CN103263458B - Liver-protecting medicine or health-care product composition as well as preparation method and use thereof - Google Patents
Liver-protecting medicine or health-care product composition as well as preparation method and use thereof Download PDFInfo
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Abstract
The invention provides a liver-protecting medicine or a health-care product composition, which is a chewable tablet prepared from the following materials in parts by weight: 100-200 parts of folium cortex eucommiae extract, 115-345 parts of honeysuckle extract, 25-100 parts of reishi shell-broken spore powder, 35-280 parts of chrysanthemum extract, 25-100 parts of beta-cyclodextrin, 130-705 parts of filler, 11-39 parts of a disintegrating agent, 1.8-6.5 parts of a binder, 0.9-3.5 parts of a flavoring agent, and 0.8-14.5 parts of a lubricating agent. The medicine or the health-care product composition disclosed by the invention plays a role of synergistic interaction after four materials of folium cortex eucommiae are used in compatibility, can effectively reduce an injury of alcohol on the liver, and reduces steatotic hepatocyte; the composition is safe and nontoxic; and a new choice is provided for the liver-protecting medicine or the health-care product. The chewable tablet prepared by the preparation method is good in mouthfeel and appearance, and has a good commercial application prospect; the compliance is improved; and the range of users is also expanded.
Description
The application is application number: the divisional application of 201110386854.4 patent application.Original application application number: 201110386854.4, the applying date: on November 28th, 2011, denomination of invention: a kind of hepatic or Halth-care composition and its production and use.
Technical field
The present invention relates to a kind of hepatic or Halth-care composition and its production and use.
Background technology
The generation of chemical liver injury is relevant with daily contact chemical toxicant, ethanol and some medicines, and these factors easily cause liver function impaired.In the Nature and mankind's industrial processes, all exist some to the virose material of liver, be called " hepatotropic poison ", these poisonous substances are general susceptible in crowd, incubation period is short; the process of pathological changes is directly related with the dosage of infection, can cause liver hepatic necrosis, steatosis, liver cirrhosis and hepatocarcinoma in various degree.
Along with growth in the living standard, people are in rising trend to the contact probability of ethanol.Thereby, also increase the probability of ethanol to hepar damnification.Alcoholic liver injury easily develops into alcoholic liver disease.Alcoholic liver disease (ALD) is the commonly encountered diseases of developed country, is the Etiological that causes liver cirrhosis.China consumes big country as wine, and the crowd that drinks is larger, causes clinically to the relevant disease of drinking and has the trend increasing gradually as fatty liver, liver cirrhosis etc.But alcoholic liver disease does not have specific drug so far, the essential measure that improves body condition is alleviating alcohol addiction, and alcohol addiction makes alleviating alcohol addiction concerning the major part comparatively difficulty of drinking crowd.Thereby, in responsible drinking, the infringement of the health food prevention ethanol of being also badly in need of having the function of protecting the liver to liver.
At present, reported that the medicine with anti-liver injury has tens of kinds, as Cordyceps, Radix Et Rhizoma Rhei, Radix Notoginseng, the Radix Astragali, Radix Sophorae Flavescentis, Radix Salviae Miltiorrhizae, Fructus Lycii, Fructus Schisandrae Chinensis, Ganoderma, Herba Portulacae, Herb Gynostemmae Pentaphylli, Rhizoma Chuanxiong etc., wherein, is no lack of the Chinese crude drug of integration of edible and medicinal herbs.Therefore, from Chinese medicine, find the medicine that can be used for preventing liver injury, also just become the focus of research.
Summary of the invention
The object of the present invention is to provide a kind for the treatment of or the medicine of preventing liver injury or Halth-care composition and its production and use of can be used for; Another object of the present invention is to provides the chewable tablet based on this medicine or Halth-care composition, and the preparation method of this chewable tablet.
The invention provides a kind of hepatic or Halth-care composition, it is the preparation being prepared from by the crude drug of following weight proportion:
Folium Eucommiae 666-2500 part, Flos Lonicerae 575-3450 part, Flos Chrysanthemi 159-2155 part, Ganoderma spore 25-100 part.
Further, it is to be the preparation that active fraction preparation forms by Folium Eucommiae extract, Flos Lonicerae extract, Flos Chrysanthemi extract, Ganoderma spore powder with cellular wall broken:
Folium Eucommiae extract 100-200 part, Flos Lonicerae extract 115-345 part, Flos Chrysanthemi extract 35-280 part, Ganoderma spore powder with cellular wall broken 25-100 part; Be preferably 150 parts of Folium Eucommiae extracts, 115 parts of Flos Lonicerae extracts, 35 parts of Flos Chrysanthemi extracts, 50 parts of Ganoderma spore powder with cellular wall brokens.
Wherein, in described Folium Eucommiae extract, chlorogenic acid content is not less than 20%; In Flos Lonicerae extract, chlorogenic acid content is not less than 20%; In Flos Chrysanthemi extract, general flavone content is not less than 2%; In Ganoderma spore powder with cellular wall broken, Ganoderma total triterpenes content is not less than 3%.
Wherein, described Folium Eucommiae extract be Folium Eucommiae with after water extraction, then use the dry thing of the supernatant of 70-90%V/V ethanol precipitate with ethanol gained; Folium Eucommiae is the dry leaves of the Eucommiaceae plant Cortex Eucommiae (Eucommia ulmoides Oliver);
Flos Lonicerae extract be Flos Lonicerae with after water extraction, then use the dry thing of the supernatant of 70-90%V/V ethanol precipitate with ethanol gained; Flos Lonicerae is caprifoliaceae plant Radix Ophiopogonis Lonicera japonica Thunb. Flos Lonicerae Lonicera confusa CD. or the dry flower of hair style Radix Ophiopogonis Lonicera dasystyla Rehd. or the flower of just opening;
Flos Chrysanthemi extract be Flos Chrysanthemi with after water extraction, then use the dry thing of the supernatant of 70-90%V/V ethanol precipitate with ethanol gained; Flos Chrysanthemi is the dry capitulum of feverfew Flos Chrysanthemi (Chrysanthemum morifolium Ramat);
Ganoderma spore powder with cellular wall broken be Ganoderma spore through breaking cellular wall gained fine powder, sporoderm-broken rate is greater than 90%; Ganoderma is the dry sporophore of On Polyporaceae Ganoderma lucidum (Leyss. Ex Fr.) Karst. (Ganoderma lucidum) or Ganoderma (Ganoderma sinensis).
