CN103338636A - Compounds influencing fatty acid uptake and metabolism and the production of inflammatory agents and methods of isolating them from cocoa products - Google Patents
Compounds influencing fatty acid uptake and metabolism and the production of inflammatory agents and methods of isolating them from cocoa products Download PDFInfo
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Abstract
The invention provides compounds and plant extract compositions that inhibit pancreatic enzymes, such as lipases and amylases, and most particularly pancreatic lipase and phospholipase A2 (PLA2), and COX-2 enzyme. The compounds and plant extracts can be used in methods and administration regimens to treat animals for obesity-related conditions, diabetes and related conditions, metabolic syndrome, and inflammatory conditions. The compounds and plant extracts can also be used to produce comestible compositions to be incorporated into a normal diet to improve health or prevent or reduce the uptake of free fatty acids during digestion or the production of inflammatory eicosanoids or cytokines. The inhibitor compounds and compositions include cocoa-derived polymers of epicatechin, such as epicatechin-rich polymers of 2 units through polymers of 14 units and combinations of them.
Description
The cross reference of related application
The application requires the senior interest of the U.S. Provisional Application submitted on December 7th, 2010 number 61/420,701, and the complete content of described provisional application thereby mode are by reference incorporated into.
Invention field and introduction
The present invention relates to improve health or reduce enzyme inhibitor and the bioactive polymer of fatty acid uptake between the period of digestion plant, can being used for of especially existing in the cocoa (Theobroma cacao).Usually, described compound and plant extract composition suppress the pancreatin class, as lipase and amylase, or influence inflammatory eicosanoid or production of cytokines.Aspect some, described compound and composition are particularly useful for suppressing pancreatic lipase and phospholipase A in the dose dependent mode of the present invention
2And can be used for animal and human's therapeutic or prophylactic treatment (PLA2).Described compound and plant extracts can be used for the treatment of in the method and application program of obesity related pathologies, diabetes and related pathologies, metabolic syndrome and inflammatory symptom of animal.Described compound and plant extracts also can be used for producing edible composition and product, and described edible composition and product mix in the normal meals in order to improve healthy or prevent or reduce the picked-up of free fatty acid between the period of digestion.Described inhibitor compound and composition comprise the epicatechin polymer that cocoa is derived, as be rich in 2 polymer to 14 units of unit (DP=2-14) of epicatechin or high polymer more, various combinations with these polymer, and the DP10 polymer of the DP5 of purifying, DP7, DP8 and purifying especially, or contain one of DP5's to DP14 or its combination purified extract.In other respects, the cocoa epicatechin dose of polymer of deriving reduces the mammal eicosanoid (as prostaglandin (PG) E in the dependence mode
2) generation.And in a further aspect, the cocoa epicatechin polymer of deriving suppresses inflammatory cytokine interleukin 6 (IL-6) and the generation of TNF (TNF) in the mammalian cell of irriate.
Relevance of the present invention and description of related art
May exist can be from hundreds of independent compounds of cocoa bean separation.More and more evidences shows manyly in these compounds have health benefits, especially cocoa antioxidant or a cocoa flavanol compound.Most of evidences relate to cell research or the condition of wherein directly passing through these compound treatment zooblasts.These researchs attempt to simulate the situation that exists by behind the intestinal absorption cocoa.
In one aspect, the invention provides the method that before normal mammal absorbs fatty acid between the period of digestion, suppresses pancreatin valuably.These methods can incorporate therapeutic scheme into or the program of using with the meals of regulating or change the slimming experimenter of needs, because of changes in diet or other health status due to metabolic syndrome or the diabetes.In addition, food or other are edible maybe can take in the cocoa derivative compound mentioned in this article that product can mix effective dose.In other respects, the present invention relates to the epicatechin polymer of bioactive composition and purifying, or the application of inflammatory symptom in the combination of some polymer and their prevention people and the mammal.These application comprise the method that reduces inflammatory eicosanoid and cell factor generation or secretion, and the method that makes PLA2 enzyme and epicatechin polymer (PC) combination.
The accompanying drawing summary
Fig. 1 (a) is presented in the various concentration ranges of cocoa derivative composition external alpha-amylase activity and the inhibiting figure of percentage in contrast thereof.Shown from conventional or natural cocoa power, the extract of fermentation or lavado cocoa and alkaline treatment or holland type cocoa power not.The lavado source composition demonstrates the inhibitory activity of highest level.
Fig. 1 (b) is presented at the identical cocoa composition shown in Fig. 1 (a) and concentration range endosome external fat enzymic activity and the inhibiting figure of percentage in contrast thereof.
Fig. 1 (c) is presented in Fig. 1 (a) and the identical cocoa composition shown in Fig. 1 (b) and the concentration range the active and inhibiting figure of percentage in contrast of external phospholipase A2.Two kinds of compositions that are derived from lavado cocoa and conventional cocoa all show remarkable inhibition of phospholipase A 2 (PLA2).
When Fig. 2 (a) uses the specific subdivision of epicatechin polymer to three kinds of enzymes testing during 2 (c) show to Fig. 1 (a) to 1 (c) to the inhibiting figure of described enzyme.Polymer composition separates with the degree of polymerization by size, and wherein DP=2 refers to that the degree of polymerization 2 (2) and DP=10 refer to the degree of polymerization 10 (10).Fig. 2 (a) shows with respect to the inhibitory action of every kind of polymer composition to α-Dian Fenmei.EC is table of comparisons catechin monomers.Fig. 2 (b) shows with respect to the inhibitory action of every kind of polymer composition to pancreatic lipase.
Fig. 2 (c) shows that PLA2 is for the inhibitory action of every kind of polymer composition.As shown in Fig. 2 (c), the polymer composition of DP5 to DP10 shows high-caliber enzyme inhibition activity with low-down concentration.
Fig. 3 show with Fig. 2 (b) in identical result, but for relatively, have the excessive data that shows medicine orlistat inhibition pancreatic lipase.
Fig. 4 is presented at the maximum inhibition concentration (IC50) of half of the polymer composition of every kind of enzyme testing among Fig. 1-3.Based on the dose-response curve of the polymer composition of purifying, DP seemingly determines the key factor that compound or composition are renderd a service.By regression analysis, between Log IC50 and DP, there is strong anti-correlation (R
20.93, Fig. 4).Relatively the similarity analysis of Log IC50 and hydrophobicity (LogP) does not show significant correlation (data not shown).
