CN108703966A - A kind of application of Saliggenon D in the drug or pharmaceutical composition for preparing treatment hyperlipidemia and/or obesity - Google Patents
A kind of application of Saliggenon D in the drug or pharmaceutical composition for preparing treatment hyperlipidemia and/or obesity Download PDFInfo
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- CN108703966A CN108703966A CN201810832493.3A CN201810832493A CN108703966A CN 108703966 A CN108703966 A CN 108703966A CN 201810832493 A CN201810832493 A CN 201810832493A CN 108703966 A CN108703966 A CN 108703966A
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- saliggenon
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- obesity
- pancreatic lipase
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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Abstract
The present invention provides a kind of application of Saliggenon D in the drug or pharmaceutical composition for preparing treatment hyperlipidemia and/or obesity, the present invention develops the strategy of a kind of new preparation treatment hyperlipidemia and/or fat drug, treatment hyperlipidemia and/or the drug of obesity are prepared with Saliggenon D, the monomeric compound of Saliggenon D or the plant extracts containing the compound or dietary supplements, the digestion and absorption of dietary fat can be reduced by potent inhibition pancreatic lipase, the effect of playing its reducing blood lipid and weight-reducing, Saliggenon D inhibits the IC of pancreatic lipase500.77 μM is can reach, can be additionally used in combination by Saliggenon D and other drugs or natural products, further play drug effect, is had broad application prospects and huge market value.
Description
Technical field
The invention belongs to biomedicine fields, are related to a kind of new application of Saliggenon D, prepared by especially a kind of Saliggenon D
The drug for treating hyperlipidemia and/or obesity or the application in pharmaceutical composition.
Background technology
Due to the increase of modern way of life and high fat diet, obesity becomes a global problem, causes extensively
Concern.Obesity is that energy absorption and energy expenditure are long-term unbalance as a result, and obesity is that the important of a variety of metabolic diseases lures
Cause, such as hyperlipidemia, hypertension, artery sclerosis, adult-onset diabetes, coronary heart disease and certain form of cancer
Disease.Thus, it is found that and prepare reducing blood lipid and slimming medicine it is very necessary, and one of them important target spot be reduce digestive organs
The digestion and absorption of middle fat.Pancreatic lipase (also referred to as triacylglycerol Acyl- hydrolase, PL) is a kind of serine in human body
Hydrolase is responsible for the key enzyme that triglyceride hydrolyzes in the gastrointestinal tract, can absorb the dietary fat of 50%-70%, right
It plays an important role in the digestion and absorption for adjusting fat.Pancreatic lipase by pancreatic secretion and enter duodenum in play a role,
Can be aliphatic acid and glycerine by lipolysis by the cooperation of the bile of hepatic secretion.Therefore, inhibit lipase and its correlation
The absorption of lipid becomes an important method for the treatment of hyperlipidemia and obesity.Orlistat is a kind of extremely effective pancreas fat
Enzyme inhibitor, and by clinical certification as antiadipositas drug object, but orlistat and its derivative can cause gastrointestinal tract pair
Effect, such as oil mark, incontinence of faces, flatulence and abdominal cramps etc..Therefore, it is developed from Chinese herbal medicine a kind of safe, high
The pancreatic lipase inhibitor of effect has important meaning.
The root bark of white mulberry (Mori Cortex) is the dry root skin of moraceae plants mulberry Morus alba L., and property is sweet, cold, return lung
Through, it is important simply traditional Chinese medicine, meanwhile, the root bark of white mulberry is also one of the article that can be used as health food ratified at present.
The root bark of white mulberry has removing heat from lung and relieving asthma, the function of inducing diuresis for removing edema.The compound mainly extracts gained, and Saliggenon D from the root bark of white mulberry
It is the Main Flavonoids substance of the root bark of white mulberry.In recent years, many studies have shown that Saliggenon D is in blood pressure lowering, antibacterial, anti-inflammatory, anti-
It plays an important role in terms of cancer, treatment heart disease and treatment atherosclerosis.
CN103156869A discloses a kind of sanggenon C extracted from the root bark of white mulberry, ramulus mori, mulberry leaf, Saliggenon D and with mulberry
The new medical use of root ketone C, Saliggenon D composition as main component, specifically sanggenon C, Saliggenon D single component
And the combination of sanggenon C, Saliggenon D and morusin, mulberry skin glucoside, oxidized resveratrol, resveratrol, 1-Deoxynojirimycin composition
Application of the object in preparing alpha-glucosidase inhibitor medicament, the composition can be by the medicinal material containing the above chemical composition
It is matched according to a certain percentage after extracting respectively, the medicinal material for containing the above chemical composition simultaneously can also be utilized several extracting methods
The composition obtained after extraction.The method is also found surprisingly that in the root bark of white mulberry, ramulus mori, mulberry leaf except alkaloids such as 1-Deoxynojirimycin
Outside, also there is the medicine that alpha-glucosidase more stronger than alkaloids such as 1-Deoxynojirimycin inhibits containing sanggenon C, Saliggenon D
Reason activity.