Wherein, described preparation is oral formulations.
Further, described preparation is capsule, granule, powder, pill, tablet, drop pill or oral liquid.
The present invention also provides a kind of method of preparing said medicine or Halth-care composition, comprises the steps:
(1) take the crude drug of following weight proportion:
Folium Eucommiae 666-2500 part, Flos Lonicerae 575-3450 part, Flos Chrysanthemi 159-2155 part, Ganoderma spore 25-100 part;
(2) get Folium Eucommiae, with after water extraction, then use 70-90%V/V ethanol precipitate with ethanol, after supernatant is dry, obtain Folium Eucommiae extract; Extracting honeysuckle, with after water extraction, then uses 70-90%V/V ethanol precipitate with ethanol, after supernatant is dry, obtains Flos Lonicerae extract; Get Flos Chrysanthemi, with after water extraction, then use 70-90%V/V ethanol precipitate with ethanol, after supernatant is dry, obtain Flos Chrysanthemi extract; Get Ganoderma spore, after broken wall treatment, gained fine powder is Ganoderma spore powder with cellular wall broken, and its sporoderm-broken rate is greater than 90%;
(3) Folium Eucommiae extract, Flos Lonicerae extract, Flos Chrysanthemi extract, Ganoderma spore powder with cellular wall broken are mixed, add pharmaceutically acceptable adjuvant to be prepared into preparation.
Further, the preparation method of Folium Eucommiae extract is: get Folium Eucommiae, warm macerating adds water, filter, filtrate merges, concentrated, concentrated solution adds ethanol to make to reach 70-90% containing alcohol amount, and preferably 80%, precipitate with ethanol, stir evenly, leave standstill, treat that precipitation completely, get supernatant, decompression and solvent recovery, dry, obtain Folium Eucommiae extract;
The preparation method of Flos Lonicerae extract is: extracting honeysuckle, decoct with water, and filter, filtrate merges, concentrated, concentrated solution adds ethanol to make to reach 70-90% containing alcohol amount, and preferably 80%, precipitate with ethanol, leaves standstill, and treats that precipitation is completely, get supernatant, concentrating under reduced pressure, dry, obtain Flos Lonicerae extract;
The preparation method of Flos Chrysanthemi extract is: get Flos Chrysanthemi, decoct with water, filter, filtrate merges, concentrated, concentrated solution adds ethanol to make to reach 70-90% containing alcohol amount, and preferably 80%, precipitate with ethanol, leaves standstill, and treats that precipitation is completely, get supernatant, concentrating under reduced pressure, dry, obtain Flos Chrysanthemi extract;
The preparation method of Ganoderma spore powder with cellular wall broken is: get Ganoderma spore, add water at 25-50 DEG C of warm macerating, then after adding wall breaking enzyme to soak, boil 10-30min, preferably 20min, filters, dry, obtains Ganoderma spore powder with cellular wall broken.
The present invention also provides said medicine or the purposes of Halth-care composition in medicine or the health product of preparation treatment/preventing liver injury.
Further, described medicine is the medicine for the treatment of/preventing alcoholic liver injury.
The present invention also provides a kind of chewable tablet of preventing/treating hepatic injury, and it is to be prepared from by the supplementary material of following weight proportion:
Folium Eucommiae extract 100-200 part, Flos Lonicerae extract 115-345 part,
Ganoderma spore powder with cellular wall broken 25-100 part, Flos Chrysanthemi extract 35-280 part,
Beta-schardinger dextrin-25-100 part, filler 130-705 part,
Disintegrating agent 11-39 part, binding agent 1.8-6.5 part,
Correctives 0.9-3.5 part, lubricant 0.8-14.5 part.
Wherein, described filler is starch, dextrin, lactose, amylum pregelatinisatum, mannitol; Described disintegrating agent is hyprolose, carboxymethyl starch sodium, low substituted hydroxy-propyl methylcellulose, crospolyvinylpyrrolidone; Described binding agent is ethanol, starch slurry, sodium carboxymethyl cellulose, PVP K30; Described lubricant is magnesium stearate, micropowder silica gel, Pulvis Talci; Described correctives is aspartame, mannitol, stevioside, sucrose.
Further, described filler is lactose, mannitol, wherein lactose: mannitol=1:1-1:3; Disintegrating agent is hyprolose; Binding agent is PVP K30; Lubricant is magnesium stearate; Correctives is aspartame.
Further preferably, it is to be prepared from by the supplementary material of following weight proportion:
115 parts of 150 parts of Flos Lonicerae extracts of Folium Eucommiae extract
35 parts of 50 parts of Flos Chrysanthemi extracts of Ganoderma spore powder with cellular wall broken
112.5 parts of 112.5 parts of lactose of mannitol
5 parts of 50 parts of PVP K30s of beta-schardinger dextrin-
2.5 parts of 15 parts of aspartames of hyprolose
2.5 parts of magnesium stearate.