Fig. 5 (a) shows that to 5 (c) dynamic analysis of pancreatic lipases (PL) and Fig. 6 (a) show the dynamic analysis of PLA2 to 6 (c), because these two kinds of enzymes are all to the inhibitory action sensitivity of cocoa extract and polymer composition.Use OPC pentamer (DP5) and ten polymers (DP10) and conventional cocoa extract as the test inhibitor.Whole 3 kinds of substances all reduce the V of PL
MaxAnd increase its K
m(Fig. 5) and as shown in the table of Fig. 7.These results show the mixed type inhibitory action for concentration of substrate.On the other hand, with respect to concentration of substrate, the Michealis-Menten curve that pentamer and ten polymers compositions suppress PLA2 shows that noncompetitive suppresses (Fig. 6 (a) is to the table of (c) and Fig. 8).On the contrary, with respect to concentration of substrate, conventional cocoa extract is showed at the inhibiting competitive pattern of PLA2 (table of Fig. 8).
Fig. 9 shows that the enzyme of every kind of polymer composition DP2 to DP10 and epicatechin (EC) monomer suppresses the table of gathering information of numerical value.
Figure 10, Figure 11 and Figure 12 show that the OPC polymer that is derived from apple suppresses α-Dian Fenmei, pancreatic lipase and phospholipase A2.Data comprise the application of polymer DP10 to DP13.As cocoa derived compounds and composition, these compounds are potent inhibitors of PLA2 activity.
Figure 13 shows the heavy polymer mixture (degree of polymerization 7 or bigger; DP7+Mix) the RAW264.7 macrophage cell that lipopolysaccharides (LPS, 1 μ g/mL) is stimulated produces inflammatory eicosanoid prostaglandin (PG) E
2Influence.Can test three kinds of processing schemes: (a) with DP7+ preliminary treatment 6 hours, stimulate 6 hours (cocoa is preceding) with LPS subsequently; Stimulate its 6 hours in advance subsequently with 6 hours (LPS is preceding) of DP7+ processing with LPS; With usefulness DP7+ and 12 hours (coprocessing) of the common processing of LPS.(0) and in the dose dependent mode, whole 3 kinds of processing schemes all reduce PGE compared with the control
2Generation.
Figure 14 shows that the DP7+ mixture of spreading out property of cocoa polymer is to the cyclo-oxygenase (inhibitory action of 2 (COX-2) enzymic activity of purifying.Mean inhibitory concentration (IC
50) be 58ug/ml.
Figure 15 (A) (left side) shows that the inflammatory cytokine (IL-6 and TNF α) in the macrophage that stimulates by the polymer DP=8 inhibition LPS that uses purifying produces.Figure 15 (B) (right side) shows by the PGE in the macrophage of the polymer DP=8 inhibition LPS stimulation of purifying
2Produce.Macrophage cell culture (RAW264.7) was with DP=8 octamer preliminary treatment 10 hours and stimulated 12 hours with LPS subsequently and measure.
Figure 16 describes PLA
2The binding interactions of enzyme.Little figure A is presented at PLA
2The ball-and-stick model substrate of combination in the tunnel area of enzyme space-filling model.Little figure B describes and PLA
2The interactional DP=2 polymer of enzyme primary structure and tertiary structure comprises with the spiral that forms the tunnel wall as shown in little figure A and being combined.Little figure C describes DP=7 and PLA
2Enzyme primary structure and tertiary structure combine.In little figure C, the extra binding site of DP=7 polymer demonstrates increase as the potentiality of the effectiveness of inhibition molecule.
The invention summary
In one aspect, the present invention satisfies suppressing fatty acid uptake and the product of metabolism and the needs of method in the mammalian subject.Before, report influenced fatty acid uptake or cocoa products, cocoa power or chocolate product are discussed in metabolism because of direct.The present invention described here has explained at least in part with the adult who accepts the contrast placebo treatment and has compared, how the application that contains the cocoa power beverage can cause littler slightly waistline (Fulgoni V. in the adult, Fulgoni, S. and Bodor, A. (2009, April), Association of Candy Consumption with Physiological Parameters in Participants from the National Health and Nutrition Examination Survey (1999-2004); At Experimental Biology, New Orleans, the placard paper that LA can propose)).Also point out, although have high-caliber relatively saturated fat, chocolate does not influence LDL-cholesterol levels (Ding, people such as E.L. unfriendly, 2006, Chocolate and prevention of cardiovascular disease:A systematic review; Nutrition and Metabolism3:2-13) and evidence show, cocoa power can even reduce LDL-cholesterol levels (Jia in short-term research, people such as L, 2010, Short-tem effects of cocoa product consumption on lipid profile:A meta-analysis of randomized controlled trials; Am.J.Clin.Nutr.92:218-25).When making up with other known compounds that exist in the cocoa, be that generation possesses the food of the natural cocoa epicatechin of useful level polymer or supplies the new possibility of food creation with the natural cocoa epicatechin of useful level polymer by favourable new cocoa products, chocolate and the food composition that provides of the present invention and product.
In yet another aspect, the present invention relates to separate and use polymer compound and the polymer composition that specificity or noncompetitive from plant suppress the PLA2 enzymic activity.Therefore, the polymer of polymer composition, the polymer that is rich in epicatechin and cocoa derived polymers and purifying and combination can be used for influencing the level of multiple inflammation correlation and immune response correlation eicosanoid compound (as Prostaglandins and Leukotrienes), and influence approach and feedback mechanism in its biosynthesis pathway.
In yet another aspect, the present invention includes polymer composition and application thereof, for example the application aspect inhibition PLA2 enzymic activity.Specifically and preferably, can use part and cocoa bean from cocoa.The sample, mixture and the extract that are derived from cocoa seed (cocoa bean) contain high-caliber especially epicatechin compound, compare the order of magnitude that is in the 30:1 epicatechin with catechin.In most of other plants, this ratio is close to 1:1.As using in this specification, term " epicatechin that cocoa is derived " polymer or composition or sample can refer to contain in polymer inside other compounds of some level such as sample or the composition of catechin.Therefore the epicatechin polymer that cocoa is derived is rich in epicatechin, but can and not exclusively be made up of epicatechin monomers unit.As used herein, " being rich in the polymer of epicatechin " refer to wherein be to the monomer unit advantage on average the epicatechin compound (as by weight on average more than 70% or more than 80% more than 90% or more than 95% or more epicatechin) polymer composition.The purification of samples of mentioning among the application refers to from the polymer of another kind of specification the polymer of purifying basically, means particular polymers existing greater than 60% or 70% or 80% or 90% or 95% with whole polymer of existing.Preferably, the present composition will be derived from the cocoa source, most preferably be derived from the point (nib) of cocoa bean or cocoa bean, and advantage ground is contained the polymer of being made up of with the ratio of about 30:1 with respect to other related compounds epicatechin, and wherein said other related compounds can be merged into the OPC polymer in plant.Yet, also can use the other plant material, as apple and Chinese sorghum, or the high other plant source of epicatechin Type B OPC polymer content.Therefore, specifically comprise among the present invention the combination of various polymer compounds and polymer compound, with the combination of his enzyme inhibitor be used for Orally administered composition.
