CN102178956B - Preparation, medical application and composition of 20S-protopanaxadiol beta-cyclodextrin inclusion compound - Google Patents
Preparation, medical application and composition of 20S-protopanaxadiol beta-cyclodextrin inclusion compound Download PDFInfo
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- CN102178956B CN102178956B CN2011101005738A CN201110100573A CN102178956B CN 102178956 B CN102178956 B CN 102178956B CN 2011101005738 A CN2011101005738 A CN 2011101005738A CN 201110100573 A CN201110100573 A CN 201110100573A CN 102178956 B CN102178956 B CN 102178956B
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- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 1
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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Abstract
The invention relates to a 20S-protopanaxadiol beta-cyclodextrin inclusion compound which can be used for preparing medicines and foods for resisting tumors, protecting the liver, reducing blood fat, reducing blood sugar, promoting gastric secretion, promoting appetite, improving digestion functions, enhancing immunity, resisting oxidization and resisting senescence. The invention also relates to a preparation process as well as composition of the inclusion compound.
Description
Technical field:
The invention belongs to pharmacy and field of food, the Benexate Hydrochloride that relates to 20S-ppD, can be used for antitumor, protect the liver, blood fat reducing, blood sugar lowering, promotion gastric secretion, improve appetite, improve digestive function, immunostimulant, antioxidation, defying age medicine and food applications, and preparation technology and compositions.
Background technology:
20S-ppD (20S-protopanaxdiol, 20S-ppD) is to utilize in Radix Panacis Quinquefolii Panax quinquefolium L or Radix Ginseng Panaxginseng the ginsengenin that extracts, separates, transforms and obtain.The foreign scholar has reported that all PPD has the effect of stronger inhibition tumor cell growth.But the water solublity of 20S-ppD low (less than 30 μ g/mL) causes its oral administration biaavailability lower, has limited to a certain extent its clinical efficacy.Chen Jing etc. (" modern medicines and clinical " 06 phase in 2009) have prepared, the hydroxypropyl-beta-cyclodextrin inclusion of 20S-ppD pharmacosomes, 20S-ppD ethosome, 20S-ppD, and in former 20S-ppD medicinal liquid relatively, the skin surplus of finding 20S-ppD is respectively 69.6%, 86.36%, 100%, 73.55%, and the Transdermal absorption effect of 20S-ppD hydroxypropyl-beta-cyclodextrin inclusion is best.But because the medicinal specification of HP-β-CD is less, the 20S-ppD hydroxypropyl-beta-cyclodextrin inclusion has hygroscopicity (affecting stability and the safety of medicine), it is more difficult to prepare, so, a kind of simple possible of preparation, cheaply, be easy to oral absorption, stable 20S-ppD clathrate is significant.
This research is found: (the lower 20S-ppD-β-CD) of being called for short has better stability than the hydroxypropyl-beta-cyclodextrin inclusion of PPD to the 20S-ppD Benexate Hydrochloride of optimal proportion preparation, especially has better sucting wet stability; And study discovery by pharmacokinetics, oral 20S-ppD-β-CD preparation, the bioavailability of 20S-ppD has improved more than 2 times.Pharmaceutical research shows, on the curative effect of the more oral 20S-ppD of the taking powder of oral 20S-ppD-β-CD or other preparations has improved 1 times (minimum effective dose has descended 1 times).
This research has been found the phenomenon of the 20S-ppD Benexate Hydrochloride promotion 20S-ppD oral administration biaavailability of optimal proportion preparation by galenic pharmacy, pharmacokinetics and the pharmaceutical research of system.Make 20S-ppD-β-CD by independent use or add various pharmaceutical adjuncts (various solid preparations, liquid preparation, gel preparation, sustained-release preparation etc.) to make Pharmaceutical composition, or with other drug matching, can realize its application in medicine, functional food, health product and food.
Summary of the invention:
The object of the present invention is to provide Benexate Hydrochloride (the lower 20S-ppD-of the abbreviation β-CD) of 20S-ppD, can be used for antitumor, protect the liver, blood fat reducing, blood sugar lowering, promotion gastric secretion, improve appetite, improve digestive function, immunostimulant, antioxidation, defying age medicine and food applications, and provide its preparation technology and compositions.
