CN106333958A - Composition for synchronous adjustment of glucolipid metabolism and treatment of type II diabetes - Google Patents
Composition for synchronous adjustment of glucolipid metabolism and treatment of type II diabetes Download PDFInfo
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- CN106333958A CN106333958A CN201510393810.2A CN201510393810A CN106333958A CN 106333958 A CN106333958 A CN 106333958A CN 201510393810 A CN201510393810 A CN 201510393810A CN 106333958 A CN106333958 A CN 106333958A
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- honokiol
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- 230000001360 synchronised effect Effects 0.000 title abstract description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title abstract description 4
- 230000004060 metabolic process Effects 0.000 title abstract description 3
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a composition for synchronous adjustment of glucolipid metabolism and treatment of type II diabetes. A composition of Coix lacryma-jobi water-soluble cellulose and honokiol has the efficacy of improving insulin resistance, also can improve lipid metabolism disorder while lowering blood glucose and reduce weight. Single oral administration application of Coix lacryma-jobi water-soluble cellulose cannot reach the efficacy of lowering blood sugar and improving blood lipid, honokiol has efficacy of synchronous adjustment of blood glucose and blood lipid, but has large dosage. Through proper compatibility of Coix lacryma-jobi water-soluble cellulose and honokiol, Coix lacryma-jobi water-soluble cellulose and honokiol are applied in a composition form, thus reducing the dosage of honokiol to one fifth that of its single use, and the blood glucose lowering efficacy is significantly superior to its separate use. Coix lacryma-jobi water-soluble cellulose and honokiol have obvious synergistic effect, and application of the two as a composition can achieve obvious advantages.
Description
Technical field
The present invention relates to the application of Semen Coiciss water-soluble cellulose and honokiol compositionss, specially Semen Coiciss water-soluble cellulose and application in pharmacy for the honokiol compositionss.
Background technology
Diabetes are the chronic incretion metabolism diseases being characterized with hyperglycemia, and its pathologic basis is that insulin definitely and/or relatively lacks, and then causes sugar, fat, protein, water and a series of metabolism disorder of electrolyte.Wherein most diabetes are ii type, account for the 90%-95% of diabeticss sum.Predicted according to fashion trend, to the year two thousand thirty, global 20-79 year suffer from diabetes adult be up to 4.39 hundred million surprising numeral.Diabetes have become the major disease of serious harm human health, and its prevention and control correlational study causes countries in the world to pay high attention to.
The key for the treatment of ii patients with type Ⅰ DM is to improve insulin resistant, there is serious disorders of lipid metabolism in 80%ii diabetes mellitus type, in blood, free fatty, triglyceride and cholesterol significantly raise, and lead to liver and peripheral insulin resistance, thus ii patients with type Ⅰ DM is referred to as glycolipid disease.Study of Thiazolidinedione derivatives as Insulin Sensitizer with rosiglitazone as representative is Peroxisome Proliferation body activated receptor γ (peroxisome proliferative activated receptor gamma, ppar γ) exclusive and full agonist, the dosage of very little just can significantly mitigate liver, fat and peripheral tissues' insulin resistant and effectively reduce the blood glucose of ii diabetes mellitus type, bring brand-new thinking and theory for the treatment of ii patients with type Ⅰ DM, be once widely used in treatment ii patients with type Ⅰ DM.But also due to this kind of medicine ppar γ is had exclusive and complete excitement feature, it is made not possess the drug effect of the metabolism disorder of blood lipid that synchronization control 80%ii diabetes mellitus type occurs together, and while improving insulin sensitivity, there is promotion Adipocyte Differentiation, regulation and control participate in inflammatory reaction, hypertension and arteriosclerosis related gene.Therefore obtaining notable blood sugar lowering clinical efficacy simultaneously, finding that it is put on weight, leads to the serious adverse reactions such as osteoporosises, water-sodium retention and heart failure, stopped rosiglitazone at present in Clinical practice.
