CN108226347A - Sodium Aescinate chemical element constituent matches and its screening technique - Google Patents
Sodium Aescinate chemical element constituent matches and its screening technique Download PDFInfo
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Abstract
The present invention relates to a kind of Sodium Aescinate chemical element constituent proportioning and its screening techniques, are related to pharmaceutical field.Screening technique includes：Obtain the sample of Sodium Aescinate different component proportioning；The chemical fingerprint for obtaining sample and sample are detected to the dosage of test body and corresponding irritation test data and pharmacodynamics test data；By grey correlation analysis, the first analysis result of the sequence of each component irritation and the pharmacodynamics sequence of Sodium Aescinate is obtained；Using dosage as input layer, using after irritation test data and pharmacodynamics test data normalization weighting processing as output layer building neural network, after being predicted with trained neural network each component of Sodium Aescinate, it is compared with the first analysis result, screening, verification.It is sieved quickly, effectively, is effectively reduced the time of screening, and reduction screening cost obtains the Sodium Aescinate chemical composition composition that irritation is low and pharmacodynamics is good, improves drug effect and clinical compliance.
Description
Technical field
The present invention relates to pharmaceutical field, and more particularly to a kind of Sodium Aescinate chemical element constituent proportioning and its screening side
Method.
Background technology
Complex chemical composition is the universals of Chinese medicine, ethnic drug, natural drug etc., effective substance/adverse reaction source object
It is its general character difficult point that matter, which is recognized with quality control,；Traditional component separation and the method for evaluation single component activity/toxicity one by one
Heavy workload, efficiency are low, and ignore the global feature between ingredient and interaction, be unsuitable for present-day systems medicine, precisely
The growth requirement of medicine and medicine big data；The present invention provides a kind of ingredient separation combination, drug effect by taking Sodium Aescinate as an example
The new strategy of substance/pungent identification, and screening and optimizing its prescription proportioning, it is low to provide a kind of good drug efficacy, irritation
New Sodium Aescinate prescription and its proportioning.
Sodium Aescinate (Sodiumaescinate) is《Chinese Pharmacopoeia》Gained is extracted in one Chinese medicine buckeye recorded
Extraction one group of triterpenoid saponin containing ester bond, main active is respectively seven by high performance liquid chromatography appearance tandem
Leaf saponin A, B, C, D, A, B are β type otoginsenosides, and C, D are α type otoginsenosides, and four contents account for more than 90%, another containing not
Otoginsenoside E, F of equal size.
Sodium Aescinate has the effects that antitumor, anti-inflammatory, impervious detumescence, antibacterial, gastric acid secretion inhibiting, and otoginsenoside faces
It is used mostly in the form of sodium salt on bed, is mainly used for the treatment of the diseases such as postoperative edema, phlebitis, to brain work(caused by brain edema
Can the not normal and disease caused by oedema and venous return obstacle as caused by wound, burn or operation have the effect of definite.
But stimulation sex chromosome mosaicism (blood vessel irritation) is the common problem for perplexing aescin for injection clinical practice.It is reported that
More than 80% patient occurs the phlebitis that degree differs using this product, more has severe patient to terminate when can't bear to bear the pain and controls
It treats, this seriously constrains the popularization and application of product.
Invention content
The purpose of the present invention is to provide a kind of Sodium Aescinate chemical composition compositions, effectively solve the above problems,
Irritation is low and pharmacodynamics is good, effectively reduces the pain of sufferer, improves drug effect and clinical compliance.
Another object of the present invention is to provide a kind of screening technique of Sodium Aescinate chemical element constituent proportioning, sieve
Divide the time quick, effective, effective reduction is sieved, reduce and sieve cost, while obtained screening result accuracy height.
The present invention is solved its technical problem and is realized using following technical scheme.
The present invention proposes a kind of screening technique of Sodium Aescinate chemical element constituent proportioning, including：
The sample of Sodium Aescinate different component proportioning is obtained, is obtained each in the chemical fingerprint and sample of sample
Component is to the dosage of test body and corresponding irritation test data and pharmacodynamics test data.
Pass through the grey correlation analysis and chemical fingerprint and drug effect of chemical fingerprint and irritation test data
Learn test data grey correlation analysis, obtain Sodium Aescinate each component irritation sequence and pharmacodynamics sequence first
Analysis result.