The present invention also provides the preparation method of above-mentioned chewable tablet, and it comprises following operating procedure:
(1) first use 25-100 part beta-schardinger dextrin-by 25-100 part Ganoderma spore powder with cellular wall broken enclose, obtain Ganoderma spore powder with cellular wall broken clathrate;
(2) get 1.8-6.5 part binding agent, be prepared into the binder solution that concentration is 3%-8%W/V; Again 100-200 part Folium Eucommiae extract, 115-345 part Flos Lonicerae extract, 35-280 part Flos Chrysanthemi extract, 50-200 part Ganoderma spore powder with cellular wall broken clathrate are mixed, add after 130-705 part filler, 11-39 part disintegrating agent, 0.9-3.5 part correctives mix homogeneously, the binder solution that adds binding agent to prepare, prepare soft material, granulate, after being dried, add 0.8-14.5 part lubricant, tabletting, obtains chewable tablet.
Further, the concentration of described binder solution is 5%W/V.
Further, it comprises following operating procedure:
(1) first getting 50 parts of beta-schardinger dextrin-s and 50-70%V/V ethanol grinds evenly by 1 ︰ 0.8-1 ︰ 1.2, then add 50 parts of Ganoderma spore powder with cellular wall brokens fully to grind, to grind clathrate dry under 50-65 DEG C ,-0.07～-0.09MP condition, obtain Ganoderma spore powder with cellular wall broken clathrate;
(2) getting 5 parts of PVP K30s is dissolved in and in 85-95%V/V ethanol, makes the binder solution that concentration is 5%W/V; Again Ganoderma spore powder with cellular wall broken clathrate is mixed with 115 parts of Flos Lonicerae extracts, 150 parts of Folium Eucommiae extracts, 35 parts of Flos Chrysanthemi extracts, and add 112.5 portions of mannitol, 112.5 parts of lactose, 15 parts of hyprolose, 2.5 parts of aspartames, after mix homogeneously, add aforementioned adhesion agent solution, prepare soft material, after granulating, being dried, sneak into 2.5 parts of magnesium stearate, tabletting, obtains chewable tablet.
After medicine of the present invention or Halth-care composition use four kinds of material combinations such as Folium Eucommiae extract, bring into play synergistic function, can more effectively alleviate the damage of ethanol to liver, alleviate hepatic cell fattydegeneration, and said composition safety non-toxic, for hepatic or health product provide a kind of new selection.Chewable tablet prepared by the present invention, mouthfeel, outward appearance are good, have improved compliance, have expanded use crowd scope, have good commercial application prospect.
Brief description of the drawings
The flow chart of Fig. 1 medicine of the present invention or Halth-care composition preparation method
The estimation limit average of Fig. 2 judging quota PTS is investigated figure
Detailed description of the invention
The preparation of embodiment 1 medicine of the present invention or Halth-care composition
First get beta-schardinger dextrin-100g and 60%V/V ethanol and grind evenly by 1 ︰ 1, then add 100g Ganoderma spore powder with cellular wall broken fully to grind, will grind clathrate and be dried 4h under 60 DEG C ,-0.08MP condition.Again by above-mentioned Ganoderma spore powder with cellular wall broken clathrate and 230g Flos Lonicerae extract, 300g Folium Eucommiae extract, 70g Flos Chrysanthemi extract mixes, and add 225g mannitol, 225g lactose, 30g hyprolose, 5g aspartame, after mix homogeneously, get 10g PVP K30 be dissolved in 90% edible ethanol make 5%(W/V) solution is as binding agent, prepare soft material, the soft material making is dried in 60 DEG C of thermostatic drying chambers, while being 3% to moisture, cross 20 mesh sieve granulate and obtain dry rear granule, sneak into the magnesium stearate of 5g, tabletting obtains 1000 of this product, 1.3g/ sheet.
In the present invention, each raw material refers to:
Folium Eucommiae extract
[name of product] Folium Eucommiae extract
[English name] Eucommiae Folium P.E.
[source] this product is the dried leaves of the Eucommiaceae plant Cortex Eucommiae Eucommiae ulmoides Oliv. extract through being processed into.Can obtain by buying commercial goods, also can prepare by method once:
Get Folium Eucommiae, dry, pulverize, add 16 times of amount purified water, be heated to 50 DEG C, dipping 3h, filter, 50 DEG C of filtrates are evaporated to relative density 1.13～1.18, add ethanol to make to reach 80% containing alcohol amount, stir evenly, leave standstill 24h, centrifugal, get supernatant, decompression recycling ethanol, concentrated solution spraying is dry, to obtain final product.The yield of Folium Eucommiae extract of the present invention is 8-15%.
[inspection]
Moisture is pressed GB/T5009.3-2003 " mensuration of moisture in food " first method, must not exceed 5%.
[assay] presses GB/T22250-2008 " mensuration of health food Content of Chlorogenic Acid ", and chlorogenic acid content must not be lower than 20%.
Flos Lonicerae extract
[name of product] Flos Lonicerae extract
[English name] Lonicera japonica Flos P.E.
[source] this product is dry flower or the extract of the first flower of opening of band through being processed into of caprifoliaceae plant Radix Ophiopogonis Lonicera japonica Thumb..Can obtain by buying commercial goods, also can prepare by method once:
Extracting honeysuckle, decocts 3 times (first and second time 1 hour, 0.5 hour for the third time) with 20,12 and 8 times of amount pure water respectively, filters, filtrate merges, concentrated, and concentrated solution adds ethanol to make to reach 80% containing alcohol amount, leaves standstill 24h, get after supernatant concentrating under reduced pressure, dry, to obtain final product.The yield of Flos Lonicerae extract of the present invention is 10-20%.
[inspection] moisture is pressed GB/T5009.3-2003 " mensuration of moisture in food " first method, must not exceed 5.0%.
[assay] presses GB/T22250-2008 " mensuration of health food Content of Chlorogenic Acid ", and chlorogenic acid content must not be lower than 20%.
Flos Chrysanthemi extract
[name of product] Flos Chrysanthemi extract
[English name] Chrysanthemi Flos P.E.