In yet another aspect, the present invention relates to be used for the treatment of animal or human experimenter in order to reduce the validity of fatty acid digestion and therefore reduce fatty acid between the period of digestion and/or the picked-up of triglycerides or suppress PLA among the experimenter
2The method of enzymic activity.The inhibition compound is particularly useful for treatment of obesity, obesity associated conditions, diabetes and disease and the symptom relevant with inflammatory approach and/or symptom with composition, in described disease and/or symptom, it can be useful that the eicosanoid of reduction or cell factor produce.On meaning more generally, described compound and composition can be used for changing fat or the fatty acid metabolism among the animal or human.
In yet another aspect, the present invention relates to described compound and composition for the preparation of or make the purposes of food or Orally administered medicine or edible composition.In yet another aspect, the composition that general or injectable are used is possible, especially adopts noncompetitive to suppress purified polymer compound and the extract of PLA2 enzyme (a kind of enzyme that can play a significant role) in inflammatory conditions, cardiovascular disease and neurological conditions.Therefore, the plant compound of purifying and composition can be as treatment people's medicines, and wherein said PLA2 enzyme participation metabolism or katabolism influence the product of disease condition.
In yet another aspect, the present invention includes inhibitor compound combination and with the composition of other enzyme inhibitors.For example, one or more inhibitor below can with PLA2 noncompetitive inhibitor of the present invention combination: tetrahydrochysene lipstatin or orlistat, cocoa bean amine, west are for department he, crocin, lipstatin, vibralactone and green tea catechins.In addition, the synergistic combination of especially preferred one or more noncompetitives PLA2 inhibitor compound as herein described, polymer or composition and another enzyme inhibitor.These comprise epicatechin polymer and orlistat that one or more cocoas are derived, or one or more cocoas epicatechin polymer and the lipstatin of deriving.Being rich in the extra combination of the polymer composition of epicatechin and purified polymer and their combination can carry out with other food supplement or vitamin or herbal medicine product (especially but not limited to caffeine, epicatechin monomers and/or theophylline).Those skilled in the art are familiar with multiple health available in food, nutritional drugs and drug world, natural or biologically active fill-in or compound, and they use in any one of combinations thereof or other listed combinations in this manual.
The compound and the composition that are derived from cocoa sources (as cocoa power and cocoa plants and cocoa bean extract) can have special validity aspect the fatty acid uptake inhibition.The epicatechin polymer that exists in the cocoa mainly is the Type B OPC, has some A type OPCs.Numerous may the arrangement during polymerization of (-)-epicatechin is known.
The Type B polymer of epicatechin
On the contrary, tea and green tea are rich in catechin especially, and wherein Epigallo-catechin gallate (EGCG) (EGCG) is the abundantest.Therefore, in some embodiments of the present invention, the extract of cocoa derived polymers, purifying or polymer composition can be important.In other preferred embodiments, be rich in the polymer of epicatechin or composition only derived from cocoa sources or cocoa bean or cocoa bean point.
An object of the present invention is to provide the method for selecting and/or processing cocoa bean, described method is for generation of cocoa composition, extract and composition, and it has the useful polymer that is rich in epicatechin of improving the standard.Another purpose of the present invention provides the cocoa composition, comprises chocolate liquid, cocoa power, low fat cocoa powder, degreased cocoa powder and the cocoa extract of the epicatechin polymer with enhanced level and the food that contains these cocoa compositions, extract and composition or made by them.
In one aspect, the cocoa bean that is used for producing edible product as described herein or composition comprises more than 10% unfermentable cocoa bean or more than 10% (fermentation does not bake, or " lavado ") cocoa bean of giving birth to.The cocoa bean of selecting can be made numerous cocoa compositions, as cocoa liq-uor, cocoa power, low fat cocoa powder, degreased cocoa powder and cocoa extract.Also cocoa bean can be baked or with alkaline treatment-" Hollandization (Dutched) ", as known in the art.Deriving from cocoa of the present invention, issuable numerous Foods or drinks products include but not limited to the epicatechin polymer composition: chocolate product, the milk chocolate product, the dark chocolate bar product, half sweet or bitter sweet chocolate product, chocolate aromatising prods, the chocolate fruit product, chocolate flavouring confectionary products, beverage, chocolate, chocolate flavouring beverage, dietary supplements, chocolate coated product, the low fat chocolate product, bake chocolate product, as cake, chocolate cake, or bread product or low sugar chocolate product.
In some embodiments of the present invention, comprise several cocoas derive the concrete cocoa derivative compound of epicatechin polymer or composition can specificity or basically specificity suppress activity of phospholipase, as phospholipase A
2(PLA2) activity.For example, in some preferred embodiments, inhibitor combination of the present invention does not suppress or not obvious inhibition or do not suppress other lipase basically, as pancreas triglyceride lipase (PTL) and carboxyl ester lipase (CEL) or amylase.In some preferred embodiments, inhibitor combination of the present invention suppresses PLA2 and preferably suppresses phosphatidase-A2IB, but does not suppress or not obvious inhibition or do not suppress PLA1 and/or PLB basically.In some embodiments, the inhibitor of phospholipase enzymes composition preferably acts on gastrointestinal tract mucous and obviously inhibition or inhibition film mating type phosphatidase wherein basically.In some embodiments, inhibitor combination of the present invention or concrete epicatechin polymer interact by the catalytic site with PLA2 and suppress the activity of PLA2.