CN105497290A discloses a kind of pharmaceutical composition and preparation method thereof for treating liver ascites, what the method provided
Pharmaceutical composition be using Saliggenon D, ivy glorybind herb or root, pachydermia fragrant flower, stevioside glycosides, golden wave oh, mesembranone as bulk pharmaceutical chemicals, proportioning
It forms, routinely various dosage forms can be made by preparation process, treatment liver ascites is significant in efficacy.
CN105641170A discloses a kind of pharmaceutical composition for treating cancer of the esophagus, with Qinghai-Tibet rough gentian, betonyleaf mazus herb, hydroxyl
Rutaecarpin, tagitinin F, Saliggenon D are bulk pharmaceutical chemicals, match, routinely various dosage forms can be made by preparation process,
It is significant in efficacy to treat cancer of the esophagus.
However, Saliggenon D has not been reported always the inhibiting effect of pancreatic lipase, also without being treated using Saliggenon D
The report of hyperlipidemia and obesity.Meanwhile in view of the clinical antiadipositas drug object-more serious stomach of orlistat being currently certified
Enteron aisle side effect, if safer, effective novel lipase inhibitor can be developed, can avoid taking during slimming drugs compared with
For serious gastrointestinal side effect, while good inhibiting effect is played to pancreatic lipase, preferably treatment is fat and hyperlipidemia
Disease.
Invention content
For the demand in the blank and present situation studied in the prior art, the purpose of the present invention is to provide a kind of mulberry roots
Applications of the ketone D in the drug for preparing treatment hyperlipidemia and/or obesity is hyperlipemia and fat prevention and novel drugs
Exploitation, provides new strategy, has broad application prospects and huge market value.
To reach the invention purpose, the present invention uses following technical scheme：
In a first aspect, the present invention provides a kind of Saliggenon Ds in the drug or drug for preparing treatment hyperlipidemia and/or obesity
Application in composition, wherein the structural formula of Saliggenon D is as follows：
In the present invention, Saliggenon D, which can be applicable to, prepares in treatment hyperlipidemia and/or the drug of obesity, is also applicable in
In the pharmaceutical composition for preparing treatment hyperlipidemia and/or obesity.
In the invention it has unexpectedly been found that the monomeric compound of Saliggenon D or plant extracts containing the compound or
Dietary supplements, can by it is potent inhibition pancreatic lipase so that reduction dietary fat digestion and absorption, play its reducing blood lipid and
The effect of weight-reducing, and main component of the Saliggenon D as " integration of drinking and medicinal herbs " Chinese herbal medicine-root bark of white mulberry, the content in the root bark of white mulberry
More than 500 μ g/g dry weights, it is directly targeted the pancreatic lipase acted in gastrointestinal tract after oral, according to People's Republic of China's medicine
Allusion quotation, recommendation root bark of white mulberry oral dose are 6-12g/d, show that the dosage of Saliggenon D is more than 7mg/d, the part in gastronintestinal system
Exposed amount reaches about 2.5 μM, far above Saliggenon D to the inhibition constant (K of pancreatic lipasei=0.43 μM), prompt its internal medicine
Object exposure concentrations can play its high efficiency inhibited to pancreatic lipase, and then improve the digestion and absorption of body fat, from
And achieve the purpose that reducing blood lipid and weight-reducing.
And in the prior art, Saliggenon D only reports the effect inhibited for alpha-glucosidase and in some medicine
Pharmacological action in compositions does not have completely studies have reported that effect of the Saliggenon D for pancreatic lipase.
Preferably, the purity of the Saliggenon D is 98%-100%, for example, can be 98%, 98.2%, 98.5%,
98.7%, 98.9%, 99%, 99.2%, 99.5%, 99.6%, 99.8%, 99.9% or 100% etc..Mulberry provided by the invention
Root ketone D in above-mentioned purity range, can safely and effectively be applied.Usually, sanggenon purity is equal 90% or more
Normal pharmacological effect can be reached.
Preferably, the dosage form of the drug include suspension, granule, capsule, powder, tablet, emulsion, solution,
Any one in pill, injection, suppository, enema, aerosol, patch or drops.