[source] this product is the dry capitulum of the feverfew chrysanthemum Chrysanthemum morifolium Ramat. extract through being processed into.Can obtain by buying commercial goods, also can prepare by method once:
Get Flos Chrysanthemi, decoct 3 times (first and second time 1 hour, 0.5 hour for the third time) respectively with 20,12 and 8 times of amount pure water, filter, filtrate merges, concentrated, and concentrated solution adds ethanol to make to reach 80% containing alcohol amount, leaves standstill 24h, gets supernatant, after concentrating under reduced pressure, is drying to obtain.The yield of Flos Chrysanthemi extract of the present invention is 13%-22%.
[inspection] moisture is pressed GB/T5009.3-2003 " mensuration of moisture in food " first method, must not exceed 5.0%.
[assay] measured by the method for " health food inspection and assessment technique specification " (2003 editions) " mensuration of total flavonoids in health food " regulation, and general flavone content must not be lower than 2%.
Ganoderma spore powder with cellular wall broken
[name of product] Ganoderma spore powder with cellular wall broken
[source] this product is that the dry spore of On Polyporaceae Ganoderma lucidum (Leyss. Ex Fr.) Karst. (Ganoderma lucidum) or Ganoderma (Ganoderma sinensis) is through breaking cellular wall gained fine powder.Can obtain by buying commercial goods, also can prepare by method once:
Get Ganoderma spore, add 3 times of water gagings, 35 DEG C of constant temperature stir and soak 12h, then add the wall breaking enzyme of Ganoderma spore 1.5%W/W to soak after 3h, and 100 DEG C are boiled 20min, filter, and dry sterilization after grinding microscopy, obtains Ganoderma spore powder with cellular wall broken.The wall-breaking method of Ganoderma spore also can carry out according to the method for existing bibliographical information, as Li Shufang etc., the research of breaking trachytectum of glossy ganoderma technology, food industry science and technology, 2008, vol.29, NO.09.In the present invention, wall breaking enzyme can adopt cellulase, cellulase-protease composite enzyme.
[inspection] moisture is pressed GB/T5009.3-2003 " mensuration of moisture in food " first method, must not exceed 5.0%.
Sporoderm-broken rate is pressed NY/T1677-2008 " mensuration of Ganoderma spore powder with cellular wall broken sporoderm-broken rate ", must not be lower than 90%.
[assay] presses DB44/T496-2008 " mensuration of triterpene substance in Ganoderma ", and Ganoderma total triterpenes content must not be lower than 3%.
The preparation of embodiment 2 medicine of the present invention or Halth-care composition
Get Folium Eucommiae extract 100g, Flos Lonicerae extract 345g, Flos Chrysanthemi extract 280g, Ganoderma spore powder with cellular wall broken 100g.After mixing, add appropriate dextrin, soluble starch, after wet granulation, obtain granule.
The preparation of embodiment 3 medicine of the present invention or Halth-care composition
Get Folium Eucommiae extract 200g, Flos Lonicerae extract 115g, Flos Chrysanthemi extract 35g, Ganoderma spore powder with cellular wall broken 25g, then add appropriate microcrystalline Cellulose, after mixing, encapsulated, obtain capsule.
The screening of embodiment 4 medicine of the present invention or Halth-care composition Raw medicine proportioning
According to list of references consumption, adopt orthogonal design to carry out optimization selection to selected raw material, filter out best proportioning.Test with reference to " health food inspection and assessment technique specification " (version in 2003); verify whether this prescription has auxiliary protection function to chemical liver injury; animal model is alcoholic liver injury model, taking lipid peroxide catabolite malonaldehyde (MDA), reduced glutathion (GSH), triglyceride (TG) in experimental animal liver as judging index.
Table 1 quadrature factor water-glass (L9 (34))
Table 2 animal tissue check result
Table 3 blank group and model group animal tissue check result
Note: △ △ represents and relatively P<0.05 of negative control group
Take each material according to formula, test by orthogonal test calendar.In reference " health food inspection and assessment technique specification " (version in 2003) selection animal subject hepatic tissue, lipid peroxidation metabolite malonaldehyde (MDA), reduced glutathion (GSH), triglyceride (TG) are as evaluation index.Under the prerequisite of setting up at model, compared with model control group, expection this product can make malonaldehyde, triglyceride concentration in animal subject body be starkly lower than model control group, makes reduced glutathion concentration apparently higher than model control group.Therefore, using the inverse of malonaldehyde, the each experimental concentration of triglyceride and empirical average concentration ratio as this index score, using the each experimental concentration of reduced glutathion and empirical average concentration ratio as index score, then be added and obtain PTS with three index scores, as orthogonal test evaluation index.
(computing formula is as follows)
Test corresponding No. 1-9 experiment for No. 10-18, as repeating controlled trial, to carry out mathematical statistics.
Formula one:
Formula two:
Formula three:
Formula four: P
pTS=P
mDA+ P
gSH+ P
tG
Table 4 orthogonal test: the inspection of effect between main body
Dependent variable: total score
A.R side=0.950(adjusts R side=0.894)
Comparative result between table 5 Folium Eucommiae extract level
Duncan
a,b
Comparative result between table 6 Flos Lonicerae extract level
Duncan
a,b
Comparative result between table 7 Flos Chrysanthemi extract level
Duncan
a,b
Comparative result between table 8 Ganoderma spore powder with cellular wall broken level
Duncana,b
Orthogonal experiments is visible, and compositions Raw portfolio ratio the best is A
2b
1c
1d
2, i.e. Folium Eucommiae extract: Flos Lonicerae extract: Flos Chrysanthemi extract: Ganoderma spore powder with cellular wall broken=150:115:35:50.From other combinations, four compositionss that raw material is combined to form in varing proportions, alcoholic liver injury is all had to certain protective role, show as the rising that can suppress the malonaldehyde that alcoholic hepatic injury causes, improve the concentration of reduced glutathion in liver and reduce the content of triglyceride, the best of breed effect optimum filtering out with orthogonal test; Under the prerequisite of setting up in model group, best of breed and model control group have significant difference, with reference to " health food inspection and assessment technique specification " (version in 2003) judgment criteria, show that the compositions of screening has auxiliary protection function to alcoholic liver injury.