For solving the above problems, in Chinese patent application cn102512403a, disclose a kind of medicine, this medicine honokiol is ppar α/gamma portion dual agonists.Compared with the exclusive and complete excitement of thiazolidinedioneses ppar γ of current clinical practice, honokiol does not only have Thiazolidinediones to put on weight and leads to the untoward reaction such as heart failure, and significantly reducing blood glucose simultaneously, have and significantly lose weight, realize the excellent drug effect of glycolipid synchronization control.But because honokiol Oral Gastrointestinal Tract only absorbs less than 6%[1].Poor bioavailability, causes the effective dose of mice to be up to 100mg/kg/d, dosage is excessive, there is potential safety hazard, and preparations shaping is poor.
The purpose of the present invention is the defect overcoming above-mentioned prior art, has Synergistic and the principle of attenuation using Chinese medicine compound, and honokiol and Semen Coiciss water-soluble cellulose compatibility realize the purpose of efficacy enhancing and toxicity reducing.When Semen Coiciss water-soluble cellulose 60mg/kg/d is applied with honokiol 20mg/kg/d compatibility, tool is significantly reduced blood glucose and slimming drug effect, and under this dosage, either it is used alone honokiol, be still used alone Semen Coiciss water-soluble cellulose and all there is no any blood sugar lowering and slimming drug effect.Document report, Semen Coiciss water-soluble cellulose is administered orally the cholate that can adsorb in bile, promote body to transfer and synthesize cholate using hepatic cholesterol, thus reducing cholesterol and blood fat, but action temperature and, long-term taking is needed just effectively, and when short-term takes Semen Coiciss water-soluble cellulose oral dose up to 200mg/kg/d, still not have any reduction blood glucose and slimming drug effect[2].This turns out Semen Coiciss water-soluble cellulose and has the reduction blood glucose of highly significant and slimming synergistic function with honokiol, makes the effective dose of honokiol reduce more than 5 times.Semen Coiciss water-soluble cellulose is extracted by food Semen Coiciss, does not have any toxic and side effects.The present invention thoroughly solves honokiol poor bioavailability, and dosage is excessive, there is potential safety hazard, simultaneously the technological deficiency of the insufficient formability of preparation.
Content of the invention
The present invention is intended to provide a kind of application in pharmacy for the compositionss of Semen Coiciss water-soluble cellulose and honokiol, press particular case compatibility using Semen Coiciss water-soluble cellulose with honokiol, Semen Coiciss water-soluble cellulose can significantly improve the bioavailability of honokiol, both have significant synergistic function, solve in prior art, to treat the drug side effect of diabetes and other untoward reaction is serious, and it is impossible to synchronous mitigate fat technical problem while reducing blood glucose.
To achieve these goals, according to an aspect of the present invention, the application that Semen Coiciss water-soluble cellulose is used in the medicine treating ii patients with type Ⅰ DM, the obesity of lipid metabolic disorder or the disease related with insulin resistant to the compositionss of honokiol in preparation is provided.
Further, wherein the related disease of insulin resistant is selected from body to insulin sensitivity reduction.
Further, wherein honokiol comes from Cortex Magnoliae Officinalis extract.
Further, wherein Semen Coiciss water-soluble cellulose is also referred to as Semen Coiciss polysaccharide, and Semen Coiciss water-soluble cellulose comes from Semen Coiciss, Radix Coiciss, Semen Coiciss other overground part extract.
According to another aspect of the present invention, provide a kind of medicine treating ii patients with type Ⅰ DM, including the wherein compositionss that form by a certain percentage of Semen Coiciss water-soluble cellulose and honokiol of therapeutically effective amount.
Further, in said composition, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 50.
Further, in said composition, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 25.
Further, in said composition, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 10.
Further, in said composition, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 5.
Further, in said composition, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 3.
Further, Semen Coiciss water-soluble cellulose and the preparation of honokiol includes pharmaceutically acceptable any mode and uniformly mixes or disperse to be prepared from.
Further, this medicine includes pharmaceutically acceptable carrier, excipient or adjuvant.
Further, the dosage form of this medicine is selected from powder, injection, capsule, tablet, oral liquid, paster.
Further, the dosage form of this medicine is slow release formulation.
Further, the dosage form of this medicine is immediate release dosage form.
Further, the dosage form of this medicine is enteric dosage form.
Further, the dosage form of this medicine is measurable injection type.
Cellular level study mechanism shows, because honokiol is total peroxisome increment activated receptor agonist, is the partial agonist of ppar γ simultaneously again.Therefore honokiol both can improve lipid metabolic disorder, loses weight, and can improve insulin resistant simultaneously again, reduces blood glucose.