(β-CD), the weight ratio that it is characterized in that beta-schardinger dextrin-and 20S-ppD is 10: 1 to 1: 2 to lower abbreviation 20S-ppD-to the Benexate Hydrochloride of 20S-ppD of the present invention, and wherein, the ratio at 1: 1 has optimum effect.
Beta-schardinger dextrin-is white crystals, in water than being easier to crystallization.Dissolubility in water is lower, is at room temperature 1.85%, increases along with temperature increases dissolubility.Do not have hygroscopicity, but easily form stable hydrate.Be insoluble to common organic solvents, but can slightly soluble in pyridine, dimethyl formamide, dimethyl sulfoxide and ethylene glycol, molecular weight: 1134.99.
When beta-schardinger dextrin-is used for inclusion compound, be all can obtain Benexate Hydrochloride with guest molecule at least 1: 1 mol ratio in textbook and various report.So, if prepare 20 (S)-protopanoxadiol Benexate Hydrochlorides, in theory or according to the conventional experience on galenic pharmacy, also should beta-schardinger dextrin-and 20 (the S)-mol ratio of protopanoxadiol at least greater than 1: 1, beta-schardinger dextrin-can be lived 20 (S)-protopanoxadiols by enclose.The molecular weight of 20 (S)-protopanoxadiols is 460, and beta-schardinger dextrin-is 1135, so their weight ratio should be greater than 2.5: 1.We are in research process, but find innovatively, the weight ratio of beta-schardinger dextrin-and 20 (S)-protopanoxadiol is 1: 1 o'clock, though the ratio of best promotion 20 (S)-protopanoxadiol oral absorption, raising 20 (S)-protopanoxadiol bioavailability, this has overturned the conventional experience on textbook and galenic pharmacy.We find in deep analysis and research, due to the special molecular structure of 20 (S)-protopanoxadiols (molecule is surrounded by 3 hydroxyls), determined that it is not only clathration that itself and beta-schardinger dextrin-interact, remain at adsorptions such as intermolecular hydrogen bondings, so, greatly reduce the use amount (be clathration requirement 1/5) of beta-schardinger dextrin-.
20S-ppD (20S-protopanaxdiol, 20S-ppD)
Another object of the present invention is to provide the compositions of the Benexate Hydrochloride that contains 20S-ppD.
Compositions of the present invention can be prepared into: medicine, functional food, health product and food.
Compositions of the present invention is comprised of Benexate Hydrochloride and the acceptable carrier of above-mentioned 20S-ppD.
In the Benexate Hydrochloride of 20S-ppD of the present invention, the clathrate of any one ratio is as pharmaceutically active substance, its shared percentage by weight in preparation can be 0.1-99.9%, all the other are the medicine acceptable carrier, and described medicine acceptable carrier shared percentage by weight in preparation is 0.1-99.9%.Pharmaceutical composition of the present invention exists with unit dosage form, and described unit dosage form refers to the unit of preparation, as every of tablet, and every capsules of capsule, every bottle of oral liquid, every bag of granule etc.
Chinese medicine composition of the present invention can be any pharmaceutically useful dosage form, and these dosage forms comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, ointment, plaster, cream, spray, drop, patch.Preparation of the present invention, peroral dosage form preferably, as: capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, unguentum etc.
Compositions of the present invention, the preparation of its oral administration can contain excipient commonly used, such as binding agent, filler, diluent, tablet agent, lubricant, disintegrating agent, coloring agent, flavoring agent and wetting agent, can carry out coating to tablet in case of necessity.
Applicable filler comprises cellulose, mannitol, lactose and other similar filler.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivatives, for example sodium starch glycollate.Suitable lubricant comprises, for example magnesium stearate.The acceptable wetting agent of suitable medicine comprises sodium lauryl sulphate.
Can fill by mixing, the method that tabletting etc. are commonly used prepares solid oral composition.Repeatedly mix active substance is distributed in those compositionss of a large amount of filleies of whole use.