Using dosage as input layer, at corresponding irritation test data and pharmacodynamics test data normalization weighting
As output layer building neural network after reason, training to neural network error is 10-5After below, with trained neural network
It after predicting each component of Sodium Aescinate, is compared, screens with the first analysis result, verification.
The present invention proposes the Sodium Aescinate chemical composition composition that a kind of irritation is low and pharmacodynamics is good, including weight ratio
It is followed successively by 0-1:0-1:2-3:2-4:1-2:Sodium Aescinate A, Sodium Aescinate B, Sodium Aescinate C, the Sodium Aescinate of 1-2
D, Sodium Aescinate E and Sodium Aescinate F.
The Sodium Aescinate chemical element constituent proportioning of the embodiment of the present invention and its advantageous effect of screening technique are：
Pass through the grey correlation analysis and chemical fingerprint and drug effect of chemical fingerprint and irritation test data
Learn test data grey correlation analysis, obtain Sodium Aescinate each component irritation sequence and pharmacodynamics sequence first
Analysis result.
By dosage, with corresponding irritation test data and pharmacodynamics test data after neural network prediction,
Prediction obtains that large range of irritation is relatively low and after the preferable Sodium Aescinate component proportion range of pharmacodynamics, at this point, passing through
The auxiliary of first analysis result, is screened within the above range, and it is low and pharmacodynamics is good to obtain really preferably irritation
After Sodium Aescinate component proportion, obtained Sodium Aescinate chemical composition composition is verified.This method screening is quick, has
Effect effectively reduces the time of screening, while the accuracy of the result after sieve is good.
Description of the drawings
It in order to illustrate the technical solution of the embodiments of the present invention more clearly, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not construed as pair
The restriction of range, for those of ordinary skill in the art, without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Fig. 1 is Sodium Aescinate each sample HPLC collection of illustrative plates provided in an embodiment of the present invention；
Fig. 2 shares peak figure spectrum for Sodium Aescinate each sample HPLC provided in an embodiment of the present invention；
Fig. 3 is the structure diagram of BP neural network provided in an embodiment of the present invention；
Fig. 4 is Neural Network Data provided in an embodiment of the present invention training figure；
Fig. 5 is neural net regression model dependency schematic diagram provided in an embodiment of the present invention.
Specific embodiment
Purpose, technical scheme and advantage to make the embodiment of the present invention are clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, builds according to normal condition or manufacturer
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
The Sodium Aescinate chemical element constituent of embodiment of the present invention proportioning and its screening technique are carried out specifically below
It is bright.
A kind of screening technique of Sodium Aescinate chemical element constituent proportioning, including：
S1. the sample of Sodium Aescinate different component proportioning is obtained.
Wherein, sample includes primary sample and test sample, and test sample is primary sample through preparing liquid phase separation institute
, i.e., test sample is the test sample of different component section.
Wherein, commercially available Sodium Aescinate prescription medicine can be used in the primary sample of Sodium Aescinate, does not do herein specific
It limits.
In preferred embodiments of the present invention, the chromatographic condition for preparing liquid phase separation is：Chromatographic column is：BETASILC18 columns,
250mm × 10mm, 5 μm；Mobile phase includes mobile phase A and Mobile phase B, and mobile phase A is methanol, and Mobile phase B is water, and flows
The volume ratio of phase A and Mobile phase B is 60:40, isocratic elution is carried out under conditions of the Detection wavelength of 220nm, is temporally collected
The corresponding set of segmentation mobile phase liquid of each chromatographic peak is enriched with, obtains test sample；Preferably, during preparing liquid phase separation, stream
The flow velocity of dynamic phase is 2.8-3.2mL/min；
It is highly preferred that test sample includes the first test sample for only including Sodium Aescinate E, contain Sodium Aescinate E
And the second test samples of Sodium Aescinate F, the third containing Sodium Aescinate E, Sodium Aescinate F and Sodium Aescinate C
Test sample, the 4th test sample containing component Sodium Aescinate E, Sodium Aescinate A and Sodium Aescinate C and contains
There are the 5th test sample of Sodium Aescinate F, Sodium Aescinate B and Sodium Aescinate D.