Specific embodiment
It should be noted that in the case of not conflicting, the embodiment in the present invention and the feature in embodiment can be mutually combined.To describe the present invention below in conjunction with experimental data in detail.
The present invention first passes through body outer cell line screening and proves that honokiol is ppar α/γ dual agonists.On this basis, activity in vivo is proved by internationally recognized spontaneity kk/upj-ay ii patients with type Ⅰ DM mouse model.Kk/upj-ay ii patients with type Ⅰ DM mouse model is the optimal animal model of internationally recognized screening treatment ii patients with type Ⅰ DM at present.This animal model of the present invention carries out treating the Pharmacodynamics research of ii patients with type Ⅰ DM, what result showed honokiol has blood sugar lowering and slimming effect, effective dose is 100mg/kg/d, and in 25mg/kg/d and 50mg/kg/d dosage, all do not observe corresponding reduction blood glucose and slimming drug effect.
Embodiment 1
1.1 experiment purpose
Give kk/upj-ay mice high lipid food and cause ii patients with type Ⅰ DM model, and gavage gives successfully to induce into the kk/upj-ay mice honokiol of mould, investigate the hypoglycemic activity to ii patients with type Ⅰ DM mouse model for the honokiol.
1.2 given the test agent
Honokiol is voluntarily prepared by China TCM Academy of Sciences Xiyuan Hospital.Low, medium and high three dosage groups are set, and dosage is respectively 25mg/kg/d, 50mg/kg/d and 100mg/kg/d.It is configured to the suspension that concentration is respectively 2.5mg/ml, 5mg/ml and 10mg/ml with sterilized water.
1.3 positive control medicine
Take hydrochloric acid pioglitazone piece (15mg × 7 piece, lot number is 120202, date of manufacture is on January 31st, 2012, valid until in December, 2014, Beijing sun pharmaceutcal corporation, Ltd produces), it is ground into fine powder, weigh 40mg, plus boil the distilled water 20ml letting cool to room temperature, give kk/upj-ay mice by the dosage gavage of 0.05ml/10g body weight.
1.4 animal subject
Source, germline, strain are spf level kk/upj-ay mice respectively, and c57bl/6j mice is provided by Beijing HFK Bio-Technology Co., Ltd..
The Quality of Experimental Animals quality certification be scxk (capital) 2009-0004, the kk/upj-ay mice quality certification number be 0237501, the c57bl/6j mice quality certification numbering be 0237502.It is syxk (army) 2007-030 that laboratory animal uses licence.Week old is 8~10w.Sex is female.
Kk/upj-ay mouse species number is model group and positive drug control group, every group 10, high, medium and low three administration groups of honokiol every group 12, totally 56;C57bl/6j mice 10.
1.5 experimental facilitiess and reagent
Exempt from bar code and visit safe and comfortable Instrument for Measuring Blood Sugar, number of registration is [state's food medicine prison tool (entering) word 2008 the 2403659th, exported product registered standard: yzd/usa4991-2008], model contour ts;Test paper is to visit safe and comfortable Test paper;Formaldehyde.
1.6 experiment condition
56 spf level spontaneity kk/upj-ay ii patients with type Ⅰ DM mice single cages are fed in spf level laboratory, raise with the special high lipid food of kk/upj-ay mice (being purchased from Beijing HFK Bio-Technology Co., Ltd.), ad lib is drunk water.Raise with conventional foundation material with 10 c57bl/6j mices of week old, ad lib is drunk water.Keep 20~25 DEG C of ambient temperature, humidity 40%-70%.
1.7 groups and dosage regimen
All laboratory animals (including 10 c57bl/6j mices and 56 kk/upj-ay mices being divided into into after the modeling success of 6 groups) are randomly divided into 5 groups.
1.7.1 Normal group: give c57bl/6j mice by the dosage gavage of 0.05ml/10g and boil the distilled water letting cool, once a day, continue 35 days.
1.7.2 model group: give kk/upj-ay mice by the dosage gavage of 0.05ml/10g and boil the distilled water letting cool, once a day, continue 35 days.