The form of oral liquid can be for example aqueous or oily suspensions, solution, Emulsion, syrup or tincture, can be perhaps a kind of available water before use or the composite dry products of other suitable carrier.This liquid preparation can contain conventional additive, such as suspending agent, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat, emulsifying agent, for example lecithin, anhydro sorbitol monooleate or arabic gum; Non-aqueous carrier (they can comprise edible oil), for example almond oil, fractionated coconut oil, such as oily ester, propylene glycol or the ethanol of the ester of glycerol; Antiseptic, for example para hydroxybenzene methyl ester or propyl p-hydroxybenzoate or sorbic acid, and if need, can contain conventional flavouring agent or coloring agent.
For injection, the liquid unit dosage forms of preparation contains active substance of the present invention and sterile carrier.According to carrier and concentration, this compound can be suspended or dissolving.Normally by active substance being dissolved in a kind of carrier, then filter-sterilized before it is packed into a kind of suitable bottle or ampoule seals in the preparation of solution.Adjuvant for example a kind of local anesthetic, antiseptic and buffer agent also can be dissolved in this carrier.In order to improve its stability, can be after the bottle of packing into, that this compositions is freezing, and under vacuum, water is removed.
compositions of the present invention optionally adds suitable medicine acceptable carrier (various solid preparations when being prepared into medicament, liquid preparation, gel preparation, sustained-release preparations etc.), described medicine acceptable carrier is selected from: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin C, EDETATE SODIUM, Ethylenediaminetetraacetic Acid Calcium Salt, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and derivant thereof, alginate, gelatin, polyvinylpyrrolidone, glycerol, POLYSORBATE 80, agar, calcium carbonate, calcium bicarbonate, surfactant, Polyethylene Glycol, cyclodextrin, beta-schardinger dextrin-, the phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
Pharmaceutical composition of the present invention is determined usage and dosage according to patient's situation in use, but takes every day three times, each 1-20 agent, as: 1-20 bag or grain or sheet, every dose of Benexate Hydrochloride 0.1mg-10.0g that contains 20S-ppD.
Another object of the present invention is to provide the pharmaceutical usage of the Benexate Hydrochloride of 20S-ppD of the present invention.
the Benexate Hydrochloride of 20S-ppD of the present invention and its compositions can be used for preparation treatment parkinson, convulsion, nervous headache, dizzy, neurodegenerative diseases, innominate high fever disappears, analgesic, antianaphylaxis, antiallergic action, analgesia, rubella, pruritus, the conjunctival congestion cataracta, convulsion with spasms, tetanus, anemopyretic cold, cough, measles without adequate eruption, the pharyngalgia hoarseness, the conjunctival congestion cataracta, pruritus, protect the liver, transfer blood fat, blood sugar lowering, promote gastric secretion, improve appetite, improve digestive function, antitumor, immunostimulant, antioxidation, antidotal medicine, functional food, application in health product and food.
Another object of the present invention is to provide the preparation method of the Benexate Hydrochloride of 20S-ppD of the present invention.
Preparation method of the present invention comprises the following steps:
Take the 20S-ppD inclusion rate as evaluation index, saturated water solution method, polishing and ultrasonic method are compared experiment, adopt orthogonal experiment method that the best clathrate process condition of the inclusion method that optimizes is investigated, and clathrate is carried out the TLC check.The inclusion method that result optimizes is following three kinds:
1, polishing: the rate of charge that best clathrate process condition is β-CD and 20S-ppD is 10: 1 to 1: 2 (g/g), wherein, and optimum effect 1g: 1g, add 3 times of water gagings, grind 3h, inclusion rate is 84.1%, 20S-ppD, clathrate productive rate are 98.2%.Before and after enclose, composition has no change.
2, ultrasonic method: preparation 20S-ppD Benexate Hydrochloride, take the integrated value of 20S-ppD inclusion rate and clathrate productive rate as index, optimize the enclose condition by orthogonal experiment, the optimum process condition of determining is: ultrasonic power is 200W, m (20S-ppD): (beta-schardinger dextrin-)=10: 1 to 1: 2 (g/g), optimum effect 1g: 1g, ultrasonic time is 30min, 30 ℃ of temperature.Inclusion rate is 89.2% under this condition, and the clathrate productive rate is 91.2%.This method simple possible can effectively prepare the 20S-ppD Benexate Hydrochloride.