It should be noted that preparative separation, bioconversion, component addition, other components separation strategy, change can also be passed through
The obtained different chemical composition composition of the strategy such as decomposing biological conversion or chemical synthesis conversion and the Sodium Aescinate of proportioning are studied,
It can be as the test sample of this patent.
S2. obtain sample chemical fingerprint and test sample in each component to the dosage of test body and right
The irritation test data and pharmacodynamics test data answered.
Wherein, the chromatographic condition of primary sample and the chemical fingerprint of test sample is：Chromatographic column is YMCC18 columns,
250mm × 10mm, 5 μm；Mobile phase includes mobile phase C and mobile phase D, and mobile phase C is acetonitrile, and mobile phase D is a concentration of
The phosphoric acid solution of 0.1wt%, and the volume ratio of mobile phase C and mobile phase D is 36:64, under conditions of the Detection wavelength of 220nm
Carry out isocratic elution.
Preferably, in detection process, the flow velocity of mobile phase is 0.9-1.1mL/min.
Preferably, in test sample each component to the dosage of test body by corresponding to the peak of component in each test sample
Area calculates gained through internal standard method, and dosage is more reasonable.
Preferably, test body is one kind in mouse, rat and rabbit；Preferably mouse or rat.
Preferably, efficacy test data includes the auricle edema degrees of data of test body, and stimulation learns test data and includes examination
Test the absorbance data of the abdominal cavity capillary of body.Specifically, auricle edema degrees of data causes scorching for caused by dimethylbenzene xylene test body auricle,
Test sample reduces auricle edema, including calculating scorching auricle weightening value, auricle edema rate (%) and swelling inhibiting rate (%).Abdominal cavity
The absorbance data of capillary diffusate is influence of the test sample to mouse peritoneal capillary permeability, by experiment
Test sample is injected intraperitoneally in body, abdominal cavity capillary permeability is caused to increase liquid body exudate, and pass through tail vein injection ivens
Indigo plant dyes peritoneal exudate, and using the absorbance of colorimetric method for determining diffusate, absorbance is higher to show that diffusate is more, stimulation
Property it is bigger, so as to discriminating test sample stimulus.
S3. by the grey correlation analysis of chemical fingerprint and irritation test data and chemical fingerprint with
The grey correlation analysis of pharmacodynamics test data, obtain Sodium Aescinate each component irritation sequence and pharmacodynamics sequence
First analysis result.
Wherein, grey correlation analysis includes：
Using the drug effect of each test sample or irritation index as auxiliary sequence, corresponding characteristic peak peak area is as sub- sequence
Row, using first value converter technique, the auxiliary sequence of transformation is denoted as { X0(t) }, subsequence is denoted as { Xi(t)}。
In t=k, auxiliary sequence is denoted as { X0(k) }, subsequence is denoted as { Xi(k) }, the absolute difference sequence of auxiliary sequence and subsequence
Row Δ0i(k)=| X0(k)-Xi(k) | (1≤i≤m) calculates auxiliary sequence and the incidence coefficient ξ (k) of subsequence in t=k,
Wherein, k be peak number, X0(k) it is irritation test data or pharmacodynamics test data；Xi(k) it is characterized peak peak area
Normalize numerical value；K is peak number；ρ is resolution ratio, and ρ ∈ (0,1), preferably ρ takes 0.5；|X0(k)-Xi(k) | for auxiliary sequence and sub- sequence
The absolute difference of row；minmin|X0(k)-Xi(k) | it is the minimum value of absolute difference, and is denoted as Δ min；maxmax|X0(k)-Xi
(k) | it is the maximum value of absolute difference, and is denoted as Δ max.
The calculation formula of degree of association r is as follows：
Wherein n is the data amount check of subsequence.
By grey correlation analysis, obtain Sodium Aescinate the sequence of each component irritation and pharmacodynamics sequence first
Analysis result；The first analysis result that method provided by the invention obtains is Sodium Aescinate C and Sodium Aescinate D validity
Preferably, irritation is smaller, and Sodium Aescinate E is minimum with Sodium Aescinate F irritations, and validity is preferable, Sodium Aescinate A and seven
The irritation of leaf saponin(e sodium B is larger, and validity is general.Sodium Aescinate G, Sodium Aescinate, Sodium Aescinate H, otoginsenoside
The validity of sodium I and Sodium Aescinate J are poor, and irritation is medium.