The screening of embodiment 5 chewable tablet adjuvant of the present invention and preparation method
The screening of 1 adjuvant
According to embodiment 1 four physico-chemical properties of taste raw material components and the feature of chewable tablet, evaluate according to the angle of repose of granule before tabletting and the index such as outward appearance, mouthfeel of hydroscopicity and finished product, determine supplementary product consumption.
For chewable tablet, adjuvant mainly comprises filler, binding agent, and lubricant, correctives etc., the tablet of making should have good outward appearance and mouthfeel, taste, can be accepted by target group.
The selectable kind of filler has starch, sucrose, dextrin, lactose, amylum pregelatinisatum, mannitol etc.; The selectable kind of adhesive has ethanol, starch slurry, sodium carboxymethyl cellulose, PVP K30 etc.; The selectable kind of lubricant has magnesium stearate, micropowder silica gel, Pulvis Talci etc.
This product raw material contains more extract, and taste is more bitter, and compressibility is poor, and hygroscopicity is strong, meets the water capacity and is easily gluey, carries out the screening of adjuvant according to these features.
Mannitol no hygroscopicity, absorbs heat when dissolving, and there is comfort sense in oral cavity, the most conventional in chewable tablet; Lactose no hygroscopicity, compressibility is good, and stable in properties is with not chemically reactive of most drug, bright and clean attractive in appearance in flakes, can improve tablet surface slickness.Meanwhile, consider that target group may exist diabetics and energy intake restriction crowd, avoid using sucrose, select mannitol and lactose as filler.Starch, dextrin, amylum pregelatinisatum etc. find in test, and abnormal smells from the patient and mouthfeel are difficult to accept, and are not suitable for the present composition.
Using mannitol and lactose as filler, mix with the raw material of drafting every consumption, using water, 70% edible ethanol, 90% edible ethanol as adhesive, carry out the screening of adhesive respectively.In preliminary experiment, find, while containing more water in adhesive, material stickiness sharply increases, and clumps together and is gluey, cannot cross sieve No. 2; 90% edible ethanol is during as adhesive, stickiness again deficiency so that material shape becomes good granule.After the adjuvant such as starch slurry, sodium carboxymethyl cellulose is made into aqueous solution, viscosity is larger, and consumption is few, is unfavorable for abundant dispersion, easily causes this formula material pelletization inhomogeneous, and tablet surface forms the phenomenons such as stain.Therefore be chosen in 90% edible ethanol and add PVP K30 as the adhesive in formula, utilize the ethanol of high concentration that PVP K30 is disperseed, during with mixing of materials, play adhesive effect.
The test of table 9 adhesive prescreen
Consider that target group may adopt the mode that contains change to take this product, tablet dissolved speed while adding therein a small amount of disintegrating agent change and chew to accelerate to contain.Select the good hyprolose of mouthfeel and compressibility.
In formula, contain more extract, mouthfeel is more bitter, add appropriate aspartame as correctives to cover bitterness; Add magnesium stearate conventional in chewable tablet as lubricant, increase mobility of particle, prevent the generation of sticking.Owing to containing Ganoderma spore powder with cellular wall broken in this product, first Ganoderma spore powder with cellular wall broken and beta-schardinger dextrin-are carried out to enclose, when the contained active component of increase Ganoderma spore powder with cellular wall broken is stable, can cover its distinctive taste and bitterness smelt, improve products taste.Biliographic data and trial test result, Ganoderma spore powder with cellular wall broken clathrate process is defined as: first beta-schardinger dextrin-and 60% edible ethanol are ground evenly by 1:1, then add with the Ganoderma spore powder with cellular wall broken of beta-schardinger dextrin-equivalent and fully grind 15mim, to grind clathrate dry 4h under 60 DEG C ,-0.08MP condition, to obtain final product.Using Folium Eucommiae extract, Flos Lonicerae extract, Flos Chrysanthemi extract in clathrate and prescription as raw material, carry out the screening of adjuvant.
Preliminary selected supplementary product kind is as shown in the table.
The preliminary definite adjuvant list of table 10
Draft the basic consumption of each adjuvant according to list of references, meanwhile, to filler, adhesive concentration, the consumption of lubricant and raw material and filler ratio totally four factors are carried out orthogonal test to determine each supplementary product consumption.Factor level sees the following form.
Table 11 L9 (3
4) quadrature factor water-glass
Note: G is mannitol, and R is lactose
Test with 100 tablet amounts, set supplementary product consumption in each experiment according to quadrature factor water-glass, mix with the raw material of formula a great deal of, add the adhesive of respective concentration, soft material processed,, records adhesive and uses volume as soft material determination methods with " gently pinching agglomerating; light pressure is broken "; The soft material of system is dried in 60 DEG C of thermostatic drying chambers, while being 3%, crossing No. 2 sieve granulate and obtain dry rear granule to moisture, sneak into the lubricant of design flow, tabletting obtains this chewable tablet.
Adopt dry after granule angle of repose, granule yield, be pressed into sheet outward appearance and hardness as evaluation index, each horizontal factor experiment is marked, the total score that above-mentioned four indices score addition is obtained to each horizontal factor experiment is evaluated, to investigate the impact of each factor on tablet molding.Orthogonal experiments sees the following form.
Table 12 orthogonal experiments
Annotation: * * is P<0.01.
Result shows, adhesive concentration (B) and raw material and filler ratio (D) different have utmost point significant difference, for affecting the major influence factors of tablet molding.Estimation limit average to judging quota PTS is shown in Fig. 2.