1.7.3 honokiol low dose group: weigh 37.5mg medicine, plus the dispersion of 15ml sterilized water is suspended, and by 0.1ml/10g gavage to kk/upj-ay mice, once a day, continues 35 days.
1.7.4 honokiol middle dose group: weigh 75mg medicine, plus the dispersion of 15ml sterilized water is suspended, and gives kk/upj-ay mice by 0.1ml/10g gavage, once a day, continues 35 days.
1.7.5 honokiol high dose group: weigh 150mg medicine, plus 15ml sterilized water, ultrasonic disperse, give kk/upj-ay mice by 0.1ml/10g gavage, once a day, continue 35 days.
1.7.6 positive control medicine pioglitazone group: gavage gives the kk/upj-ay pioglitazone hydrochloride of mice 0.05ml/10g, once a day, continues 35 days.
1.8 experimental technique
1.8.1 the screening of model
Kk/upj-ay mice is raised with special high lipid food, and in feeding process, random blood sugar is surveyed in sampling weekly, when random blood sugar >=13.9mmol/l, is considered as Glycemia Decline success.
1.8.2 observation index
Mice fasting can't help 4 hours survey blood glucose of water once weekly, and second day after last dose, mice fasting can't help water 4 hours, and measurement body weight, blood glucose value, as the blood glucose value after last dose.Carry out carbohydrate tolerance experiment, by 4 hours surveyed blood glucose values of mice fasting as 0 minute blood glucose value, then gavage gives the glucose of 2.5g/kg, measures blood glucose value respectively with behind 30 minutes, 60 minutes and 120 minutes simultaneously.And area (auc) under calculated curve, auc=(0min+30min) × 0.25+ (30min+60min) × 0.25+ (60min+120min) × 0.5.
1.9 experimental result and discussion
Table 1 is the impact to kk/upj-ay ii patients with type Ⅰ DM Mouse Weight for each dosage group of honokiol;The impact to kk/upj-ay ii patients with type Ⅰ DM mouse blood sugar value for table 2 medicine;The impact to kk/upj-ay ii patients with type Ⅰ DM glucose tolerance in mice for table 3 medicine.The impact to kk/upj-ay ii patients with type Ⅰ DM Mouse Weight for Fig. 1 medicine;The impact to kk/upj-ay ii patients with type Ⅰ DM mouse blood sugar value for Fig. 2 medicine;The impact to kk/upj-ay ii patients with type Ⅰ DM glucose tolerance in mice for Fig. 3 medicine.
The present embodiment establishes kk/upj-ay ii patients with type Ⅰ DM mouse model, the hypoglycemic activity of each dosage group of honokiol using this model evaluation.Experimental result is: in whole dosage period, model group blood glucose value is significantly higher than normal group, and the blood glucose value of honokiol high dose group is substantially less than model group, statistically significant.Middle dose group blood glucose value is slightly below model group, only statistically significant at first week and the 3rd week of administration, and the blood glucose value of other each time points compares all not statistically significant with model group.Honokiol low dose group compares equal zero difference in the blood glucose value of Each point in time with model group.In carbohydrate tolerance experiment, the blood glucose value of each time point of model group and auc value are all remarkably higher than normal group, and it is less than model group and statistically significant that each time point blood glucose value that honokiol high dose group is tested in carbohydrate tolerance and auc value compare equal significance with model group.
The impact to kk/upj-ay ii patients with type Ⅰ DM Mouse Weight for each dosage group of table 1 honokiol (Unit: g)
Compare with model group:*P < 0.05,**P < 0.01;Compare with normal group:##P < 0.01
The impact to kk/upj-ay ii patients with type Ⅰ DM mouse blood sugar value for each dosage group of table 2 honokiol (Unit: mmol/l)
Compare with model group:*P < 0.05,**P < 0.01;Compare with normal group:##P < 0.01
The impact to kk/upj-ay ii patients with type Ⅰ DM glucose tolerance in mice for each dosage group of table 3 honokiol (Unit: mmol/l)
Compare with model group:*P < 0.05,**P < 0.01;Compare with normal group:##P < 0.01
1.10 conclusion
Honokiol has clear and definite blood sugar reducing function, has significant improvement adjustment effect to ii patients with type Ⅰ DM model blood glucose, has the effect mitigating animal pattern body weight simultaneously, but effective dose is larger, druggability is poor, needs to find the solution improving its bioavailability.