S4. using the practical dosage of each component as input layer, with corresponding irritation test data and pharmacodynamics test number
According to, collectively as output layer building neural network, training to neural network error is 10 after normalization weighting processing-5After below, fortune
The each component of Sodium Aescinate is predicted with trained neural network, obtains that irritation is relatively low and pharmacodynamics preferable seven
It after leaf saponin(e sodium component proportion range, is compared, screens with the first analysis result, verification.
Wherein, neural network is the BP neural network of four-layer structure, and neural network is implied including input layer, multiple first
Layer, the second hidden layer and output layer, input layer are connected in parallel with multiple first hidden layers and are transmitted to multiple first hidden layers
Data, multiple first hidden layers and the second hidden layer be connected in parallel and to the second hidden layer transmit data, the second hidden layer with it is defeated
Go out layer to be connected in series with and transmit data to output layer.
Preferably, weighting processing is by the pharmacodynamics with corresponding 40% of normalized 60% irritation test data
Test data carries out addition processing.
Specifically, in the weighting of each test sample obtained treated data, the weighting processing of one of sample
Data afterwards are verified for being input to trained neural network, the weighting of remaining sample treated data are as nerve
The training sample of network is trained neural network using gradient descent method.For further verifying the accurate of neural network
Property and stability.
The Sodium Aescinate component proportion obtained after finally, it is verified that is followed successively by 0-1 including weight ratio:0-1:2-3:2-4:1-
2:Sodium Aescinate A, Sodium Aescinate B, Sodium Aescinate C, Sodium Aescinate D, Sodium Aescinate E and the seven leaf soaps of 1-2
Glycosides sodium F.Its irritation is low and pharmacodynamics is good.
Meanwhile the present invention also provides that a kind of a kind of irritation screened by above-mentioned screening technique is low and pharmacodynamics is good
Sodium Aescinate chemical composition forms, and 0-1 is followed successively by including weight ratio:0-1:2-3:2-4:1-2:The Sodium Aescinate of 1-2
A, Sodium Aescinate B, Sodium Aescinate C, Sodium Aescinate D, Sodium Aescinate E and Sodium Aescinate F.
The feature and performance of the present invention are described in further detail with reference to embodiments.
It should be noted that in the present embodiment, sodium chloride injection, Binghu Shuanghe Pharmaceutical Co., Ltd., Wuhan, state
Medicine H42020475.Glacial acetic acid, Sinopharm Chemical Reagent Co., Ltd., physiological saline are directly made into 1% concentration.Evans blue
(EvansBlue), Shanghai Aladdin biochemical technology limited company, physiological saline are directly made into 0.5% concentration.Dimethylbenzene,
Sinopharm Chemical Reagent Co., Ltd..
The instrument being related to includes：DL28R refrigerated centrifuges (Shanghai centrifugal machine research institute)；Assay balance, Shanghai person of outstanding talent difficult to understand
This Instrument Ltd.；UV-1800PC type ultraviolet-uisible spectrophotometers, Shanghai U.S. spectrum reach Instrument Ltd.；Wear peace U-
3000 high performance liquid chromatographs.
Embodiment 1
A kind of Sodium Aescinate chemical composition composition sieves its chemical constituent proportioning according to following screening technique
Choosing, the screening technique include：
1) common aescin for injection primary sample S2, S3, S4, S5 in the market and middle inspection institute standard items are acquired
(S1)。
Specifically, the specifying information of the primary sample of Sodium Aescinate is：Sodium Aescinate standard items standard items (S1), in
Examine institute, lot number：10346-0001；Spring flower board aescin for injection (S2), specification：10mg, the one limited public affairs of lattice pharmacy of Hunan
Department, authentication code：Chinese medicines quasi-word H20057666；Nation's human relations board aescin for injection (S3), specification：10mg, Wuhan length connection come
Good fortune Pharmacy stock Co., Ltd, authentication code：Chinese medicines quasi-word H20067083；Pu Yetong boards aescin for injection (S4), rule
Lattice：5mg, Wuhan Pusheng Pharmaceutical Co., Ltd., authentication code：Chinese medicines quasi-word H20057826；Pu Yetong board injection otoginsenosides
Sodium (S5), specification：10mg, Wuhan Pusheng Pharmaceutical Co., Ltd., authentication code：Chinese medicines quasi-word H20033703；Physiology during use
Brine is fresh to be configured to required concentration.