Adhesive concentration application Duncan method is carried out to multiple comparisons discovery, and the adhesive of 5% concentration is better than the adhesive of other two concentration; Use volume and concentration according to adhesive, the consumption of determining adhesive PVP K30 is 10g/1000 sheet (1000=10g of 5g/100ml*200ml/100 sheet *).
Table 13 adhesive concentration is investigated
In the multiple comparisons of raw material and filler ratio, raw material and filler ratio are better than other two ratios while being 80:45.The results are shown in following table.
Table 14 raw material and filler ratio are investigated
Meanwhile, to mannitol in filler and lactose ratio, lubricant quantity by intuitive analysis, taking mannitol: lactose=1:1, lubricant quantity as 0.4% better.
Can select following proportioning:
150 parts of Folium Eucommiae extracts, 115 parts of Flos Lonicerae extracts, 50 parts of Ganoderma spore powder with cellular wall brokens, 35 parts of Flos Chrysanthemi extracts, 112.5 parts, mannitol, 112.5 parts of lactose, 50 parts of beta-schardinger dextrin-s, 5 parts of PVP K30s, 15 parts of hyprolose, 2.5 parts of aspartames, 2.5 parts of magnesium stearate.
Comprehensive orthogonal experiments and sheet are heavily determined result, determine the end formulation of this product, as follows:
Folium Eucommiae extract 300g Flos Lonicerae extract 230g
Ganoderma spore powder with cellular wall broken 100g Flos Chrysanthemi extract 70g
Mannitol 225g lactose 225g
Beta-schardinger dextrin-100g PVP K30 10g
Hyprolose 30g aspartame 5g
Magnesium stearate 5g
1300g, makes 1000,1.3g/ sheet altogether
Further prove beneficial effect of the present invention by concrete test example below.
Test example 1 medicine of the present invention or Halth-care composition and each raw material use separately effect contrast
1 takes each raw material according to formula proportion, i.e. Folium Eucommiae extract, Flos Lonicerae extract, Flos Chrysanthemi extract and Ganoderma spore powder with cellular wall broken, and mix homogeneously is as compositions effect experimental group; Take each raw material as independent use effect experimental group by formula proportion respectively.
2 test groupings and dosage design: female kunming mice is divided into seven groups at random, every group of 10 animals.If compositions group and Folium Eucommiae extract group, Flos Lonicerae extract group, Flos Chrysanthemi extract group and four independent use groups of spore powder with crushed sporoderm group.Present composition group per os gavage compositions suspension (embodiment 1 compositions is mixed with water, and the used time shakes up), dosage is that 350mg/kg.BW(is equivalent to 10 times of human body recommendation doses); Each independent use group is per os gavage 350mg/kg.BW Folium Eucommiae extract, 350mg/kg.BW Flos Lonicerae extract, 350mg/kg.BW Flos Chrysanthemi extract, 350mg/kg.BW spore powder with crushed sporoderm suspension (raw material mixes with water, and the used time shakes up) respectively.Separately establish distilled water matched group and 50% ethanol model matched group.Cause liver injury model with ethanol (analytical pure), concentration of alcohol is that 50%(is with distilled water diluting), the dosage that gavage amount 12ml/kg.BW(amounts to ethanol is 6000mg/kg.BW).
3 test methods: adopt alcoholic hepatic injury modelling, compositions group and separately use group give corresponding tested material, and negative control group and model control group give distilled water, press 10ml/kg.BW per os every day gavage once, give continuously 30 days, claim weekly body weight twice, adjust dosage with this.When off-test, give 50% ethanol by model control group, compositions group and independent per os gavage of use group, dosage is 12ml/kg.BW, negative control group gives the distilled water of same volume, after fasting 16h, putting to death animal gets liver and weighs, calculate dirty body ratio, and carry out biochemical indicator detection and histopathological examination with liver.
4 detect index: in liver homogenate, the mensuration of lipid peroxide catabolite malonaldehyde (MDA), reduced glutathion (GSH): MDA and GSH mensuration test kit build up Bioengineering Research Institute by Nanjing provides, the UV1100 spectrophotometric determination of producing with Shanghai Tian Mei scientific instrument company limited.
5 test data statistics: test data statistics adopts the processing of SPSS11.0for windows software kit.The data of matched group and each dosage group are through homogeneity test of variance, and variance is neat, carry out variance analysis, as P value is less than 0.05, compare between two by Dunnett method; If heterogeneity of variance, carries out data transaction, still uneven, use rank test instead, as P value is less than 0.05, use Dunnett ' s T3 method to compare between two.Negative control group and model control group data adopt T inspection.
6 experimental results
6.1 compositionss and each raw material use separately the impact on MDA, reduced form GSH content in mouse liver even slurry, and comparing result is in table 15.
The impact of table 15 on MDA, reduced form GSH content in mouse liver even slurry
△ △ represents and negative control group compares P<0.05, and * * represents and relatively P<0.05 of model control group.
Test shows, model control group and negative control group mouse liver even slurry MDA content have significant difference (P < 0.05), and model group causes mouse liver MDA content significantly to rise, and shows that it is successful that model group is set up.In embodiment 1 compositions group and Folium Eucommiae extract group, Flos Lonicerae extract group, Flos Chrysanthemi extract group, Ganoderma spore powder with cellular wall broken group, only embodiment 1 compositions group has contrasted significant difference (P < 0.05) with model group, and embodiment 1 compositions can effectively reduce the Liver MDA rising that alcoholic liver injury causes; When four kinds of raw materials use separately and model group contrast there is no significant difference (P > 0.05), but still shown certain reduction MDA trend.
Simultaneously, model control group and negative control group mouse liver even slurry reduced form GSH content have significant difference (P < 0.05), be that model group causes mouse liver reduced form GSH content significantly to decline, show that it is successful that model group is set up.In embodiment 1 compositions and Folium Eucommiae extract group, Flos Lonicerae extract group, Flos Chrysanthemi extract group, Ganoderma spore powder with cellular wall broken group, only embodiment 1 compositions group has contrasted significant difference (P < 0.05) with model group, shows that embodiment 1 compositions can effectively reduce the hepatic tissue reduced form GSH content reduction that alcoholic liver injury causes; When four kinds of raw materials use separately and model group contrast there is no significant difference (P > 0.05), but Folium Eucommiae extract and Ganoderma spore powder with cellular wall broken have shown certain rising GSH trend.
