CN101744914A - Method for rapidly detecting quality of anti-hepatitis-jaundice injection - Google Patents
Method for rapidly detecting quality of anti-hepatitis-jaundice injection Download PDFInfo
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Abstract
The invention relates to a method for rapidly detecting quality of anti-hepatitis-jaundice injection; the method comprises the following steps: bacterial strains are inoculated under an aseptic condition, so as to prepare blank solution and sample solution, a thermal power-time curve in the bacterial strain growing process is detected and recorded in a differential scanning calorimeter, and the quality of the anti-hepatitis-jaundice injection can be rapidly detected according to the curve. In the method, sensitizers of microorganisms or other organisms in the anti-hepatitis-jaundice injection can be rapidly and accurately detected, and the method is a feasible novel detection measure, so as to provide basis for early-warning untoward effect of traditional Chinese medicine injection.
Description
Technical field
The present invention relates to the quality determining method of Chinese medicine, be specifically related to a kind of method of fast detecting quality of anti-hepatitis-jaundice injection, belong to field of traditional Chinese.
Background technology
Yinzhihuang Injection is mainly used in the jaundice that a variety of causes causes, particularly damp and hot YANG jaundice person; Its jaundice eliminating effect is best with acute icterohepatitis, is better than the therapeutic effect to chronic persistent hepatitis, hepatitis gravis and hepatitis cirrhosis.Its main clinical adaptation disease has: the high gallbladder haemachrome of neonate mass formed by blood stasis, viral hepatitis hyperbilirubinemia, cholestatic hepatitis A, fatty liver, acute edematous pancreatitis, children's's favism etc.
Chinese medicine is at duration of storage, because acid-base value, clarity, oxidoreduction condition and microbial environment such as the conditions such as sterilising conditions, aseptic assurance degree of storage time, illumination, temperature, humidity and solution change, the safety meeting of medicine is affected.
The 98th page of method of quality control that discloses Yinzhihuang Injection of " Chinese traditional patent formulation preparation " (the 14th), comprise pH value inspection technique, pyrogen test, residue on ignition detection method, and adopt the method for quality control of spectrophotography Chinese medicine injections such as content of baicalin mensuration.
Though existing method has played control action to the effectiveness and the safety of Yinzhihuang Injection to a certain extent, but the quality that can not comprehensively reflect injection especially can't detect multiple mass-sensitive information such as the microorganism that causes untoward reaction or other biological sensitizer.Because above-mentioned information can not detect by conventional method, thereby cause the adverse reaction rate that causes by quality still higher.In addition, existing method complicated operating process, consuming time longer, also be unfavorable for fast, test sample in bulk.
Chinese medicine is the important directions of Chinese medicine industry modernization development, but because the adverse reaction of tcm/incident due to the quality problems takes place frequently, has become the key issue that influences industry development.Therefore early stage early warning fast guarantees clinical drug safety to reduce the untoward reaction of Chinese medicine, has become problem demanding prompt solution.One of key that addresses the above problem be exactly to be set up the method that can fast, accurately detect microorganism in the Chinese medicine or other biological sensitizer.
Summary of the invention
The method that the purpose of this invention is to provide a kind of fast detecting quality of anti-hepatitis-jaundice injection, described method comprises the steps:
1) under aseptic condition, with the inoculation of exponential phase of growth in culture medium;
2) add the culture medium solution that contains described bacterial strain in ampoule bottle, sealing obtains blank solution;
3) add culture medium solution and the Yinzhihuang Injection that contains described bacterial strain in ampoule bottle, sealing obtains sample solution;
4) described blank solution and sample solution are put into 37 ℃ of homothermic micro-calorimeters respectively, the thermal power-time graph of record strain growth process;
5) thermal power-time graph of described sample solution and blank solution is compared, what the peak time of the first and second maximum heat production power was delayed in the sample solution is qualified samples, and what described peak time shifted to an earlier date is failed test sample.
Method of the present invention can further include after step 5):
6) adopt the SAS statistical software that the parameter of the thermal power-time graph of qualified sample sets and failed test sample group is carried out pattern recognition respectively, set up discriminant equation separately, the described discriminant equation of parameter substitution of the thermal power-time graph of the yellow injection of mattress Cape jasmine to be checked is calculated the result, the result value that compares gained, according to the gained result value the yellow injection of mattress Cape jasmine to be checked is declared in the bigger group of numerical value, judged the quality of the yellow injection of mattress Cape jasmine to be checked with this.