2) primary sample is obtained into test sample through preparing liquid phase separation.
Preparation HPLC：WatersPrepLCW600 (UV detector Waters996)；Methanol is chromatographically pure, and water is super
Pure water.Other reagents, reagent are that analysis is pure.
Prepare liquid phase separation chromatographic condition be：Chromatographic column is：BETASILC18 columns, 250mm × 10mm, 5 μm；Mobile phase
Including mobile phase A and Mobile phase B, mobile phase A is methanol, and Mobile phase B is water, and the volume ratio of mobile phase A and Mobile phase B is
60:40, it is 3mL/min in the flow velocity of mobile phase, carries out isocratic elution under conditions of the Detection wavelength of 220nm, temporally collect
The corresponding set of segmentation mobile phase liquid of each chromatographic peak is enriched with, is concentrated to give each preparation group sample S6, S7, S8, S9 and S10 as survey
Test agent.
Using each preparation sample chemical ingredient of analytic type liquid phase detection, wherein, the chromatographic condition of chemical fingerprint is：Color
Spectrum column be YMCC18 columns, 250mm × 10mm, 5 μm；Mobile phase includes mobile phase C and mobile phase D, and mobile phase C is acetonitrile, is flowed
The phosphoric acid solution that dynamic phase D is a concentration of 0.1wt%, and the volume ratio of mobile phase C and mobile phase D is 36:64, in the stream of mobile phase
Speed is 1mL/min, and isocratic elution is carried out under conditions of the Detection wavelength of 220nm.
Each sample HPLC chemical fingerprints are obtained, as shown in Figure 1 and shown in table 1, while obtain the HPLC of each sample
Shared peak, as shown in Fig. 2, obtaining Sodium Aescinate A in S1, S2, S3, S4, S5, S6, S7, S8, S9 and S10, seven leaves simultaneously
Saponin(e sodium B, Sodium Aescinate C, Sodium Aescinate D, Sodium Aescinate E and Sodium Aescinate F ratio (chromatographic peak area
Than %), as shown in table 2.
1 practical peak area of table
The ratio (chromatographic peak area ratio, %) of different Sodium Aescinate A, B, C, D, E, the F of table 2
Can be obtained by table 1-2 and Fig. 1-Fig. 2, in each commercial samples containing Sodium Aescinate A, B, C, D, E and F into
Point, but ratio is not quite similar；It prepares and contains component E in sample S8, contain component E, F (about 1 in sample S9：5), in sample S10
Contain component E, F, C (about 19:5:6), contain component E, A, C (about 7 in sample S7:8:25), contain component F, B, D in sample S6
(about 8:3:8).
3) acquisition of irritation test data
Male mouse of kunming is divided into 11 groups：Blank control group, spring flower group, nation's human relations group, general leaf lead to 3 groups, general leaf lead to 4 groups,
Standard item group, S8 groups, S9 groups, S10 groups, S7 groups, S6 groups.Except a concentration of 0.9% physiological saline of blank control group tail vein injection
Outside, by each group peak area with internal standard method calculate other each group dosages are followed successively by：25mg/kg, 25mg/kg, 25mg/kg,
25mg/kg, 25mg/kg, 26.9mg/kg, 8.05mg/kg, 11mg/kg, 22.75mg/kg, 17mg/kg, as shown in table 3.Each group
Administered volume is 25ml/kg.After each group administration 12h, 0.5% Evans blue 6.25ml/kg of tail vein injection, while abdominal cavity is noted
Mouse is put to death after penetrating glacial acetic acid 6.25ml/kg, 30min, the accurate physiological saline 5ml/ that draws only injects abdominal cavity, gently rubs abdominal cavity, in
Abdomen cuts off an osculum, and for careful about 3ml peritoneal fluids of drawing in 5ml centrifuge tubes, 3500rpm × 10min takes supernatant after centrifugation
OD values are surveyed at 590nm.It the results are shown in Table 4：
3 practical dosage (unit of table：mg)
4 mouse peritoneal permeability experimental result of table
It can be obtained by table 4, sample S8, S9, S10, S7 and S6 can cause obvious ascites to be oozed out, and show its irritation more
By force；Sample S10, S7 and S6 ascites seepage discharge is less, illustrates that the irritation of sample S10, S7 and S6 are smaller.