Preferably, the drug further includes pharmacologically acceptable auxiliary material.
Preferably, the auxiliary material includes carrier, diluent, excipient, filler, adhesive, wetting agent, disintegrant, breast
Agent, cosolvent, solubilizer, osmotic pressure regulator, surfactant, coating material, pH adjusting agent, antioxidant, bacteriostatic agent or
In buffer any one or at least two combination.
In the present invention, Saliggenon D can be administered alone the composition dosage form appropriate that can also arrange in pairs or groups with auxiliary material and be administered.One
As preferably add suitable auxiliary material and carry out collocation administration.
In the present invention, when the dosage form of drug is prepared as tablet, it may include there is excipient, such as microcrystalline cellulose, shallow lake
Powder or calcium carbonate etc.；It can also include disintegrant, such as can be croscarmellose sodium etc.；When the dosage form of drug is glue
When wafer：It can be prepared as hard capsule or soft capsule, and Saliggenon D and auxiliary material can be prepared as powdered or particulate filler
Into in capsule；In addition, when medicine preparation is suspension, can also flavor adjustments and the mouthfeels such as corrigent, suspending agent be added
Deng；When the dosage form of drug be emulsion when, emulsifier, cosolvent can be properly added adjust solubility, emulsifiability is administered.
Illustratively, when medicine preparation becomes tablet, it may include Saliggenon D, microcrystalline cellulose, cross-linked carboxymethyl fiber
Plain sodium, starch and magnesium stearate composition, by wet granulation, prepared by tabletting become tablet, and the effective content of wherein Saliggenon D can
To be selected according to the symptom effect of reagent, general Saliggenon D is 0.01mg-500mg as the content of active constituent, preferably
Content be 50mg or so.
In the present invention, the administering mode of drug can select various ways.Such as can be oral medication, per rectum,
Non-digestive tract or local administration etc..
In the present invention, it is preferred to which administering mode is oral medication, generally taken orally in a manner of tablet or capsule
Administration.In addition, when tablet or capsule are administered orally, it can be prepared into controlled release preparation or sustained release preparation, as needed
Drug effect and action time select the controlled-release excipient or slow-release auxiliary material of suitable dose.
In the present invention, when preparing the drug for the treatment of hyperlipidemia and/or obesity, drug can pharmaceutically connect Saliggenon D
The salt received has good function and effect similarly for hyperlipidemia, obesity.Such as can by medicine preparation become lithium salts, sodium salt,
Any one in sylvite, magnesium salts or calcium salt.
The pharmaceutical composition of the drug or treatment hyperlipidemia and/or obesity for the treatment of hyperlipidemia provided by the invention and/or obesity
Object can be applied to prepare pancreatic lipase inhibitor.
Saliggenon D can inhibit the activity of pancreatic lipase potently in the present invention, and confirm mulberry by experiment in vitro
The function and effect of root ketone D, Saliggenon D inhibit the IC of pancreatic lipase500.77 μM is can reach, and pancreatic lipase is the pass of fat absorption
Key enzyme, to reach reducing blood lipid and antiobesity action, the new inhibitor that such compound can be used as pancreatic lipase is used to prepare drop
Blood fat and slimming medicine.
Saliggenon D provided by the invention can utmostly be combined with lipase active center, reach efficient inhibition
Function and effect.
Pharmaceutical composition provided by the invention can be made of Saliggenon D and natural products or natural extract, according to not
It arranges in pairs or groups in proportion, collective effect plays effect.Such as can be collocation carbohydrate natural products, Coumarins natural products,
Flavonoids natural products, alkaloids natural products etc., can also with ginseng, matrimony vine, honeysuckle, Radix Notoginseng, Radix Glycyrrhizae etc. into
Row collocation composition pharmaceutical composition, further plays good effect.
Pharmaceutical composition provided by the invention can also be that Saliggenon D is used in combination with other blood lipid-lowering medicines, reducing blood lipid
Drug for example can be linoleic acid, probucol, fibrate, Hydroxymethylglutaryl list acyl coenzyme A HMG-CoA Reductase Inhibitor HMG-CoA objects
In statins etc..
Compared with the existing technology, the invention has the advantages that：
The present invention develops the strategy of a kind of new preparation treatment hyperlipidemia and/or fat drug, i.e., with Saliggenon D system
The drug of standby treatment hyperlipidemia and/or obesity, the monomeric compound of Saliggenon D or the plant extracts containing the compound or meals
Replenishers are eaten, the digestion and absorption of dietary fat can be reduced by potent inhibition pancreatic lipase, its reducing blood lipid is played and subtracts
Effect of fertilizer.