Although it is not following examples show the inhibition level, most important to the present invention to the complete or irreversibility inhibition of PLA2 or pancreatic lipase.Therefore, term " inhibition " and grammatical variants thereof are not intended to and require complete inhibitory enzyme activity.For example, it can refer to reduce the enzymic activity that exists in the duodenum small intestine sample between the period of digestion, or under the situation that other illustrate especially at some, when described inhibitor does not exist, reduce described enzymic activity at least about 30%, preferably at least about 50%, at least about 75%, preferably at least about 90%, more preferably at least about 98% and even more preferably at least about 99%.Most preferably, it refers to reduce enzymic activity with the effective dose that produces therapeutic and/or preventative benefit in the experimenter at least a symptom of enough treating.On the contrary, phrase " does not suppress " or " not suppressing basically " and grammatical variants thereof do not need thoroughly lacking the inhibition effect of enzymic activity.For example, it refers to this class situation, wherein exist less than about 5%, preferably less than about 2% with more preferably reduce less than about 1% enzymic activity.Most preferably, it refers to that such enzymic activity reduces, thereby can not observe measurable effect.
Not with scope of the present invention prior to any ad hoc hypothesis or action method, the benefit of the epicatechin polymer that cocoa is derived can be because of numerous one or more the results on due to the PLA2 activity that reduces.For example, suppress the PLA2 activity and can reduce phosphatide through the intestines and stomach tube chamber or through the transhipment of small intestine top film, cause phosphatide in the enterocyte (for example phosphatid ylcholine) pond to exhaust.This can be the situation in the mammal of high lipid diet of feeding.In this case, from the beginning synthesizing of phosphatide may be not enough to keep the height turnover of carrying the needed phosphatide of triglycerides (for example phosphatid ylcholine) in the chylomicron.
Use numerous approach or mode of administration, can be delivered to the experimenter with can be used for inhibitor of phospholipase enzymes among the present invention or pharmaceutically acceptable variant or its salt.Preferably, described inhibitor combination is sent with oral way or as the part (as B.Minifie, Chocolate, Cocoa, and Confectionery, the 3rd edition, one or more described in the Aspen Publishers) of chocolate or cocoa products.Term " pharmaceutically acceptable variant or salt " means those variant compound and salt, they keep the biology effect of polymer compound of the present invention and performance and be not biologically or other side undesired.The pharmaceutical compositions use of the state of known in the art or obtainable one or more pharmaceutically suitable carrier, excipient or mixing diluents or mixing with it can be used or be in reactive compound to inhibitor of phospholipase enzymes (or pharmaceutically acceptable variant or its salt) separately.Pharmaceutical composition used according to the invention can use one or more physiology that promote that described reactive compound is processed into goods can accept carrier, comprises excipient and auxiliary material, and wherein said goods can use by the pharmacy mode.Correct preparation depends on selected route of administration.Multiple pharmaceutical composition can be by the known or apparent method preparation of those skilled in the art and at Remington's Pharmaceutical Science, the 17th edition, Mack Publishing Company, Easton, Pa. describe in more detail in (1985) and afterwards the 18th edition and the 19th edition thereof, described document all by reference mode is incorporated this paper into.
In preferred embodiments, the present invention includes a kind of method that suppresses fatty acid uptake in the following manner in animal: use edible composition, described edible composition contains epicatechin polymer that the cocoa with 2-14 epicatechin unit of effective dose derives or 2 or the cocoa of the multilist catechin unit epicatechin polymer of deriving more.The effect of using is measuring of pancreatic lipase A2 or pancreatic lipase activity or effectively reduces, and preferably reduces untreated normal activity in the animal or being untreated of existing in the sample of digestible fluid in animal duodenum or stomach is active 50% or more.In yet another aspect, can select and use that cocoa is derived or be rich in various scopes or the specific subdivision of the polymer of epicatechin, comprise 2 to 14 unit polymer (DP=2-14, wherein DP refers to the degree of polymerization), 5-13 unit's polymer (DP5-13) 5 or more units (DP〉5) 2 or the polymer of more units (DP〉2) in any one or more.Hereinafter embodiment refers to DP5, DP7, DP8, DP10 and DP2-DP10 and DP7+ polymer composition particularly, wherein can select or unite to use in them any one.
Described method also comprises mixes cocoa or chocolate food or composition with edible composition, in chocolate liquid, cocoa power or cocoa bean extract.Except exist in the natural cocoa power for example those, the epicatechin polymer of extra cocoa can being derived is added into described composition.Therefore edible composition can comprise cocoa butter, and wherein the inhibitor of Cun Zaiing reduces the picked-up of the fatty acid that exists in the cocoa butter effectively.Therefore, the chocolate product with fatty acid " availability " of reduction is possible, and is measured as the actual amount of the fatty acid that enters blood from enteron aisle.
The present invention comprises that also epicatechin polymer that cocoa is wherein derived or its composition specificity are as the method for the competitive inhibitor of pancreatic lipase A2 enzymic activity.
Can use various sample of cocoa beans or product as the source of polymer composition of the present invention.In a preferred examples, " lavado " cocoa bean that the cocoa derived polymer is derived from unfermentable cocoa bean or gives birth to.With " routine " cocoa bean as an example, also can use those cocoa beans that fermented and baked by conventional method known in the art.As mentioned, " Hollandization " sample has been used alkaline treatment, as known in the art.
In addition, the invention provides a kind of cocoa composition, it is selected from chocolate liquid, cocoa power, cocoa extraction, low fat cocoa powder, degreased cocoa powder and fat-free cocoa solid content, wherein the level of the cocoa with 2-14 polymer unit of the Cun Zaiing epicatechin polymer of deriving is more than 50 μ g/mg, or 100 μ g/mg, or 200 μ g/mg, or 500 μ g/mg or more.Some example that is used for the dosage of human oral delivery can change, but example comprises 5-80mg or 600mg/ day or more.
Spread all over the disclosure, the applicant is with reference to list of references, webpage and other information sources of text, journal article, patent documentation, publication.Those skilled in the art can use the complete content of any information source of quoting to produce and utilize many aspects of the present invention.Particularly, with people such as Gu (2011) J.Agric.Food Chem.59 (10): the paper of 5305-5311 mode is by reference incorporated this paper into.With the complete this paper of incorporating into of each information source of quoting mode by reference.As allowing or needing, can in the literature, comprise the part of these information sources.Yet concrete definition or any term of explaining or the implication of phrase are not modified by the content of any information source should in the disclosure.The description of this paper and example only are the examples of the scope of the invention and present disclosure and do not limit the scope of the invention.In fact, those skilled in the art can and make up many modifications and not depart from the scope of the present invention the embodiment that hereinafter lists design.