Brief description:
Fig. 1 honokiol and the impact to kk/upj-ayii patients with type Ⅰ DM mouse model body weight for the pioglitazone
Fig. 2 honokiol and the impact to kk/upj-ayii patients with type Ⅰ DM mouse model blood glucose value for the pioglitazone
The dose-effect relationship that Fig. 3 honokiol affects on kk/upj-ay ii patients with type Ⅰ DM mouse model blood glucose value.
Embodiment 2
2.1 experiment purpose
Give kk/upj-ay mice high lipid food and cause ii patients with type Ⅰ DM model, and gavage gives successfully to induce into the kk/upj-ay mice Semen Coiciss water-soluble cellulose of mould, and the compositionss of Semen Coiciss water-soluble cellulose and honokiol, investigate Semen Coiciss water-soluble cellulose, and whether Semen Coiciss water-soluble cellulose has hypoglycemic activity and its action intensity with honokiol compositionss to ii patients with type Ⅰ DM mouse model.
2.2 given the test agent
Semen Coiciss water-soluble cellulose, Semen Coiciss water-soluble cellulose and honokiol (both weight than for 2: 1) are voluntarily prepared by China TCM Academy of Sciences Xiyuan Hospital.Semen Coiciss water-soluble cellulose dosage is configured to, for 60mg/kg/d sterilized water, the suspension that concentration is 6.0mg/ml;Honokiol/Semen Coiciss water-soluble cellulose group accumulated dose is 80mg/kg/d, the wherein 60mg/kg/d of water-soluble cellulose containing Semen Coiciss, honokiol 20mg/kg/d, is configured to Semen Coiciss water-soluble fibre with sterilized water and honokiol concentration is respectively the suspension of honokiol 6.0mg/ml and 2.0mg/ml.
2.3 animal subject
Source, germline, strain are spf level kk/upj-ay mice respectively, and c57bl/6j mice is provided by Beijing HFK Bio-Technology Co., Ltd..
The Quality of Experimental Animals quality certification is scxk (capital) 2014-0004, and it is 11401300015756 that the kk/upj-ay mice quality certification is numbered, and mice age in days is 70 days, and sex is male, totally 18.
2.4 experimental facilitiess and reagent
Exempt from bar code and visit safe and comfortable Instrument for Measuring Blood Sugar, number of registration is [state's food medicine prison tool (entering) word 2008 the 2403659th, exported product registered standard: yzd/usa4991-2008], model contour ts;Test paper is using visiing safe and comfortable blood sugar test reagent paper.
2.5 experiment condition
18 spf level spontaneity kk/upj-ay ii patients with type Ⅰ DM mice single cages are fed in spf level laboratory, raise with the special high lipid food of kk/upj-ay mice (being purchased from Beijing HFK Bio-Technology Co., Ltd.), ad lib is drunk water.Keep ambient temperature 20-25 DEG C, humidity 40%-70%.
2.6 groups and dosage regimen
18 kk/upj-ay ii patients with type Ⅰ DM mices are randomly divided into 3 groups, respectively model group, Semen Coiciss water soluble vitamins group, and honokiol/Semen Coiciss water-soluble fibre promotor composition group.
2.6.1 model group: give kk/upj-ay mice by the dosage gavage of 0.1ml/10g and boil the distilled water letting cool, once a day, continue 28 days.
2.6.2 Semen Coiciss water-soluble cellulose group: weigh 60mg medicine, plus the dispersion of 10ml sterilized water is suspended, and by 0.1ml/10g gavage to kk/upj-ay mice, once a day, continues 28 days.
2.6.3 honokiol/Semen Coiciss water-soluble fibre promotor composition group: weigh 80mg honokiol/Semen Coiciss water-soluble fibre promotor composition, plus the dispersion of 10ml sterilized water is suspended, and gives kk/upj-ay mice by 0.1ml/10g gavage, once a day, continues 28 days.
2.7 experimental techniques:
2.7.1 the screening of model
Kk/upj-ay mice is raised with special high lipid food, and in feeding process, random blood sugar is surveyed in sampling weekly, when random blood sugar >=13.9mmol/l, is considered as Glycemia Decline success.