The application of Saliggenon D provided by the invention has following advantage：1. raw material is cheap and easy to get：With cheap mulberry
White skin is raw material, and extracted acquisition is simple for process feasible, and Saliggenon D content in the root bark of white mulberry is higher；2. inhibitory activity is strong：
The key enzyme that pancreatic lipase is metabolized as body fat, half-inhibition concentration IC of the Saliggenon D to it50It can reach nM grades；3. innings
Portion's exposed amount is high：The dosage of Saliggenon D is more than 7mg/d, and this natural component of the root bark of white mulberry can direct target after oral administration
To the pancreatic lipase for acting on gastrointestinal tract, therefore part exposure of the Saliggenon D in gastronintestinal system is up to about 2.5 μM, remote high
In the inhibition constant (K of such inhibitori)0.43μM；4. safe：The root bark of white mulberry is the object that can be used as health food of approval
One of product have good safety, avoid the reducing blood lipid of preparation and the side effect of slimming medicine.
Saliggenon D provided by the invention not only can be with independent medication, and can also jointly arrange in pairs or groups medication with various other components,
Widely used, application prospect is wide, and application value is high.
Description of the drawings
Fig. 1 is the IC that the Saliggenon D measured in the embodiment of the present invention 3 inhibits pancreatic lipase50Curve graph.
Fig. 2 is the time dependence curve graph of the Saliggenon D that is measured in the embodiment of the present invention 3 to pancreatic lipase.
Fig. 3 A are the dynamic curve diagrams that the Saliggenon D that the embodiment of the present invention 4 measures inhibits pancreatic lipase.
Fig. 3 B are the kinetic curve double reciprocal plots that the Saliggenon D that the embodiment of the present invention 4 measures inhibits pancreatic lipase.
Fig. 4 A are the molecular simulation docking schemes of Saliggenon D and pancreatic lipase in the present invention.
Fig. 4 B are the activated centre molecular simulation docking schemes of Saliggenon D and pancreatic lipase in the present invention.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.Those skilled in the art should be bright
, the embodiment, which is only to aid in, understands the present invention, should not be regarded as a specific limitation of the invention.
The equipment and its model used in following embodiment in the present invention：Fluorescent emission/excitation spectrum is by BioTek
Synergy H1The detection of global function micropore board detector is completed.
Embodiment 1
The present embodiment prepares Saliggenon D tablet
It is accurate to weigh 20g Saliggenon Ds monomer (purity is more than 98%), medical starch 180g is added, after the two is sufficiently mixed
400 are made, every weight 0.5g, 50mg containing Saliggenon D.
Embodiment 2
The present embodiment prepares Saliggenon D capsule
It is accurate to weigh 20g Saliggenon Ds monomer (purity is more than 98%), medical starch 180g is added, after the two is sufficiently mixed
Particle is made with 20 mesh sieve, dispenses and insert Capsules later, is distributed into 400 capsules, every capsule weight 0.5g, root containing mulberry
Ketone D 50mg.
Embodiment 3
The IC that Saliggenon D inhibits pancreatic lipase50It measures
To be metabolized as probe reaction to 4-methyl umbelliferone oleic acid ester hydrolysis, by pancreatic lipase incubated in vitro system,
Measure the IC that Saliggenon D inhibits pancreatic lipase50, the results are shown in Figure 1；Meanwhile drawing time of the Saliggenon D to pancreatic lipase
Dependence suppression curve, as shown in Figure 2.
A.200 in microlitre In vitro metabolism reaction system, the phosphate buffer of the 0.1M containing pH 7.4, pancreatic lipase is dense
Degree is 2 μ g/mL, under the conditions of ranging from 0.1 μM -50 μM, 37 DEG C of inhibitor final concentration respectively concussion incubate in advance 5min, 10min,
25min；
B. substrate (10 μM of final concentration) is added into 96 orifice plates, 96 orifice plates, starting reaction then is added in pre- liquid of incubating；Yu Duo
Function microplate reader continuously detects 40 minutes metabolism hydrolysate.
C. the IC of Saliggenon D after measured50Value is 0.77 ± 0.08 μM.
Embodiment 4
The K that Saliggenon D inhibits pancreatic lipaseiIt measures and its molecular simulation is docked
To be metabolized as probe reaction to 4-methyl umbelliferone oleic acid ester hydrolysis, by pancreatic lipase incubated in vitro system,
Measure the K that Saliggenon D inhibits pancreatic lipasei, as a result as shown in Figure 3A and Figure 3B.