6.2 compositionss and each raw material use separately the impact on AST, ALT, SOD and liver index in blood, and comparing result is in table 16.
Table 16 is on AST, ALT, SOD and liver index impact contrast in blood
△ △ represents and negative control group compares P < 0.05, and * * represents and relatively P < 0.05 of model control group.
In each experimental group animal blood, AST, ALT, SOD and liver index are heavier visible, and model group and negative control group SOD index have significant difference (P < 0.05), show that model group is successfully established; Compositions group SOD indicator and model group has significant difference (P < 0.05), shows that compositions can effectively suppress the SOD content reduction that alcoholic liver injury causes; AST, ALT, liver index do not have significant difference (P > 0.05) in negative control group, model group and each experimental group.
Above-mentioned test all compares under Isodose, and result of the test shows, after four kinds of material combinations are used, has produced synergistic function.
Test example 2 Ergonomy tests
Definite formula is carried out to middle trial production, make finished product, entrust disease prevention and control center of Sichuan Province to carry out the tests such as Ergonomy, safe toxicology, show that this product has auxiliary protection function to Alcoholic chemical liver, and belong to No Poison, safety is good.
1 test grouping and dosage design: female sd inbred rats is divided into five groups at random, every group of 10 animals, 325mg/kg.BW, 975mg/kg.BW, tri-dosage groups of 1950mg/kg.BW (be equivalent to respectively human body recommended amounts every day 5,15,30 times) are established in test, take respectively 8.13g, 24.38g, 48.75g tested material, adding distil water mixes for subsequent use to 250ml successively, Refrigerator store, is finished and joins.Separately establish distilled water matched group and 50% ethanol model matched group.Cause liver injury model with ethanol (analytical pure), concentration of alcohol is that 50%(is with distilled water diluting), the dosage that gavage amount 12ml/kg.BW(amounts to ethanol is 6000mg/kg.BW).
2 test methods: adopt alcoholic hepatic injury modelling, three dosage groups give the tested material of various dose, and negative control group and model control group give distilled water, press 10ml/kg.BW per os every day gavage once, give continuously 30 days, claim weekly body weight twice, adjust dosage with this.When off-test, give 50% ethanol by model control group and per os gavage of three dosage groups, dosage is 12ml/kg.BW, negative control group gives the distilled water of same volume, after fasting 16h, putting to death animal gets liver and weighs, calculate dirty body ratio, and carry out biochemical indicator detection and histopathological examination with liver.
3 detect index
In 3.1 liver homogenate, the mensuration of lipid peroxide catabolite malonaldehyde (MDA), reduced glutathion (GSH) and triglyceride (TG): MDA and GSH mensuration test kit build up Bioengineering Research Institute by Nanjing provides, the UV1100 spectrophotometric determination of producing with Shanghai Tian Mei scientific instrument company limited; TG measures test kit and is provided by Guangzhou Biao Jia Science and Technology Ltd., measures with the CX4 automatic clinical chemistry analyzer of Beckman Coulter Inc. of U.S. production.
3.2 livers are weighed and the calculating of organ coefficient
3.3 pathology of hepar diagnostic criterias
3.3.1 pathological observation material: do from animal leftlobe of liver middle part to draw materials, cut into slices in cross section, dyeing, Microscopic observation fat drops in distribution, scope and area liver.
3.3.2 pathological observation method: every routine animal liver tissue, is marked by 0,1,2,3,4 point according to the how many scopes with distributing of positive cell with 70 visuals field of 40 times of object lens continuous records, each visual field.Fat stains scoring using the meansigma methods of 70 visual field obatained scores as this example hepatic tissue.
3.3.3 pathological diagnosis standard: histopathology is observed using hepatocyte fat and dripped dyeing as observation index, and quantizes according to pathological change degree " 0 ", " 1 ", " 2 ", " 3 ", " 4 ", carries out the evaluation of hepatic injury degree.
3.3.4 hepatocyte fat stains is divided into Pyatyi:
Hepatocyte lactone drip be dispersed in, rare 0 point
The hepatocyte of dripping containing fat is no more than 1/4 1 points
The hepatocyte of dripping containing fat is no more than 1/2 2 points
The hepatocyte of dripping containing fat is no more than 3/4 3 points
Hepatic tissue is almost dripped and replaces 4 points by fat
4 test data statistics
Test data statistics adopts the processing of SPSS11.0for windows software kit.The data of matched group and each dosage group are through homogeneity test of variance, and variance is neat, carry out variance analysis, as P value is less than 0.05, compare between two by Dunnett method; If heterogeneity of variance, carries out data transaction, still uneven, use rank test instead, as P value is less than 0.05, use Dunnett ' s T3 method to compare between two.Negative control group and model control group data adopt T inspection.
5 experimental results
5.1 medicines of the present invention or Halth-care composition on the impact of MDA, reduced form GSH, TG content in rat liver homogenate in table 17.
The impact of table 17 on MDA, reduced form GSH, TG content in rat liver homogenate
Note: △ △ represents and negative control group compares P<0.01, * represents and relatively P<0.05 of model control group.
5.2 medicines of the present invention or Halth-care composition affect in table 18 rat liver histopathology.
Table 18 rat liver histopathological examination result
Note: △ △ represents and negative control group compares P<0.01, * represents and relatively P<0.05 of model control group.
5.3 medicines of the present invention or Halth-care composition the results are shown in Table 19 to large and small Mus acute oral toxicity test.