3, saturated water solution method: obtaining best preparation technology by orthogonal test is that 20S-ppD and beta-schardinger dextrin-rate of charge are 10: 1 to 1: 2 (g/g), optimum effect 1g: 1g, the enclose time is 3h, the enclose temperature is 60 ℃, inclusion rate can reach 94%, and the clathrate productive rate is 95.5%.
novel compound of the present invention, through bioactivity research, Benexate Hydrochloride and the discovery of its compositions of finding 20S-ppD of the present invention can be used for treating parkinson, convulsion, nervous headache, dizzy, neurodegenerative diseases, innominate high fever disappears, analgesic, antianaphylaxis, antiallergic action, analgesia, rubella, pruritus, the conjunctival congestion cataracta, convulsion with spasms, tetanus, anemopyretic cold, cough, measles without adequate eruption, the pharyngalgia hoarseness, the conjunctival congestion cataracta, pruritus, protect the liver, transfer blood fat, blood sugar lowering, promote gastric secretion, improve appetite, improve digestive function, antitumor, immunostimulant, antioxidation, the anti-ageing effect of waiting for a long time.
The present invention comprises that also the analytical method of the Benexate Hydrochloride of 20S-ppD of the present invention: HPLC analyzes, take mass spectrum (MS) detection, ultraviolet (UV) 190-203nm detection, circular dichroism spectra (CD) 190-210nm detection, evaporative light scattering detector etc. as detector.
The configuration of reference substance solution: get 20S-ppD chemical reference substance precision and take in right amount, be mixed with appropriate reference substance solution with methanol.
The configuration of sample solution: precision takes the Benexate Hydrochloride of 20S-ppD or its composition sample, and each is appropriate, with 50 times of amount methanol extraction, reclaims extracting solution, dissolve with methanol, and standardize solution filters, and get final product.
Method of testing:
High performance liquid chromatography (HPLC) or Ultra Performance Liquid Chromatography (UPLC) method are measured the content of 20S-ppD in the Benexate Hydrochloride sample of 20S-ppD: carry out the analyses of high performance liquid chromatography (HPLC) or Ultra Performance Liquid Chromatography (UPLC), with mass spectrum (MS) detector (461.4[M+H]
+) detect, flight time mass spectrum (TOF-MS) detector (461.3995[M+H]
+) detection, UV, visible light (UV) detector 190-203nm detection, UV, visible light diode array detector 190-203nm detection, circular dichroism spectra (CD) detector 190-210nm detection, evaporative light scattering detector etc. be detector.With the chromatographic peak area of 20S-ppD in sample, chromatographic peak area corresponding to the standard control sample according to standard curve method (or 1 method of external standard, 2 methods of external standard etc.), carries out quantitative analysis, calculates, and get final product.
Or
Measure the content of 20S-ppD in the 20S-ppD Benexate Hydrochloride with UV-VIS spectrophotometry, method is as follows:
Working curve: the accurate 20S-ppD reference substance solution 0.2,0.4,0.6 of drawing, 0.8,1.0,1.2ml, water-bath volatilizes, and adds 5% vanillin-glacial acetic acid liquid 0.4ml, adds perchloric acid 0.8ml, put 60 ℃ of heating in water bath 15min, after ice bath is cooling, add glacial acetic acid 5.0ml, shake up, measure trap at the 550nm place, take 20S-ppD concentration as abscissa, absorption value is vertical coordinate, the working curve of mapping to get
Precision takes the 20S-ppD Benexate Hydrochloride in right amount in the 25ml volumetric flask, uses the dehydrated alcohol ultrasonic dissolution, and is settled to 25ml, water-bath volatilizes, add 5% vanillin-glacial acetic acid liquid 0.4ml, add perchloric acid 0.8ml, put 60 ℃ of heating in water bath 15min, after ice bath is cooling, add glacial acetic acid 5.0ml, shake up, measure trap at the 550nm place, utilize working curve, calculate 20S-ppD content.
The Benexate Hydrochloride of 20S-ppD of the present invention is compared with the clathrate of existing 20S-ppD, and drug metabolism study shows that oral administration biaavailability is higher, activity is stronger, and stability is better, instant effect, dosage is few, has significant therapeutic effect.