Wherein, SAS statistical software full name is Statistics Analysis System, is the large-scale integrated information system that is used for decision support, and its Core Feature is a statistical analysis, in date processing and statistical analysis field, the SAS system is the recognized standard software system in the world.
In the present invention, preferred SAS8.0 statistical software carries out pattern recognition to the parameter of thermal power-time graph, and sets up discriminant equation separately.
Wherein, described bacterial strain is escherichia coli or staphylococcus aureus; Preferred escherichia coli;
Described culture medium is a nutrient broth medium: peptone 10g, Carnis Bovis seu Bubali cream 6g, NaCl 5g are dissolved in the 1000mL distilled water pH=7.2; Preferably, described culture medium is the L.B culture medium: peptone 10g, yeast extract 5g, NaCl 5g are dissolved in the 1000mL distilled water pH=7.2;
The concentration of described inoculation is 0.5-1 * 10
6Cell/ml;
Preferably, the concentration of described inoculation is 0.5 * 10
6Cell/ml;
Step 2) and 3) in, the described culture medium solution that adds in ampoule bottle is 5-10ml;
The described Yinzhihuang Injection that adds in the step 3) is 100-150 μ l.
The whole growth metabolic process of organism all is accompanied by the transfer and the thermal change of energy, have highly sensitive micro-calorimeter and can measure the heat production curve of biology growing directly, continuously, be biological heat living features collection of illustrative plates, be also referred to as " thermogram ", " thermal power-time graph ".Therefore, by comparing the biological heat spectral curve of bacterial strain in the presence of different samples, sample quality can be described.Based on above-mentioned principle, this research adopts microcalorimetry to carry out quality testing.
Under set condition, the growth of antibacterial meets the microbial growth curve model.With escherichia coli is example, and as abscissa, the Production by Bacteria thermal power writes down the thermal power-time graph of escherichia coli growth course as vertical coordinate with incubation time, and this curve is divided into the fourth phase:
The system balancing phase (System balance phase): system is in the thermal balance stage, and heat production power descends rapidly and rises to normal level, and this moment, antibacterial was in the of short duration adaptive phase of new environment, and required time was generally 0.5 hour;
Exponential phase of growth (Logarithmic phase): also claim first trophophase, escherichia coli utilize condition growths such as culture medium in the ampoule and oxygen rapidly, and the thermal power straight line rises, and reaches the first maximum heat production power; The effect of environmental factors is very sensitive to external world for bacterial strain in this period, shown in AB section among Fig. 1 a;
Lag phase (Lag phase): the phase of adjustment of also the title, along with colibacillary quick growth, nutritional condition consumes rapidly in the ampoule, and antibacterial adjustment self physiological activity is to adapt to the process of external environment, this stage heat production power drops to valley, shown in BC section among Fig. 1 a;
Stable phase (Stationary phase): also claim second trophophase, because nutrient substance consumption in the culture medium, harmful metabolite gathers, this phase escherichia coli reproduction speed decrescence, the increase of heat production power slows down, but because the escherichia coli radix is big, heat production power finally reaches the second heat production power, shown in CD section among Fig. 1 a;
Decline phase (Decline phase): behind the stable phase, the nutrient substance approach exhaustion, escherichia coli are dead rapidly, and heat production power descends rapidly, and returns baseline, shown in DE section among Fig. 1 a.
Wherein, exponential phase of growth antibacterial growth curve meet microorganism exponential growth mathematical model:
P
t=P
0Exp (kt) or lnP
t=lnP
0+ kt (1)
In the formula, P
0Be the bacterial strain heat production power of baseline starting point, P
tBe t bacterial strain heat production power constantly, k is a growth rate constant.Also can extract maximum heat production power (P simultaneously
1M, P
2M), peak time (T
1M, T
2M), the characteristic parameter of quantity of heat production hot active collection of illustrative plates such as (Q).