The detailed description of exemplary
In one aspect, the present invention relates to make or the application of the product of deriving from them from the cocoa bean in any source with by them.Term " cocoa extract ", " cocoa bean composition (cocoa bean composition) " and " cocoa bean composition (cacao bean composition) " can be the combinations of any and cocoa bean derivative products of the multiple product pointed out in the disclosure." cocoa bean composition ", " cocoa bean composition " and " cocoa products " are interchangeable and mean the product of being made by cocoa bean basically." sample of cocoa beans (cacao bean sample) " or " sample of cocoa beans (cocoa bean sample) " is from the set of required source or the cocoa bean of processing conditions set or the general designation of this class cocoa bean point.In addition, relate under conventional method handle, the combination of the cocoa products of processing or the cocoa bean selected or cocoa extract can with close cocoa bean combination of compositions of the present invention.These compositions and extract can use in any cocoa composition, and described cocoa composition then can be used in any composition or product for human consumption comprises food, confectionery, beverage and fill-in.
Understand as this area, cocoa power contains about 10-25% lipid part (cocoa butter).Yet, as known in the art, can be from powder by compacting, extract or any numerous additive method removes all or the fat of certain percentage by solvent or supercritical solvent.Therefore, in cocoa products as herein described or composition, comprise natural, degreasing and/or low fat or do not have the fat cocoa power particularly.Also can produce other cocoa products from the present invention, as breakfast cocoa, cocoa extract and chocolate liquid.
In some embodiments, the inhibitor of phospholipase enzymes dosage of recommendation is in about 0.1mg/kg/ day and about 1, and 000mg/kg/ is between day, or in other embodiments, about 100mg/ day to about 1,000mg/ is between day.Can be identified for effective dose the mankind from animal model.For example, can prepare human dosage to realize having been found that in animal for example effectively circulation composition and/or intestines and stomach concentration in (mouse model).Those skilled in the art can determine the phosphatidase inhibitory action by the amount of measuring phosphatidase product such as lysophosphatidyl choline (LPC) (product of PLA2).Can be for example by measuring small intestine, lymph and/or serum levels after the meal, determine the amount of LPC.Another technology of be used for determining the amount that phosphatidase suppresses relates to from intestines and stomach and obtains direct fluid sample.Those skilled in the art also can supervise the effect of inhibitor of phospholipase enzymes of the present invention among the side experimenter, as passing through monitoring cholesterol and/or triglycerides serum levels.Other technologies will be that those of ordinary skills are apparent.Hereinafter further specify in an embodiment for measuring other schemes of effect that phosphatidase suppresses and/or be used for to show the inhibitor of phospholipase enzymes of some embodiments.
By replenishing or be added into the level of purifying source or extract, cocoa composition of the present invention and product can contain epicatechin polymer or the polymer composition of improving the standard.
The present invention also comprises the food that contains the cocoa composition, and described cocoa composition has the polymer that is rich in epicatechin or the composition of improving the standard.Term " food " comprises and can be taken in to provide nutrition or any edible or the consumable product of fill-in are provided by the human or animal, and include but not limited to chocolate food, chocolate bars, chocolate, brew cocoa, chocolate, chocolate flavouring food, chocolate flavouring rod, chocolate flavouring candy, chocolate flavouring beverage, chocolate coated food, chocolate dressing rod, chocolate dressing candy, milk chocolate, dark chocolate bar, bake chocolate, half sweetly bakes broken chocolate, bake chocolate product, as cake, chocolate cake and bread, subtract sugared chocolate and reduced-fat chocolate.
In yet another aspect, the present invention includes composition or composition (comprising pharmaceutical composition), it has the polymer compound that is rich in natural epicatechin that is derived from cocoa, and described compound can comprise one or more of the DP2-14 polymer mentioned or other polymer compositions herein.
Embodiment
Preparation dimer to ten polymers (degree of polymerization=2 are to 10) cocoa epicatechin polymer or OPC from one of 3 kinds of cocoa bean extracts (routine, lavado and Hollandization).The two all can be used for analysis as described herein polymer composition and extract.Can prepare described extract at first by with the hexane degreasing of cocoa sample, this relates to sample is mixed with hexane.Sample is centrifugal, and inclining hexane, and allows the residue dried overnight.Dried residue was extracted 30 minutes with 70/30/05 (v/v/v) acetone/acetic acid, accompanied by jolting.This solution can be filtered through Whatman#4 filter paper or equivalent.Remove solvent by placing under the vacuum or spending the night at fume hood, and resulting extract can be directly used in research.Can pass through at DMSO (EMD Chemicals Inc.; Gibbstown, NJ) middle dissolving cocoa sample preparation mother liquor.Check the purity level of whole cocoa OPC compositions by HPLC, show greater than 85% purity.The reference material of (-) epicatechin (EC) available from Sigma Chemical Co. (St.Louis, MO), and orlistat (Xenical is Alii) available from Sigma Chemical Company.Can use the MALDI mass spectrometry to carry out the analysis at HPLC purifying peak with the sodium adduct.The common result of various cocoa polymer m/z is that DP=2 is at 601 places; DP=3 is at 889 places; DP=4 is at 1,177 place; DP=5 is at 1,465 place; DP=6 is at 1,753 place; DP=7 is at 2,041 places; DP=8 is at 2,329 places; DP=9 is at 2,617 places; And DP=10 is at 2,907 places.These values are consistent as the epicatechin polymer of the nominal degree of polymerization with polymer.
The vitro enzyme activity measurement:
The activity of pancreas α-Dian Fenmei, pancreatic lipase and phospholipase A2 is measured and is expressed as the percentage of contrast (blank) by external inhibition determination method.α-Dian Fenmei can take from pig pancreas and red starch (Red-Starch) can available from Megazyme (Wicklow, Ireland).Lipase can take from pig pancreas (II type) and 4-nitrobenzophenone butyrate (4-NPB, 98%) can available from Sigma-Aldrich (St.Louis, MO).
Phospholipase A2 measure kit can available from Invitrogen (Carlsbad, CA) and Molecular Probes Inc. (Eugene, OR).All other reagent are AG.By with the range of concentrations mapping of enzymic activity (contrast) to cocoa OPC and cocoa extract thing, set up dose-response curve.(SanDiego CA) to dose-response curve interpolation or extrapolation, determines the inhibition constant 50% (IC50) of every kind of cocoa OPC and extract by using GraphPad Prism software.The concentration of cocoa OPC and cocoa extract is respectively 0-100uM and 0-200ug/ml after testing.