Description of drawings
The UPLC-TOF-MS of the Benexate Hydrochloride of Fig. 1 20S-ppD analyze chromatogram (take ODS as immobile phase, with acetonitrile-water (85: 15V/V) eluting), (461.3995[M+H]
+) detect.
The specific embodiment:
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
Embodiment 1: the preparation of the Benexate Hydrochloride of 20S-ppD of the present invention
A) get 20S-ppD 1g, add beta-schardinger dextrin-1g, add 6ml water, grind 3h, measuring inclusion rate is 84.1%, and 20S-ppD clathrate productive rate is 98.2%.Before and after enclose, composition has no change.
B) get 20S-ppD 1g, add beta-schardinger dextrin-1g, add the 6ml dehydrated alcohol, ultrasonic power is that 200W, ultrasonic time are 30min, 30 ℃ of temperature.Inclusion rate is 89.2% under this condition, and the clathrate productive rate is 91.2%.
C) get beta-schardinger dextrin-1g, add 60 ℃ of dissolvings of 6ml water, under stirring, constantly add wherein the ethanol solution of 20S-ppD 1g, the enclose time is 3h, and the enclose temperature is 60 ℃, and inclusion rate can reach 94%, and the clathrate productive rate is 95.5%.
Embodiment 2: the qualitative and quantitative analysis of the Benexate Hydrochloride of 20S-ppD of the present invention
Chromatographic condition and system suitability octadecyl silane are filler, and (85: 15V/V), 30 ℃ of column temperatures, flow velocity are 1.0ml/min to acetonitrile-water.Number of theoretical plate is pressed 20S-ppD and is calculated, and all should be not less than 2000.20S-ppD and adjacent peak separating degree are all greater than 1.5.
Detector: ultraviolet detection, the detection wavelength is 203nm; With mass spectrum (MS) detector (461.4[M+H]
+) detect; Flight time mass spectrum (TOF-MS) detector (461.3995[M+H]
+) detect; UV, visible light diode array detector 190-203nm detects; Circular dichroism spectra (CD) detector 190-210nm detects; Evaporative light scattering detector.
The configuration of reference substance solution: get 20S-ppD chemical reference substance precision and take in right amount, be mixed with appropriate reference substance solution with methanol.
The configuration of sample solution: the Benexate Hydrochloride powder that precision takes 20S-ppD is 1g approximately, puts in tool plug triangular flask, and precision adds ethanol 25mL, accurately weighed quality, supersound process 0.5h under room temperature takes out and is cooled to room temperature, supply the quality of minimizing with 70% methanol, shake up rear standingly, get supernatant centrifugal, get in supernatant 5ml to 50ml volumetric flask after centrifugal, water is settled to scale, after shaking up, cross 0.22 μ m filter membrane, be need testing solution.
Method of testing: high performance liquid chromatography (HPLC) or Ultra Performance Liquid Chromatography (UPLC) method are measured the content of 20S-ppD in the Benexate Hydrochloride sample of 20S-ppD: carry out the analyses of high performance liquid chromatography (HPLC) or Ultra Performance Liquid Chromatography (UPLC), with mass spectrum (MS) detector (461.4[M+H]
+) detect, flight time mass spectrum (TOF-MS) detector (461.3995[M+H]
+) detection, UV, visible light (UV) detector 190-203nm detection, UV, visible light diode array detector 190-203nm detection, circular dichroism spectra (CD) detector 190-210nm detection, evaporative light scattering detector etc. be detector.With the chromatographic peak area of 20S-ppD in sample, chromatographic peak area corresponding to the standard control sample according to standard curve method (or 1 method of external standard, 2 methods of external standard etc.), carries out quantitative analysis, calculates, and get final product.
Embodiment 3: the preparation of pharmaceutical composition
Any one compound of the present invention and medicine acceptable carrier, or with the other drug compatibility, mix to be prepared into tablet with the galenic pharmacy routine techniques, capsule, granule, oral liquid, the preparations such as injection.