2.7.2 observation index
Mice fasting can't help 4 hours survey blood glucose of water once weekly, and second day after last dose, mice fasting can't help water 4 hours, and measurement body weight, blood glucose value, as the blood glucose value after last dose.
2.8 experimental results and discussion
Table 1 is the impact to kk/upj-ay ii patients with type Ⅰ DM Mouse Weight of Semen Coiciss water-soluble cellulose group and Semen Coiciss water-soluble cellulose/honokiol compositionss;The impact to kk/upj-ay ii patients with type Ⅰ DM mouse blood sugar value of table 2 Semen Coiciss water-soluble cellulose group and Semen Coiciss water-soluble cellulose/honokiol compositionss.
The present embodiment have rated Semen Coiciss water-soluble cellulose group and the hypoglycemic activity of Semen Coiciss water-soluble cellulose/honokiol compositionss using setting up kk/upj-ay ii patients with type Ⅰ DM mouse model.Experimental result is: in whole dosage period, Semen Coiciss water-soluble cellulose group blood glucose value is suitable with model group blood glucose value, and both do not have difference substantially;Semen Coiciss water-soluble cellulose/honokiol compositionss blood glucose value, compared with model group, starts persistently to reduce from being administered first week, starts by the 3rd week, both have significant difference, and both 4th weeks have pole significant difference, and blood glucose reduces amplitude and reaches 40%.In terms of the impact to body weight, in whole dosage period, the average weight of Semen Coiciss water-soluble cellulose group and the average weight value of model group are suitable, and both do not have differences;Semen Coiciss water-soluble cellulose/honokiol compositionss body weight, compared with model group, starts persistently to reduce from being administered first week, shows obvious weight loss trend.
The impact to kk/upj-ay ii patients with type Ⅰ DM Mouse Weight for the table 1 each group sample (Unit: g)
Compare with model group:*P < 0.05,**P < 0.01
The impact to kk/upj-ay ii patients with type Ⅰ DM mouse blood sugar for the table 2 each group sample (Unit: mmol/l)
Compare with model group:*P < 0.05,**P < 0.01
2.9 conclusion
Semen Coiciss water-soluble cellulose compatibility oral application with 60mg/kg/d, honokiol is in dosage as little as 20mg/kg/d, just tool is significantly reduced blood glucose and slimming drug effect, and under this dosage, 1 carries out comprehensive analysis in conjunction with the embodiments, either single honokiol, or individually Semen Coiciss water-soluble cellulose does not all have any blood sugar lowering and slimming effect, particularly document report, when Semen Coiciss water-soluble cellulose oral dose is up to 200mg/kg/d, there is no any reduction blood glucose and slimming drug effect.Semen Coiciss water-soluble cellulose and honokiol have the reduction blood glucose of highly significant and slimming synergistic function.
According to a kind of typical embodiment of the present invention, provide the application that Semen Coiciss water-soluble cellulose is used in the medicine treating ii patients with type Ⅰ DM, the obesity of lipid metabolic disorder or the disease related with insulin resistant to honokiol compositionss in preparation.Preferably, the related disease of insulin resistant is impaired selected from insulin, and insulin secretion lacks.Semen Coiciss water-soluble cellulose and honokiol compositionss can be to be respectively from Semen Coiciss and Cortex Magnoliae Officinalis extract.
According to another aspect of the present invention, according to a kind of typical embodiment of the present invention, provide a kind of medicine treating ii patients with type Ⅰ DM, including Semen Coiciss water-soluble cellulose and the honokiol compositionss of therapeutically effective amount.This medicine includes pharmaceutically acceptable carrier, excipient or adjuvant.The dosage form of this medicine is selected from powder, injection, capsule, tablet, oral liquid, paster.The dosage form of this medicine is slow release formulation, immediate release dosage form, enteric dosage form or measurable injection type.
These are only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.All any modification, equivalent substitution and improvement within the spirit and principles in the present invention, made etc., should be included within the scope of the present invention.
Non- patent citation list of references
[1] Wang Lianhua, Gai Yumei, Yuan Cheng, etc. the experimentation of Magnolol and Honokiol pharmacokineticss. practical medical magazine, 2004,21 (2): 137-139.