The pancreas α-Dian Fenmei suppresses determination method
Use reorganization to carry out pancreas α-Dian Fenmei (PA) from the method for adding lustre to of Megazyme and suppress determination method.Use red starch as substrate, it is the starch with the red MX-5B dyeing of Procion.By dissolving in containing the 20mM phosphate buffer (pH6.9) of 6.7mM sodium chloride, preparation pancreas α-Dian Fenmei solution.In water-bath in 37 ℃ of preincubates after 5 minutes, with the red starch in the α-Dian Fenmei solution of Klorvess Liquid and buffering and the former extract of cocoa OPC/cocoa or contrast (distilled water) combination.In case 37 ℃ of mixtures incubated 10 minutes, then red starch depolymerization was dyed red fragment to produce low-molecular-weight, and by adding 95% ethanol cessation reaction.In balance to room temperature, by the centrifugal high molecular weight material that removes.Supernatant is transferred to cuvette and uses spectrophotometer (BECKMAN
650) measure its absorbance at 510nm.
Pancreatic lipase suppresses determination method
The active measurement of pancreatic lipase (PL) relates to the cracking of 4-nitrobenzophenone butyrate (4-NPB) to discharge butyric acid and 4-nitrophenols (4-NP).The release of 4-NP causes the change color that can monitor in spectrophotometric metering mode at 400nm.Cocoa OPC or cocoa extract and pancreatic lipase and 0.1M Tris-HCI buffer solution (pH8) merge, and add 4-NPB subsequently to start reaction.After the incubated at room 10 minutes, read absorbance at 400nm.Use orlistat (a kind of PL inhibitor of clinical use) as positive control.
Phospholipase A2 suppresses determination method
Adopt the phospholipase A2 assay kit, use fluorescent measurement to measure phospholipase A2 (PLA2) activity.Substrate is red/and green
PC-A2 is a kind of usefulness
Glycerophosphonolipid phatidylcholine dyestuff at sn-1 and sn-2 place mark.The sn-2 ester bond of phospholipase A2 hydrolytic phosphatide is to discharge lysophosphatide and fluorogen.PLA2 solution (pH8.9) and cocoa OPC or the cocoa extract thing of buffering are added into each hole of trace flat board, 96 holes.The PLA2 substrate of aliquot is assigned to each micro-plate well to start reaction.After room temperature (lucifuge protection) is hatched 10 minutes; determine the PLA2 activity by measuring its fluorescence intensity (Fluoroskan Ascent FL is from ThermoFisher Scientific Inc.) at the excitation wavelength that equals 485nm and 538nm respectively and emission wavelength.
Dynamic analysis
Select cocoa OPC pentamer (DP=5) and ten polymers (DP=10) and conventional cocoa extract to carry out the inhibiting dynamic analysis at pancreatic lipase (2.2.2) and phospholipase A2 (2.2.3).With the cocoa OPC or cocoa extract remains on constant density and in the presence of the substrate of cumulative concentration with enzyme and the buffering solution hatch.(2.2) described definite enzymic activity as mentioned.(SanDiego CA), is used for making up the Michaelis-Menten curve with these data, and assessment Vmax (maximal rate) and Km (Michaelis constant produces the concentration of substrate of half maximal rate) by Graph Pad Prismm software.Vmax and the Km value in the presence of inhibitor (cocoa OPC pentamer, ten polymers and conventional cocoa extract) by one-way analysis of variance (one-way ANOVA) or every kind of enzyme of Si Shi t-check analysis, and the inhibitory action of therefore definite every kind of inhibitor (competitiveness, noncompetitive or mixed type suppress) pattern.
Statistical analysis
Data are expressed as the mean ± standard deviation (SD) of at least 3 independent experiments.P-value less than 0.05 is considered as statistically significant.GraphPad Prism software is all used in whole statistical analyses, and (SanDiego CA) carries out.
The table 1 of Fig. 9 shows that the EC polymer is especially to the highly inhibited activity of PLA2 activity.From DP7 to DP10, suppress to increase considerably.
Fig. 7 comprises that the cocoa OPC pentamer, ten polymers and the conventional cocoa extract that are presented at various concentration do not exist and exist the Vmax of following pancreatic lipase and the table of Km.Fig. 8 comprises that the cocoa OPC pentamer, ten polymers and the conventional cocoa extract that are presented at various concentration do not exist and exist the Vmax of following phospholipase A2 and the table of Km.The inhibiting type that occurs when also listing based on this analysis in each table.As shown, pentamer and the equal noncompetitive of ten polymers compounds ground suppress PLA2.
Competitive inhibition expression inhibitor and substrate competition arrive at the active site of enzyme.Surpass inhibitor if the substrate of q.s exists, then can overcome this inhibitory action.On the contrary, noncompetitive inhibitor is combined with the site except active site on the enzyme.This combination causes conformation change, and the latter makes enzymic activity lower.The noncompetitive inhibitory action can not overcome by adding more substrates.Mixed type suppresses to mean inhibitor and demonstrates the two feature of competitive inhibitor and noncompetitive inhibitor.In order to treat the animal or human or to suppress fatty acid in animal or human's class and/or the purpose of the inventive method of triglycerides picked-up, the noncompetitive inhibitory action of being showed by the cocoa epicatechin polymer of purifying is particularly advantageous.
As shown in Figure 10,11 and 12, plant-derived senior OPC polymer is to suppress α-Dian Fenmei, pancreatic lipase and phospholipase A2 with the same way as shown in the result above.Data among these figure comprise the purposes of polymer DP10 to DP13.As cocoa derived compounds and composition, these compounds are potent inhibitors of PLA2 activity.Thereby the OPC polymer that can use in product of the present invention, composition and method comprises the polymer of two or more epicatechin units.
Figure 13 and Figure 15 demonstration are rich in the polymer of epicatechin and the derivative polymer composition of cocoa and purifying to the influence of the mammalian cell of cultivation, the customary determination method that is used for following compound of wherein said mammalian cell, described compound interacts with the generation that participates in the compound of inflammatory process among mammal and the mankind.During irriate, these cells produce inflammatory eicosanoid and inflammatory cytokine.Figure 13 shows the heavy polymer compound (degree of polymerization 7 or bigger; In this figure, being designated as DP7+Mix) RAW264.7 macrophage cell that lipopolysaccharides (LPS, 1 μ g/mL) is stimulated produces inflammatory eicosanoid prostaglandin (PG) E
2Influence.Three kinds of processing schemes have been shown: (a) with DP7+ preliminary treatment 6 hours, stimulate 6 hours (cocoa is preceding) with LPS subsequently; Stimulate its 6 hours in advance subsequently with 6 hours (LPS is preceding) of DP7+ processing with LPS; With usefulness DP7+ and 12 hours (coprocessing) of the common processing of LPS.(0) and in the dose dependent mode, whole 3 kinds of processing schemes all reduce PGE compared with the control
2Generation.Therefore, be rich in epicatechin polymer composition use the inflammatory reaction that can be used for reducing mammal and philtrum.
