterised in that by the natural product system of following weight portion
Become: tea polyphenols 60～80 parts, olive oil 190～230 parts, perilla oil 190～230 parts.
Composition of natural products the most according to claim 4, it is characterised in that by the natural product system of following weight portion
Become: tea polyphenols 70 parts, 210 parts of olive oil, perilla oil 215 parts.
6. according to the composition of natural products described in any one of claim 1-5, it is characterised in that also include adjuvant, by weight
Part is calculated as: Cera Flava 6～14 parts, gelatin 86～130 parts, glycerol 43～65 parts, Cacao pigment 1.2～1.8 parts, purified water 86
～130 parts of compositions.
Composition of natural products the most according to claim 6, it is characterised in that described adjuvant is calculated as by weight: honeybee
10 parts of wax, 108 parts of gelatin, glycerol 54 parts, Cacao pigment 1.5 parts, purified water 108 parts composition.
8. prepare the preparation method of composition of natural products described in any one of claim 1-5 for one kind, it is characterised in that many by tea
Phenol, olive oil and perilla oil add customary adjuvant, according to common process make soft capsule, oral liquid, drop pill, powder,
Tablet, granule, hard capsule.
9. prepare the preparation method of composition of natural products described in any one of claim 1-5 for one kind, it is characterised in that by following
Step is made:
1), time perilla oil, olive oil are heated to 50-90 DEG C, add the Cera Flava of formula ratio so that it is melted, stir, cold
But to 25～35 DEG C, oily wax liquid is obtained, standby；Tea polyphenols is crossed 100 mesh sieves, adds in above-mentioned oil wax liquid, be uniformly mixed, take out
Vacuum extremely-0.06～-0.08MPa, de-bubbled, obtain capsule-core feed liquid；
2), by glycerol and purified water putting into glue tank, when being heated to 50～90 DEG C, adding gelatin, Cacao pigment, stirring is endured
1.5-2h processed, is evacuated to-0.06～-0.08MPa, takes off bubble, 100 mesh screen, obtains capsule hide glue gelatin, 55～65 DEG C of guarantors
Temperature is standby；
3), at indoor temperature 18～26 DEG C, relative humidity 45～55%, capsule-core feed liquid is transported in the stock chest of pellet press；By capsule
Hide glue gelatin is transported to, in the storage glue groove of pellet press, start pellet press and can be prepared by soft capsule.
The preparation method of composition of natural products the most according to claim 9, it is characterised in that be made up of following steps:
1), time perilla oil, olive oil are heated to 70-80 DEG C, add the Cera Flava of formula ratio so that it is melted, stir, cold
But to 30 DEG C, oily wax liquid is obtained, standby；Tea polyphenols is crossed 100 mesh sieves, adds in above-mentioned oil wax liquid, after being uniformly mixed, take out true
Empty to-0.06～-0.08MPa, de-bubbled, obtain capsule-core feed liquid；
2), by glycerol and purified water putting into glue tank, when being heated to 70-80 DEG C, adding gelatin, Cacao pigment, stirring is endured
1.5-2h processed, is evacuated to-0.06～-0.08MPa, takes off bubble, 100 mesh screen, obtains capsule hide glue gelatin, 55～65 DEG C of guarantors
Temperature is standby；
3), at indoor temperature 18～26 DEG C, relative humidity 45～55%, capsule-core feed liquid is transported in the stock chest of pellet press；By capsule
Hide glue gelatin is transported to, in the storage glue groove of pellet press, start pellet press and can be prepared by soft capsule.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101229233A (en) * | 2008-01-18 | 2008-07-30 | 贵州同济堂制药有限公司 | Chinese traditional medicine preparation for antiatheroscloresis and liver-protection, and preparingng method thereof |
| CN101234160A (en) * | 2008-03-06 | 2008-08-06 | 贵州同济堂制药有限公司 | Fat-reducing and liver-protecting Chinese medicine preparation and preparation thereof |
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2016
- 2016-08-03 CN CN201610628772.9A patent/CN106214850A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101229233A (en) * | 2008-01-18 | 2008-07-30 | 贵州同济堂制药有限公司 | Chinese traditional medicine preparation for antiatheroscloresis and liver-protection, and preparingng method thereof |
| CN101234160A (en) * | 2008-03-06 | 2008-08-06 | 贵州同济堂制药有限公司 | Fat-reducing and liver-protecting Chinese medicine preparation and preparation thereof |
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Address after: 550009 Guiyang economic and Technological Development Zone, Guizhou Province, No. 99 Tongji Hall Applicant after: Sinopharm group (Guizhou) Pharmaceutical Co., Ltd. Address before: 550009 No. 296 Southwest Ring Road, Xiaohe District, Guizhou, Guiyang Applicant before: Sinopharm group (Guizhou) Pharmaceutical Co., Ltd. |
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Application publication date: 20161214 |