Embodiment 4: the pharmacodynamic study of the Benexate Hydrochloride of 20S-ppD of the present invention
with bioactive ingredients in prior art as Yuanhuadine, chlorogenic acid, the ginseng polysaccharide, Radix Ginseng total saponinss etc. are contrast, treat parkinson with the Benexate Hydrochloride of 20S-ppD of the present invention, convulsion, nervous headache, dizzy, convulsion with spasms, neurodegenerative diseases, innominate high fever disappears, analgesic, analgesia, antianaphylaxis, antiallergic action, rubella, pruritus, the conjunctival congestion cataracta, tetanus, anemopyretic cold, cough, measles without adequate eruption, the pharyngalgia hoarseness, the conjunctival congestion cataracta, pruritus, protect the liver, antitumor, transfer blood fat, blood sugar lowering, promote gastric secretion, improve appetite, improve digestive function, immunostimulant, antioxidation, anti-ageing wait for a long time pharmacology and toxicity comparison.The Benexate Hydrochloride of 20S-ppD of the present invention is better than the prior art compound as a result.
Data such as the following table of its treatment parkinson, convulsion, convulsion with spasms, nervous headache, the Benexate Hydrochloride that 20S-ppD is described has treatment parkinson, convulsion, convulsion with spasms, nervous headache effect, and is stronger than known compound dopamine activity:
Table 1
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 10 |
| 20S-ppD | 50 |
| Dopamine | 50 |
Data such as the following table of its treatment neurodegenerative diseases illustrate that the Benexate Hydrochloride of 20S-ppD is stronger than known compound ginsenoside Rg l20S-protopanoxadiol and activity:
Table 2
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 10 |
| 20S-ppD | 50 |
| Ginsenoside Rg l | 200 |
The data of its antianaphylaxis, antiallergic action such as following table illustrate that the Benexate Hydrochloride of 20S-ppD is stronger than known compound chlorphenamine, 20S-ppD activity:
Table 3
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 10 |
| 20S-ppD | 50 |
| Chlorphenamine | 150 |
Data such as the following table of its treatment rubella, pruritus, conjunctival congestion cataracta, tetanus, anemopyretic cold, cough, measles without adequate eruption, pharyngalgia hoarseness, conjunctival congestion cataracta, pruritus illustrate that the Benexate Hydrochloride of 20S-ppD and Periostracum Cicadae extract and 20S-ppD activity are stronger:
Table 4
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 10 |
| 20S-ppD | 50 |
| Periostracum Cicadae extract | 500 (mg/Kg body weight) |
The data of its antitumor action such as following table illustrate that the Benexate Hydrochloride of 20S-ppD is stronger than known compound Yuanhuadine, 20S-ppD activity:
Table 5
| The compound title | To Hela cell medium effective concentration (μ mol/L) |
| The Benexate Hydrochloride of 20S-ppD | 3 |
| 20S-ppD | 20 |
| Yuanhuadine | 34 |
Data such as the following table of its anti-hepatic fibrosis and protection hepatic injury illustrate that the Benexate Hydrochloride of 20S-ppD is stronger than known compound chlorogenic acid, 20S-ppD activity:
Table 6
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 20 |
| 20S-ppD | 100 |
| Chlorogenic acid | 120 |
Its hypoglycemic data such as following table illustrate that the Benexate Hydrochloride of 20S-ppD and known compound metformin, miglitol are quite active:
Table 7
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 20 |
| 20S-ppD | 100 |
| Metformin | 10 |
| Miglitol | 50 |
Data such as following table that it transfers blood fat illustrate that the Benexate Hydrochloride of 20S-ppD and known compound Fructus Crataegi extract are quite active:
Table 8
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 20 |
| 20S-ppD | 100 |
| Fructus Crataegi extract | 80 |
The data of its immunostimulant such as following table illustrate that the Benexate Hydrochloride of 20S-ppD and known compound ginseng polysaccharide are quite active:
Table 9
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 20 |
| 20S-ppD | 100 |
| The ginseng polysaccharide | 100 |
Its antioxidative data such as following table illustrate that the Benexate Hydrochloride of 20S-ppD and known compound chlorogenic acid activity are stronger:
Table 10
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 20 |
| 20S-ppD | 100 |
| Chlorogenic acid | 100 |
It promotes gastric secretion, improve appetite, improve data such as the following table of digestive function, illustrate that the Benexate Hydrochloride of 20S-ppD is suitable with known compound Fructus Crataegi extract activity:
Table 11
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 20 |
| 20S-ppD | 100 |
| Fructus Crataegi extract | 80 |
Its antidotal data such as following table illustrate that the Benexate Hydrochloride of 20S-ppD is stronger than known compound ginsenoside Rg l activity:
Table 12
| The compound title | Effective dose (mmol/Kg body weight) |
| The Benexate Hydrochloride of 20S-ppD | 20 |
| 20S-ppD | 100 |
| Ginsenoside Rg l | 250 |
Embodiment 5: the pharmacokinetics research-Bioavailability Determination of the Benexate Hydrochloride of 20S-ppD of the present invention
Adopt Ultra Performance Liquid Chromatography (UPLC) analysis in embodiment 2, with [M+H] of flight time mass spectrum (TOF-MS) detector 20S-ppD
+Peak (461.3995Da).According to " assay method of bioavailability in Chinese pharmacopoeia, the bioavailability of 20S-ppD of Benexate Hydrochloride of testing respectively the 20S-ppD of different proportion.