Figure 14 shows that the DP7+ compound of spreading out property of cocoa polymer is to the purity ring oxygenase (inhibitory action of 2 (COX-2) enzymic activity.Mean inhibitory concentration (IC
50) be 58ug/ml.Because the COX-2 enzyme is participated in the generation of inflammatory eicosanoid directly, because inhibitory action due to the polymer that is rich in epicatechin represents that these polymer can play a role at level (similar to other Orally administered cox 2 inhibitors) and the PLA2 enzyme level of inhibition COX-2 enzyme with the people mammal.Adopt under the situation of application program and dosage, the potentiality that are used for essential these the two kinds of enzymes at least of double inhibition eicosanoid biosynthetic process can provide concertedness or especially effectively treatment, so that hurried, temporary transient or reduce the level of the eicosanoid that produces by cell or by some tissue in a period of time scope.
Figure 15 describes the excessive data to mammalian cell cultures.The generation of inflammatory cytokine IL-6 and TNF in the macrophage that the figure in left side (A) demonstration stimulates by the polymer DP=8 composition inhibition LPS that uses purifying.Show that at the figure on right side (B) polymer DP=8 composition by purifying suppresses the PGE in the macrophage that LPS stimulates
2Produce.In these determination methods, macrophage cell culture (RAW264.7) was with DP=8 octamer composition preliminary treatment 10 hours and stimulated 12 hours with LPS subsequently and measure.As among Figure 13 above, these data show the inflammatory reaction that can be used for reducing mammal and philtrum of using of the polymer DP=8 that specifically is rich in epicatechin.
Figure 16 describes PLA
2The binding interactions of enzyme.Little figure A is presented at PLA
2The ball-and-stick model substrate of combination in the tunnel area of enzyme space-filling model.Little figure B describes and PLA
2The interactional DP=2 polymer of enzyme primary structure and tertiary structure comprises with the spiral that forms the tunnel wall as shown in little figure A and being combined.Little figure C describes DP=7 and PLA
2Enzyme primary structure and tertiary structure are interactional.In little figure C, the extra binding site of DP=7 polymer demonstrates increase as the potentiality of the effectiveness of inhibition molecule.
Embodiment proposed above and the application's content limits and has described the embodiment of many cocoa compositions, product and the method that can produce according to the present invention or use.The embodiment of this specification and part all not will be understood that restriction as a whole the scope of the invention or limit the scope of following claim.
Claims (27)
1. method that in animal, suppresses fatty acid uptake, comprise and use edible composition, the epicatechin polymer that the cocoa that described edible composition contains the 2-14 unit of effective dose is derived, the wherein activity inhibited 50% of phospholipase A2 or pancreatic lipase or more.
2. method according to claim 1, the epicatechin polymer that wherein said cocoa is derived is 5-13 unit.
3. method according to claim 1 and 2, wherein said edible composition comprises chocolate liquid, cocoa power or cocoa bean extract, and the epicatechin polymer that extra cocoa is derived is added into described composition.
4. method according to claim 1 and 2, the epicatechin polymer that wherein said cocoa is derived is as the competitive inhibitor of phospholipase A2 (PLA2) enzymic activity.
5. method according to claim 1 and 2, wherein at least a epicatechin polymer of Cun Zaiing is as the noncompetitive inhibitor of PLA2 enzymic activity.
6. method according to claim 3, wherein the described extra epicatechin polymer of Tian Jiaing is as the noncompetitive inhibitor of PLA2.
7. method according to claim 1 and 2, wherein said edible composition also comprises cocoa butter.
8. method according to claim 1 and 2, the epicatechin that wherein said cocoa is derived is derived from unfermentable cocoa bean.
9. cocoa composition, it is selected from chocolate liquid, cocoa power, cocoa extract, low fat cocoa powder, degreased cocoa powder and fat-free cocoa solid content, wherein the level of 2-14 unit's cocoa of Cun Zaiing epicatechin polymer of deriving is more than 200ug/mg, and comprises PLA2 inhibitor combination or the compound that is not derived from cocoa.
10. method that is used for to the human administration diet program, it comprises the baseline triglyceride levels of measuring among the experimenter with baseline meals, based on described baseline values and meals, recommend the epicatechin polymer composition and the canteen that reduces fatty acid uptake to be taken in every day of effective dose.
11. a preparation is used for Orally administered composition, the epicatechin polymer that the cocoa that its polymer length that comprises the amount that suppresses fatty acid uptake is 2 to 10 units is derived, the wherein amount of the epicatechin polymer of Cun Zaiing about 50% the PLA2 enzymic activity that can noncompetitive suppresses to exist in the animal digestive system.
12. a combination, it is PLA2 noncompetitive inhibitor and the PLA2 of purifying or the combination of PA competitive inhibitor that is selected from least a purifying of DP5 to DP14 epicatechin polymer.
13. combination according to claim 12, it also comprises tetrahydrochysene lipstatin, cocoa bean amine, west for department he, in crocin, lipstatin, vibralactone and the green tea catechins one or more.
14. one kind is used for Orally administered product, it comprises the plant resource purified extract, described plant resource purified extract contains Type B epicatechin polymer, wherein the level of the type of the polymer of Cun Zaiing and amount is so selected, and makes described product can noncompetitive suppress about 20% or more PLA2 enzymes that exists between the period of digestion at the duodenum of average canteen.
15. product according to claim 14 also comprises the competitive inhibitor of PLA2 or pancreatic lipase.
16. product according to claim 14, it also comprises tetrahydrochysene lipstatin, cocoa bean amine, west for department he, in crocin, lipstatin, vibralactone and the green tea catechins one or more.
17. product according to claim 14 is wherein selected DP5 or the more senior polymer that is rich in epicatechin.
18. product according to claim 14, wherein the polymer that is rich in epicatechin of Xuan Zeing is one or more among the DP2 to DP10.