A.200 in microlitre In vitro metabolism reaction system, the phosphate buffer of the 0.1M containing pH 7.4, pancreatic lipase is dense
Degree is 2 μ g/mL, and the inhibitor of various concentration is added, is shaken under the conditions of 37 DEG C and incubates 10min in advance；
B. the substrate of various concentration is added into 96 orifice plates, then pre- liquid of incubating is added in 96 orifice plates (i.e. in different substrates
A series of concentration Saliggenon Ds are added in concentration group, with 0 it is micro- rub, 1 micro- rub micro- is rubbed as concentration gradient with 2), starting reaction；In multi-functional
Microplate reader continuously detects 40 minutes metabolism hydrolysate.
C. the K of Saliggenon D after measurediValue is 0.43 ± 0.20 μM.
It is carried out by Interactions Mode of the Surflex-Dock software packages between pancreatic lipase and ligand and affinity
Research, concrete outcome are as shown in Figure 4 A and 4 B shown in FIG..Generate the biological activity combination conformation of pancreatic lipase and Saliggenon D, Neng Goufa
Existing Saliggenon D can utmostly be combined with lipase active center, it was demonstrated that Saliggenon D efficiently inhibits pancreatic lipase to make
With.
Embodiment 5
Saliggenon D is to the serum lipids in rats for slowing down high fat diet induction and fat research
Choose 30 Adult SD male rats (weight 180g-200g) be randomly divided into normal group, hyperlipidemia group, Sang Gen
Ketone D groups (200mg/kg), every group of 10 rats.Normal group takes the normal diet of equivalent to feed, other groups are formulated using D12492
Made high in fat, high heat food carries out limitation feeding, and every mouse feeds 20g in the 1st week, increases 2g weekly later, often
Day raising supplies at twice, is no longer added after eating up, free water, until the 8th week.In addition, since the 4th week, Saliggenon D
Group gives Saliggenon D by 200mg/kg (daily afternoon) dosage oral administration gavage.It is carried out continuously 5 weeks (i.e. 4-8 experiment weeks), every 2 weeks
It weighs to mouse.After the 8th week, from mouse abdominal aortic blood, the content of Triglycerides in Serum is measured.Such as table 1, table
Shown in 2.
Table 1
| Group | Number of cases | Content of triglyceride (mmol/L) |
| High fat diet group | 10 | 5.82±1.08 |
| Saliggenon D group | 10 | 3.72±0.42 |
Table 2
Experimental result shows that lipid in rat blood caused by high fat diet can be effectively relieved by giving rat Saliggenon D
Content be excessively increased and rat body weight excessively increases, prompt Saliggenon D may inhibit stomach by inhibiting pancreatic lipase
The digestion and absorption of dietary fat in enteron aisle, to inhibit hyperlipidemia and fat generation.
Applicant states that the present invention illustrates that the Saliggenon D of the present invention is preparing treatment hyperlipidemia by above-described embodiment
And/or the application in fat drug or pharmaceutical composition, but the invention is not limited in above-mentioned processing step, that is, do not mean that
The present invention, which has to rely on above-mentioned processing step, to be implemented.Person of ordinary skill in the field is it will be clearly understood that the present invention's
Any improvement, the addition of equivalence replacement and auxiliary element to raw material selected by the present invention, the selection etc. of concrete mode, all falls within
Within protection scope of the present invention and the open scope.
Claims (5)
1. a kind of application of Saliggenon D in the drug or pharmaceutical composition for preparing treatment hyperlipidemia and/or obesity.
2. application according to claim 1, which is characterized in that the purity of the Saliggenon D is 98%-100%.
3. application according to claim 1 or 2, which is characterized in that the dosage form of the drug include suspension, granule,
In capsule, powder, tablet, emulsion, solution, pill, injection, suppository, enema, aerosol, patch or drops
Any one.
4. application according to any one of claim 1-3, which is characterized in that the drug further includes that can pharmacologically connect
The auxiliary material received.
5. application according to claim 4, which is characterized in that the auxiliary material includes carrier, diluent, excipient, filling
Agent, adhesive, wetting agent, disintegrant, emulsifier, cosolvent, solubilizer, osmotic pressure regulator, surfactant, coating material
In material, pH adjusting agent, antioxidant, bacteriostatic agent or buffer any one or at least two combination.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110025603A (en) * | 2019-05-15 | 2019-07-19 | 大连天星本草生物科技有限公司 | Application of the Bavachalcone compounds in the drug of preparation treatment obesity |
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| CN106551962A (en) * | 2016-11-21 | 2017-04-05 | 昆明理工大学 | Fructus rhois chinensiss fruit extract and preparation method and application |
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Application publication date: 20181026 |