Biological sample is processed: plasma containing drug (the PD storing solution 10.0 μ L that add simultaneously 1.0mg/10ml), join in the SPE pillar of pretreated ODS 0.5g filling, first with 10% washed with methanol 5ml (discarding), continue with chromatograph washed with methanol 5.0ml, chromatograph washed with methanol part N
2Air-blowing is done, and 0.22 μ m filter membrane is crossed in methanol 200 μ L dissolvings, is need testing solution.
The Bioavailability Determination result:
| Sample * | The bioavailability of 20S-ppD (%) |
| 20S-ppD Benexate Hydrochloride (6: 1) | 12.2 |
| 20S-ppD Benexate Hydrochloride (4: 1) | 15.5 |
| 20S-ppD Benexate Hydrochloride (2: 1) | 30.4 |
| 20S-ppD Benexate Hydrochloride (1: 1) | 61.5 |
| 20S-ppD Benexate Hydrochloride (1: 2) | 62.1 |
| 20S-ppD Benexate Hydrochloride (1: 4) | 63.7 |
| 20S-ppD Benexate Hydrochloride (1: 6) | 63.9 |
| 20S-ppD Benexate Hydrochloride (1: 8) | 62.7 |
| 20S-ppD Benexate Hydrochloride (1: 10) | 64.0 |
| 20S-ppD Benexate Hydrochloride (1: 12) | 65.1 |
| 20S-ppD | 10.2 |
* the clathrate ratio is 20S-ppD: the weight ratio of beta-schardinger dextrin-.
Can find out from the bioavailability of the 20S-ppD Benexate Hydrochloride of above different proportion, 20S-ppD: the Benexate Hydrochloride part by weight surpasses after 1: 1, the raising of bioavailability has just reached a limit, increase the proportion of Benexate Hydrochloride, its biological utilisation is not solely improving yet again.So selected best 20S-ppD: the Benexate Hydrochloride part by weight is 1: 1.
Claims (13)
1. 20S-ppD Benexate Hydrochloride, the weight ratio that it is characterized in that beta-schardinger dextrin-and 20S-ppD is 1:1.
2. clathrate claimed in claim 1, is characterized in that, by the following method preparation: get 20S-ppD 1g, add beta-schardinger dextrin-1g, add 6ml water, grind 3h, measuring inclusion rate is 84.1%, 20S-ppD clathrate productive rate is 98.2%, and before and after enclose, composition has no change.
3. clathrate claimed in claim 1, it is characterized in that, preparation by the following method: get 20S-ppD 1g, add beta-schardinger dextrin-1g, add the 6ml dehydrated alcohol, ultrasonic power is that 200W, ultrasonic time are 30min, 30 ℃ of temperature, inclusion rate is 89.2% under this condition, and the clathrate productive rate is 91.2%.
4. clathrate claimed in claim 1, it is characterized in that, preparation by the following method: get beta-schardinger dextrin-1g, add 60 ℃ of dissolvings of 6ml water, under stirring, constantly add wherein the ethanol solution of 20S-ppD 1g, the enclose time is 3h, the enclose temperature is 60 ℃, and inclusion rate can reach 94%, and the clathrate productive rate is 95.5%.