19. product according to claim 14, the wherein said polymer that is rich in epicatechin only is derived from cocoa or cocoa bean point.
20. product according to claim 14, wherein said epicatechin source of polymer is from apple.
21. product according to claim 14, wherein said epicatechin source of polymer is from Chinese sorghum.
22. a pharmaceutical composition, it comprises the DP5 of the purifying that is derived from cocoa or the more senior polymer that is rich in epicatechin.
23. treatment people experimenter's method comprises the pharmaceutical composition according to claim 22 of using effective dose, thereby suppresses the PLA2 enzyme.
24. one kind is suppressed the method that the inflammatory eicosanoid produces in the mammalian immune cell, it comprises uses edible composition, the polymer composition of epicatechin is rich in the 2-14 unit that described edible composition contains effective dose, wherein suppresses COX-2 enzymic activity 30% or more.
25. one kind is suppressed the method that inflammatory cytokine produces in the mammalian immune cell, it comprises uses edible composition, the polymer composition of epicatechin is rich in the 2-14 unit that described edible composition contains effective dose, wherein reduces the generation 50% of IL-6 or TNFa in the cell of irriate.
26. according to the composition described in the claim 22, it also comprises in epicatechin monomers, caffeine, theobromine or the theophylline one or more.
27. according to the composition described in the claim 22, wherein said polymer is the polymer composition that one or more purifying is rich in epicatechin among DP5, DP6, DP7, DP8, DP or the DP10.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42070110P | 2010-12-07 | 2010-12-07 | |
| US61/420,701 | 2010-12-07 | ||
| PCT/US2011/063806 WO2012078797A1 (en) | 2010-12-07 | 2011-12-07 | Compounds influencing fatty acid uptake and metabolism and the production of inflammatory agents and methods of isolating them from cocoa products |
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| CN103338636A true CN103338636A (en) | 2013-10-02 |
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Country Status (5)
| Country | Link |
|---|---|
| CN (1) | CN103338636A (en) |
| BR (1) | BR112013014307A2 (en) |
| CA (1) | CA2820883A1 (en) |
| MX (1) | MX2013006503A (en) |
| WO (1) | WO2012078797A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974118A (en) * | 2014-04-01 | 2015-10-14 | 中国科学院昆明植物研究所 | First-grade alcohol acid ester derivative of vibralactone, pharmaceutical composition of first-grade alcohol acid ester derivative, preparation methods and application of first-grade alcohol acid ester derivative of vibralactone, pharmaceutical composition of first-grade alcohol acid ester derivative |
| CN104974117A (en) * | 2014-04-01 | 2015-10-14 | 中国科学院昆明植物研究所 | Secondary alcohol acid ester derivative of Vibralactone as well as pharmaceutical composition and application of secondary alcohol acid ester derivative |
| CN104974116A (en) * | 2014-04-01 | 2015-10-14 | 中国科学院昆明植物研究所 | Vibralactone amide derivative, and preparation method and application thereof |
| CN112703007A (en) * | 2018-08-31 | 2021-04-23 | 伊诺弗斯公司 | Anti-inflammatory plant extracts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0476849A2 (en) * | 1990-08-24 | 1992-03-25 | Eli Lilly And Company | Human cytosolic phospholipase A2 |
| CN1221344A (en) * | 1996-04-02 | 1999-06-30 | 火星有限公司 | Extractable compounds and method for making and using the same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6297273B1 (en) * | 1996-04-02 | 2001-10-02 | Mars, Inc. | Use of cocoa solids having high cocoa polyphenol content in tabletting compositions and capsule filling compositions |
| US20070003640A1 (en) * | 2005-06-29 | 2007-01-04 | Hammerstone John F Jr | Process for controlling the isomerization of (-)-epicatechin and (+)-catechin in edible products |
| WO2007053641A2 (en) * | 2005-11-01 | 2007-05-10 | Mars, Incorporated | A-type procyanidins and inflammation |
| WO2009114716A2 (en) * | 2008-03-13 | 2009-09-17 | The Regents Of The University Of California | Use of epicatechin and derivatives and salts thereof for cardiac protection of ischemic myocardium and to ameliorate adverse cardiac remodeling |
-
2011
- 2011-12-07 MX MX2013006503A patent/MX2013006503A/en unknown
- 2011-12-07 BR BR112013014307A patent/BR112013014307A2/en not_active IP Right Cessation
- 2011-12-07 WO PCT/US2011/063806 patent/WO2012078797A1/en active Application Filing
- 2011-12-07 CA CA2820883A patent/CA2820883A1/en not_active Abandoned
- 2011-12-07 CN CN2011800654607A patent/CN103338636A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0476849A2 (en) * | 1990-08-24 | 1992-03-25 | Eli Lilly And Company | Human cytosolic phospholipase A2 |
| CN1221344A (en) * | 1996-04-02 | 1999-06-30 | 火星有限公司 | Extractable compounds and method for making and using the same |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974118A (en) * | 2014-04-01 | 2015-10-14 | 中国科学院昆明植物研究所 | First-grade alcohol acid ester derivative of vibralactone, pharmaceutical composition of first-grade alcohol acid ester derivative, preparation methods and application of first-grade alcohol acid ester derivative of vibralactone, pharmaceutical composition of first-grade alcohol acid ester derivative |
| CN104974117A (en) * | 2014-04-01 | 2015-10-14 | 中国科学院昆明植物研究所 | Secondary alcohol acid ester derivative of Vibralactone as well as pharmaceutical composition and application of secondary alcohol acid ester derivative |
| CN104974116A (en) * | 2014-04-01 | 2015-10-14 | 中国科学院昆明植物研究所 | Vibralactone amide derivative, and preparation method and application thereof |
| CN104974117B (en) * | 2014-04-01 | 2017-12-01 | 中国科学院昆明植物研究所 | Vibralactone secondary alcohol acid ester derivant and its pharmaceutical composition and its application |
| CN104974116B (en) * | 2014-04-01 | 2017-12-01 | 中国科学院昆明植物研究所 | Vibralactone amide derivatives and preparation method and application |
| CN112703007A (en) * | 2018-08-31 | 2021-04-23 | 伊诺弗斯公司 | Anti-inflammatory plant extracts |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2013006503A (en) | 2015-05-26 |
| CA2820883A1 (en) | 2012-06-14 |
| WO2012078797A1 (en) | 2012-06-14 |
| BR112013014307A2 (en) | 2016-08-02 |
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Application publication date: 20131002 |