4) acquisition of pharmacodynamics test data
Take weight 35-40g male mices 55, be randomly divided into 11 groups, respectively blank control group, spring flower group, nation's human relations group,
3 groups of Pu Yetong, general leaf lead to 4 groups, standard item group, S8 groups, S9 groups, S10 groups, S7 groups, S6 groups.Normal is injected intraperitoneally in blank group
30 μ l dimethylbenzene after administration group distinguishes the corresponding drugs of ip (0.5ml/ is only) 30min, are applied to mouse right ear exterior feature and cause inflammation by brine,
Mouse is put to death in dislocation after causing inflammation 30min, cuts two ears respectively, with the reciprocity position of two ear of card punch, weighs the weight of left and right auricle
Amount calculates and causes scorching auricle weightening value, auricle edema rate (%) and swelling inhibiting rate (%).
Auricle edema rate (%)=(left ear quality-auris dextra quality)/auris dextra quality × 100%；
Swelling inhibiting rate (%)=(control group swelling rate-experimental group swelling rate)/control group swelling rate × 100%.As a result
It is shown in Table 5.
5 mice auricle swelling experimental result of table
It can be obtained by table 5, sample S9 and S6 paraxylene induced mice auricle edema has inhibiting effect, but the inhibition of S6
More notable, illustrate sample S6 has preferable anti-inflammatory anti-transudation
Note：The data processing of table 5 is carried out using MicrosoftOfficeExcel2007 and SPSS19.0 statistical softwares, respectively
Group data useIt represents.
5) grey correlation analysis includes：
Using the pharmacodynamics index of each test sample as auxiliary sequence, corresponding characteristic peak peak area is used as subsequence
First value converter technique, the auxiliary sequence of transformation are denoted as { X0(t) }, subsequence is denoted as { Xi(t)}。
In t=k, auxiliary sequence is denoted as { X0(k) }, subsequence is denoted as { Xi(k) }, the absolute difference sequence of auxiliary sequence and subsequence
Row Δ0i(k)=| X0(k)-Xi(k) | (1≤i≤m) calculates auxiliary sequence and the incidence coefficient ξ (k) of subsequence in t=k,
Wherein, k be peak number, X0(k) it is irritation test data OD values or pharmacodynamics test data auricle edema；Xi(k) it is
Characteristic peak peak area normalizes numerical value；K is peak number；ρ is resolution ratio, and ρ ∈ (0,1), preferably ρ takes 0.5；|X0(k)-Xi(k) | be
Auxiliary sequence and the absolute difference of subsequence；minmin|X0(k)-Xi(k) | it is the minimum value of absolute difference, and is denoted as Δ min；
maxmax|X0(k)-Xi(k) | it is the maximum value of absolute difference, and is denoted as Δ max.
The calculation formula of degree of association r is as follows：
Wherein n is the data amount check of subsequence.
Obtained chemical fingerprint and the grey correlation analysis of OD values are as shown in table 6, chemical fingerprint and swelling of auricle
Swollen grey correlation analysis is as shown in table 7.
6 OD value degree of association results of table
| Peak number | r | Peak number | r |
| A | 0.7898 | F | 0.6388 |
| B | 0.7924 | G | 0.7156 |
| C | 0.6389 | H | 0.7007 |
| D | 0.6618 | I | 0.7050 |
| E | 0.6463 | J | 0.7117 |
It can be obtained by table 6, i.e. the irritation sequence of Sodium Aescinate each component is followed successively by B>A>G>J>I>H>D>E>C>F.
7 ear edema rate degree of association result of table
| Peak number | r | Peak number | r |
| A | 0.8075 | F | 0.8005 |
| B | 0.8179 | G | 0.7943 |
| C | 0.8116 | H | 0.7834 |
| D | 0.8192 | I | 0.7298 |
| E | 0.7963 | J | 0.7097 |
It can be obtained by table 7, i.e. the pharmacodynamics of Sodium Aescinate each component, i.e. effectiveness sequence is followed successively by i.e. J<I<H<G<E<
F<A<C<B<D。
The content of consolidated statement 6 and table 7, obtains the first analysis result, i.e. Sodium Aescinate C and Sodium Aescinate D are effective
Property is best, and irritation is smaller；Sodium Aescinate E and Sodium Aescinate F irritations are minimum, and validity is preferable；Sodium Aescinate A
Larger with the irritation of Sodium Aescinate B, validity is general.Sodium Aescinate G, Sodium Aescinate H, Sodium Aescinate I and
The validity of Sodium Aescinate J is poor, and irritation is medium.