Table 19 medicine of the present invention or Halth-care composition are to large and small Mus acute oral toxicity test result
Continuous 30 days per os gavages of medicine of the present invention or Halth-care composition give after female sd inbred rats, and visible animal growth is normal.On the basis of setting up at alcoholic liver injury model, middle and high dosage group can significantly reduce the lipid peroxide catabolite mda content (P < 0.05) in rat liver homogenate; Reduced glutathion content in middle and high amount group rat liver homogenate raises significant difference (P < 0.05); And there was no significant difference (P>0.05) between content of triglyceride in each dosage group rat liver homogenate and model control group; The hepatic tissue fat stains scoring of high dose group reduces significant difference (P < 0.05), and histopathological examination result is positive.According to the regulation in " health food inspection and assessment technique specification " (version in 2003), medicine of the present invention or Halth-care composition have alcoholic liver injury assistant protection function to female sd inbred rats.
Medicine of the present invention or Halth-care composition, to the equal > 15000mg/kg.BW of large and small Mus acute oral toxicity test result MTD value, by acute toxicity classification, belong to nontoxic level.
Three genetic toxicity tests (Salmonella reversion test, PCEMNR micronucleus test and mouse sperm deformity test) result has no medicine of the present invention or Halth-care composition mutagenic action.
30 days feeding trials, visible animal growth is normal, body weight sustainable growth, figure is active, smooth submissive by hair, and stool, urine no abnormality seen changes.Duration of test has no animal and occurs poisoning symptom and death.The body weight weekly of three dosage group male and female rats, food-intake, weekly food utilization and total foodstuff utilization rate, dirty body ratio and matched group comparison weekly, difference that there are no significant (P > 0.05); The hematological indices of three dosage group male and female rats and latter stage Biochemistry test result and matched group comparison, in male Mus, the numeration of leukocyte of dosage group and triglyceride reduce (P < 0.05) significant difference, all the other indexs there are no significant difference (P > 0.05), above institute measured value is all in this chamber range of normal value.Histopathological examination result, except the spontaneous pathological changes of animal, has no tested material high dose group and causes that animal toxic injury changes.
In sum, after medicine of the present invention or Halth-care composition use four kinds of material combinations such as Folium Eucommiae extract, bring into play synergistic function, can more effectively alleviate the damage of ethanol to liver, alleviate hepatic cell fattydegeneration, and said composition safety non-toxic, for hepatic or health product provide a kind of new selection.
Claims (6)
1. hepatic or a Halth-care composition, is characterized in that: it is the chewable tablet being prepared from by the supplementary material of following weight proportion:
115 parts of 150 parts of Flos Lonicerae extracts of Folium Eucommiae extract
35 parts of 50 parts of Flos Chrysanthemi extracts of Ganoderma spore powder with cellular wall broken
112.5 parts of 112.5 parts of lactose of mannitol
5 parts of 50 parts of PVP K30s of beta-schardinger dextrin-
2.5 parts of 15 parts of aspartames of hyprolose
2.5 parts of magnesium stearate;
Described Folium Eucommiae extract be Folium Eucommiae with after water extraction, then use the dry thing of the supernatant of 70-90%V/V ethanol precipitate with ethanol gained; Flos Lonicerae extract be Flos Lonicerae with after water extraction, then use the dry thing of the supernatant of 70-90%V/V ethanol precipitate with ethanol gained; Flos Chrysanthemi extract be Flos Chrysanthemi with after water extraction, then use the dry thing of the supernatant of 70-90%V/V ethanol precipitate with ethanol gained; Ganoderma spore powder with cellular wall broken be Ganoderma spore through breaking cellular wall gained fine powder, sporoderm-broken rate is greater than 90%.
2. medicine according to claim 1 or Halth-care composition, is characterized in that:
In described Folium Eucommiae extract, chlorogenic acid content is not less than 20%W/W; In Flos Lonicerae extract, chlorogenic acid content is not less than 20% W/W; In Flos Chrysanthemi extract, general flavone content is not less than 2% W/W; In Ganoderma spore powder with cellular wall broken, Ganoderma total triterpenes content is not less than 3% W/W.
3. the preparation method of medicine claimed in claim 1 or Halth-care composition, comprises the steps:
(1) take by weight ratio supplementary material;
(2) first with beta-schardinger dextrin-by Ganoderma spore powder with cellular wall broken enclose, obtain Ganoderma spore powder with cellular wall broken clathrate;
(3) taking adhesive, adds ethanol, is prepared into the binder solution that concentration is 3%-8%W/V; Again Folium Eucommiae extract, Flos Lonicerae extract, Flos Chrysanthemi extract, Ganoderma spore powder with cellular wall broken clathrate are mixed, add after filler, disintegrating agent, correctives mix homogeneously, add binder solution, prepare soft material, granulate, after being dried, add lubricant, tabletting, obtains chewable tablet;
Wherein, described filler is lactose, mannitol; Disintegrating agent is hyprolose; Binding agent is PVP K30; Lubricant is magnesium stearate; Correctives is aspartame.
4. preparation method according to claim 3, is characterized in that: in step (3), the concentration of described binder solution is 5%W/V.
5. preparation method according to claim 3, is characterized in that:
The concrete operations of step (2) are as follows: first get beta-schardinger dextrin-and 50-70%V/V ethanol and grind evenly by 1 ︰ 0.8-1 ︰ 1.2, then add Ganoderma spore powder with cellular wall broken fully to grind, to grind clathrate dry under 50-65 DEG C ,-0.07 ~-0.09MP condition, obtain Ganoderma spore powder with cellular wall broken clathrate;
The concrete preparation method of the described binder solution of step (3) is as follows: get PVP K30 and be dissolved in and in 85-95%V/V ethanol, make the binder solution that concentration is 5%W/V.
6. the medicine described in claim 1 or 2 or Halth-care composition are treated or/and the purposes in medicine or the health product of preventing liver injury or alcoholic liver injury in preparation.
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