[2] Xu Zihui, all world, Huang Lin please wait. the separation and Extraction of coixan and its experimentation of hypoglycemic activity. Third Military Medical University's journal, 2000,20 (6): 578-581.
Claims (17)
1. Semen Coiciss water-soluble cellulose and honokiol are used for treating the obesity of ii patients with type Ⅰ DM, lipid metabolic disorder in preparation
Disease or with insulin resistant relevant disease medicine in application.
2. apply according to claim 1, wherein said insulin resistant relevant disease is selected from body to insulin sensitivity
Property reduce.
3. application according to claim 1, wherein said honokiol comes from Cortex Magnoliae Officinalis extract or chemosynthesis.
4. application according to claim 1, wherein Semen Coiciss water-soluble cellulose are also referred to as Semen Coiciss polysaccharide, Semen Coiciss water
Cellulose of solubleness comes from Semen Coicis extract.
5. in title compositionss, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 50.
6. in title compositionss, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 25.
7. in title compositionss, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 10.
8. in title compositionss, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 5.
9. in title compositionss, the ratio of honokiol and Semen Coiciss water-soluble cellulose is 1: 1-1: 3.
10. the preparation of title compositionss includes the uniform mixing of pharmaceutically acceptable any mode or dispersion is prepared from.
A kind of 11. medicines treating ii patients with type Ⅰ DM are it is characterised in that include the Semen Coiciss water-soluble cellulose of therapeutically effective amount
With honokiol.
12. medicines according to claim 11 are it is characterised in that further include pharmaceutically acceptable carrier, tax
Shape agent or adjuvant.
13. medicines according to claim 11 it is characterised in that described medicine dosage form be selected from powder, injection,
Capsule, tablet, oral liquid, paster.
14. medicines according to claim 11 are it is characterised in that the dosage form of described medicine is slow release formulation.
15. medicines according to claim 11 are it is characterised in that the dosage form of described medicine is immediate release dosage form.
16. medicines according to claim 11 are it is characterised in that the dosage form of described medicine is enteric dosage form.
17. medicines according to claim 11 are it is characterised in that the dosage form of described medicine is measurable injection type.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20090021561A (en) * | 2007-08-27 | 2009-03-04 | 재단법인서울대학교산학협력재단 | Composition for the prevention and treatment of fatty liver diseases containing honokiol as an active ingredient |
CN101642152A (en) * | 2009-09-03 | 2010-02-10 | 河南梦想食品有限公司 | Assistant hypoglycemic healthcare biscuits |
CN102512403A (en) * | 2011-12-06 | 2012-06-27 | 中国中医科学院西苑医院 | Application of honokiol in pharmacy, and medicine used for treating type II diabetes mellitus |
CN102698137A (en) * | 2012-06-21 | 2012-10-03 | 王杰 | Composition with blood pressure reducing function and preparation method of same |
CN104324310A (en) * | 2014-07-11 | 2015-02-04 | 张红敏 | Traditional Chinese medicine composition for treating mycotic keratitis after immune suppression and preparation method thereof |
-
2015
- 2015-07-08 CN CN201510393810.2A patent/CN106333958B/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20090021561A (en) * | 2007-08-27 | 2009-03-04 | 재단법인서울대학교산학협력재단 | Composition for the prevention and treatment of fatty liver diseases containing honokiol as an active ingredient |
CN101642152A (en) * | 2009-09-03 | 2010-02-10 | 河南梦想食品有限公司 | Assistant hypoglycemic healthcare biscuits |
CN102512403A (en) * | 2011-12-06 | 2012-06-27 | 中国中医科学院西苑医院 | Application of honokiol in pharmacy, and medicine used for treating type II diabetes mellitus |
CN102698137A (en) * | 2012-06-21 | 2012-10-03 | 王杰 | Composition with blood pressure reducing function and preparation method of same |
CN104324310A (en) * | 2014-07-11 | 2015-02-04 | 张红敏 | Traditional Chinese medicine composition for treating mycotic keratitis after immune suppression and preparation method thereof |
Non-Patent Citations (1)
Title |
---|
徐梓辉 等: "薏苡仁多糖的分离提取及其降血糖作用的研究", 《第三军医大学学报》 * |
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