6) the artificial neural network tool box selected in Matlab language is programmed, with practical dosage (such as 3 institute of table
Show) neuron is inputted as neural network, two hidden layer neuron numbers are respectively 20 and 1, and experimental result is (normalized
+ 40% auricle swelling degree of 60%OD values, as shown in table 8) as output neuron, with reference to the BP nerves for establishing a four-layer structure
Network, structure are as shown in Figure 3.Input layer in neural network procedure, hidden layer transmission function be Tansig, the transmission of output layer
Function is Purelin.In 10 groups of obtained data, using wherein 9 groups of experimental results as the training sample of neural network, using gradient
Descent method is trained network, and model is made to reach satisfied degree.Trained nerve is input to 1 group of experiment parameter of residue
Network is verified, the Stability and veracity of verification neural network is compared to experimental result.
8 experimental result of table
With the increase of training iterations, neural network error of fitting constantly reduces.As shown in Figure 4, Figure 5, training knot
Shu Hou, model error 10-5Left and right.Model coefficient of determination R2Value has reached (0.999922) 0.9998, matched curve and target
Curve essentially coincides, and exports result and objective result obtains preferable linear regression effect, can be relatively accurately to otoginsenoside
The safety of sodium ABCDEF each components and the influence of Usefulness Pair user are emulated.
Desired Sodium Aescinate A, B, C, D, E and F each component ratio is carried out with trained neural network pre-
It surveys, as a result in A:B:C:D:E:F is in 0-2:0-2:2-5:2-5:0-3:Effect is preferable between 0-3, i.e., irritation is smaller, validity
It is good.
It is compared simultaneously with the first analysis result, best proportion range 0-1:0-1:2-3:2-4:1-2:1-2.
7) replication experiment is carried out for the Sodium Aescinate component proportion in the range of obtained best proportion, referring to step
And 4) 3) method in obtains the experiment of mouse peritoneal permeability and mice auricle swelling experimental result, as shown in table 9.
9 mouse peritoneal permeability of table is tested and mice auricle swelling experimental result
Data and table 9 in table 9 are compared with the data of table 4, table 5, made from method provided by the invention
Sodium Aescinate component optimum proportioning is followed successively by 0-1 including weight ratio:0-1:2-3:2-4:1-2:The Sodium Aescinate A of 1-2, seven
Leaf saponin(e sodium B, Sodium Aescinate C, Sodium Aescinate D, Sodium Aescinate E and Sodium Aescinate F.I.e. component proportion is above-mentioned
The Sodium Aescinate chemical composition composition of component proportion reduces its irritation while effectively improving its drug effect, improves drug effect with facing
Bed compliance.
To sum up, the Sodium Aescinate chemical element constituent proportioning and its screening technique of the embodiment of the present invention, effectively solves
The above problem reduces irritation while effectively improving pharmacodynamics, reduces the pain of sufferer, has excellent clinical expansion valency
Value.
Embodiments described above is part of the embodiment of the present invention, instead of all the embodiments.The reality of the present invention
The detailed description for applying example is not intended to limit the range of claimed invention, but is merely representative of the selected implementation of the present invention
Example.Based on the embodiments of the present invention, those of ordinary skill in the art are obtained without creative efforts
Every other embodiment, shall fall within the protection scope of the present invention.
Claims (10)
1. a kind of screening technique of Sodium Aescinate chemical element constituent proportioning, which is characterized in that including：
The sample of Sodium Aescinate different component proportioning is obtained, obtains the chemical fingerprint of the sample and the sample
Middle each component is to the dosage of test body and corresponding irritation test data and pharmacodynamics test data；
Pass through the grey correlation analysis and the chemical fingerprint figure of the chemical fingerprint and the irritation test data
Spectrum and the grey correlation analysis of the pharmacodynamics test data, obtain the Sodium Aescinate the sequence of each component irritation and
First analysis result of pharmacodynamics sequence；
Using the dosage as input layer, added with the corresponding irritation test data and pharmacodynamics test data normalization
As output layer building neural network after power processing, training to the neural network error is 10-5After below, utilization is trained
It after the neural network predicts each component of Sodium Aescinate, is compared with first analysis result, screens, test
Card.