5. the compositions that contains the clathrate of claim 1.
6. the compositions of claim 5, be pharmaceutical preparation, functional food, health product or food.
7. the compositions of claim 5, be comprised of clathrate and carrier.
8. the compositions of claim 7, wherein the shared percentage by weight of clathrate is 0.1-99.9%, the shared percentage by weight of carrier is 0.1-99.9%.
9. the compositions of claim 5, be any pharmaceutically useful dosage form, and these dosage forms are selected from: tablet, capsule, oral liquid, suck agent, granule, pill, powder, unguentum, sublimed preparation, powder, injection, suppository, spray, drop, patch.
10. the preparation method of the clathrate of claim 1, method is as follows: raw material mixes, and adds 3 times of water gagings, grinds 3h, and inclusion rate is 84.1%, and 20S-ppD, clathrate productive rate are 98.2%.
11. the preparation method of the clathrate of claim 1, method is as follows: raw material mixes, and ultrasonic time is 30min, 30 ℃ of temperature, and inclusion rate is 89.2% under this condition.
12. the preparation method of the clathrate of claim 1, method is as follows: raw material mixes, and the enclose time is 3h, and the enclose temperature is 60 ℃, inclusion rate 94%.
13. the detection method of the clathrate of claim 1 is characterized by: utilize high performance liquid chromatography or Ultra Performance Liquid Chromatography method to measure the content of 20S-ppD in 20S-ppD Benexate Hydrochloride sample:
HPLC analyzes, take Mass Spectrometer Method, ultraviolet 190-203nm detection, circular dichroism spectra 190-210nm detection, evaporative light scattering detector as detector;
The configuration of reference substance solution: get 20S-ppD chemical reference substance precision and take in right amount, be mixed with appropriate reference substance solution with methanol;
The configuration of sample solution: precision takes the Benexate Hydrochloride of 20S-ppD or its composition sample, and each is appropriate, with 50 times of amount methanol extraction, reclaims extracting solution, dissolve with methanol, and standardize solution filters, and get final product;
Method of testing:
The content of 20S-ppD in the Benexate Hydrochloride sample of high performance liquid chromatography or Ultra Performance Liquid Chromatography method mensuration 20S-ppD:
Carry out high performance liquid chromatography or Ultra Performance Liquid Chromatography analysis, with mass detector 461.4[M+H]
+Detection, flight time mass spectrum detector 461.3995[M+H]
+Detection, UV-vis detector 190-203nm detect, UV, visible light diode array detector 190-203nm detects, circular dichroism spectra detector 190-210nm detects, evaporative light scattering detector is detector, chromatographic peak area with 20S-ppD in sample, chromatographic peak area corresponding to the standard control sample, according to standard curve method or 1 method of external standard, 2 methods of external standard, carry out quantitative analysis, calculate, and get final product
Or
UV-VIS spectrophotometry is measured the content of 20S-ppD in the 20S-ppD Benexate Hydrochloride, and method is as follows:
Working curve: the accurate 20S-ppD reference substance solution 0.2,0.4,0.6 of drawing, 0.8,1.0,1.2ml, water-bath volatilizes, and adds 5% vanillin-glacial acetic acid liquid 0.4ml, adds perchloric acid 0.8ml, put 60 ℃ of heating in water bath 15min, after ice bath is cooling, add glacial acetic acid 5.0ml, shake up, measure trap at the 550nm place, take 20S-ppD concentration as abscissa, absorption value is vertical coordinate, the working curve of mapping to get
Precision takes the 20S-ppD Benexate Hydrochloride in right amount in the 25ml volumetric flask, uses the dehydrated alcohol ultrasonic dissolution, and is settled to 25ml, water-bath volatilizes, add 5% vanillin-glacial acetic acid liquid 0.4ml, add perchloric acid 0.8ml, put 60 ℃ of heating in water bath 15min, after ice bath is cooling, add glacial acetic acid 5.0ml, shake up, measure trap at the 550nm place, utilize working curve, calculate 20S-ppD content.
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| CN114159450B (en) * | 2020-09-10 | 2023-10-27 | 上海交通大学 | Use of protopanaxadiol compounds for treating physical dependence, mental dependence and addiction of pain and addiction substances |
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