2. screening technique according to claim 1, which is characterized in that the neural network is the BP nerve nets of four-layer structure
Network, the neural network includes the input layer, multiple first hidden layers, the second hidden layer and the output layer, described defeated
Enter layer to be connected in parallel with the multiple first hidden layer and transmit data to the multiple first hidden layer, the multiple first is hidden
Be connected in parallel containing layer and second hidden layer and transmit data to second hidden layer, second hidden layer with it is described defeated
Go out layer to be connected in series with and transmit data to the output layer.
3. screening technique according to claim 2, which is characterized in that at the obtained normalization weighting of each sample
In data after reason, the weighting of one of them sample treated data are for being input to the trained neural network
It is verified, weighting treated training sample of the data as the neural network of remaining sample, using under gradient
Drop method is trained the neural network.
4. screening technique according to claim 2, which is characterized in that weighting processing is by normalized 60% thorn
That swashs property test data carries out addition processing with corresponding 40% pharmacodynamics test data.
5. screening technique according to claim 1, which is characterized in that the dosage in each sample by corresponding to group
The peak area divided calculates gained through internal standard method.
6. screening technique according to claim 1, which is characterized in that the Sodium Aescinate group distribution obtained after verification
0-1 is followed successively by than including weight ratio:0-1:2-3:2-4:1-2:Sodium Aescinate A, Sodium Aescinate B, the Sodium Aescinate of 1-2
C, Sodium Aescinate D, Sodium Aescinate E and Sodium Aescinate F.
7. screening technique according to claim 1, which is characterized in that the sample includes primary sample and test specimens
Product, the test sample are the primary sample through preparing obtained by liquid phase separation；
Preferably, the chromatographic condition for preparing liquid phase separation is：Chromatographic column is：BETASILC18 columns, 250mm × 10mm, 5 μm；Stream
Dynamic mutually to include mobile phase A and Mobile phase B, mobile phase A is methanol, and Mobile phase B is water, and the volume of mobile phase A and Mobile phase B
Than being 60:40, isocratic elution is carried out under conditions of the Detection wavelength of 220nm, it is corresponding temporally to collect each chromatographic peak of enrichment
Set of segmentation mobile phase liquid, obtains the test sample；
Preferably, during preparing liquid phase separation, the flow velocity of the mobile phase is 2.8-3.2mL/min；
Preferably, the test sample includes only including the first test sample of Sodium Aescinate E, containing Sodium Aescinate E with
And the second test samples of Sodium Aescinate F, the third containing Sodium Aescinate E, Sodium Aescinate F and Sodium Aescinate C are surveyed
Test agent, the 4th test sample containing component Sodium Aescinate E, Sodium Aescinate A and Sodium Aescinate C and contains
The 5th test sample of Sodium Aescinate F, Sodium Aescinate B and Sodium Aescinate D.
8. screening technique according to claim 1, which is characterized in that the chromatographic condition of the chemical fingerprint is：Color
Spectrum column be YMCC18 columns, 250mm × 10mm, 5 μm；It is second that mobile phase, which includes mobile phase C and mobile phase D, the mobile phase C,
Nitrile, the mobile phase D is the phosphoric acid solution of a concentration of 0.1wt%, and the volume ratio of mobile phase C and mobile phase D is 36:64,
Isocratic elution is carried out under conditions of the Detection wavelength of 220nm；
Preferably, in detection process, the flow velocity of the mobile phase is 0.9-1.1mL/min.
9. screening technique according to claim 1, which is characterized in that the test body is in mouse, rat and rabbit
One kind；
Preferably, the irritation test data include the auricle edema degrees of data of the test body, the pharmacodynamics test number
According to the absorbance data of the abdominal cavity capillary including the test body.
The Sodium Aescinate chemical composition composition that 10. a kind of irritation is low and pharmacodynamics is good, which is characterized in that it includes weight ratio
It is followed successively by 0-1:0-1:2-3:2-4:1-2:Sodium Aescinate A, Sodium Aescinate B, Sodium Aescinate C, the Sodium Aescinate of 1-2
D, Sodium Aescinate E and Sodium Aescinate F.
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Application publication date: 20180629 |