In molecular biology and genetic engineering research, escherichia coli and staphylococcus aureus are important experiment materials, the In vitro culture technology maturation, metabolic heat power is bigger, therefore gathering different samples obtains thermal power-time graph to above-mentioned strain effect, set up the biological heat living features collection of illustrative plates of Yinzhihuang Injection, in order to control its quality, for the untoward reaction of early warning Chinese medicine provides technical support.
Method of the present invention can fast, accurately detect multiple mass-sensitive information such as the microorganism that causes untoward reaction in the Chinese medicine or other biological sensitizer, and above-mentioned information adopts the rules of preparations inspection still can not effectively to detect, and therefore method of the present invention can reduce the incidence rate of adverse reaction that is caused by quality.
In addition, method operating process of the present invention is simple, is beneficial to fast, detects the Chinese medicine sample in bulk, is a kind of practicable novel detection means, and the untoward reaction that can be the early warning Chinese medicine provides foundation.
Description of drawings
Fig. 1 is colibacillary growth metabolism thermal power-time graph, and wherein Fig. 1 a illustrates each growth of bacterial strain by stages, and Fig. 1 b illustrates each parameter information on the curve;
Fig. 2 is based on each sample thermal power-time graph of colibacillary Yinzhihuang Injection;
Fig. 3 is based on each the sample cluster analysis of colibacillary Yinzhihuang Injection;
Fig. 4 is each the qualified samples thermal power-time graph of Yinzhihuang Injection based on staphylococcus aureus;
Fig. 5 is each the particular sample thermal power-time graph of Yinzhihuang Injection based on staphylococcus aureus;
Fig. 6 is each the sample cluster analysis of Yinzhihuang Injection based on staphylococcus aureus.
The specific embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
The preparation of embodiment 1 qualified samples and particular sample
For investigating the accuracy and the reliability of method of the present invention microorganism or other biological sensitizer in detecting the yellow injection sample of mattress Cape jasmine, qualified samples and underproof particular sample have been prepared respectively.
The preparation of qualified samples
The present invention adopts a plurality of batches Yinzhihuang Injection of three manufacturer production, and above-mentioned batch sample is qualified samples.
The Yinzhihuang Injection qualified samples that collection Shijiazhuang martial prowess Pharmaceutical (SW) is produced is totally 10 batches (S1-S10), batch number is respectively: SW06060811, SW06060813, SW06060912, SW07010242, SW07010243, SW07021042, SW07021141, SW07021142, SW07020942, SW07020943,50 every batch, every 10ml.
The Yinzhihuang Injection qualified samples that collection Shanxi Taihang Pharmaceutical (TH) is produced is totally 6 batches (S11-S16), and batch number is respectively TH070401, TH070402, TH070403, TH070405, TH070501, TH070502, and 50 every batch, every 10ml.
Gather totally 2 batches of the Yinzhihuang Injection qualified samples (S17, S18) that Beijing Double-Crane Pharmaceutical Co., Ltd (SH) produces, batch number is respectively SH070210 and SH070414, and 50 every batch, every 10ml.
The inventor is according to the Yinzhihuang Injection homemade sample (FF) [always making word (2006) F04008 number] totally 7 batches (S21-S25, S27, S28) of writing out a prescription, batch number is respectively FF070308, FF070318, FF070405, FF070415, FF070620, FF070704, FF070720,50 every batch, every 10ml.
The preparation of particular sample
For investigate the mass change sensitive information that causes the Chinese medicine untoward reaction from factors such as the external environment that concerns with the injection quality, internal medium, microbial environment, holding time comprehensively, this research prepares particular sample under maximum conditions.The particular sample of setting comprises following classification.
Expired sample (S19, S20): gather Double-Crane Pharmaceutical Co., Ltd's spend effect duration lot number of (producing in 1999) and be each 30 in the Yinzhihuang Injection sample of SH990812 and SH990522, be inventor's reserved sample observing sample.
The semi-finished product (S26) of not sterilizing: gather do not sterilize 30 in sample of same batch of martial prowess Pharmaceutical SW07040341.
High temperature accelerated test sample (S29): get 30 of martial prowess Pharmaceutical SW07040341 qualified samples, put in 60 ℃ of baking ovens and toast 10d.
Illumination accelerated test sample (S30): get 30 of martial prowess Pharmaceutical SW07040341 qualified samples, put Continuous irradiation 10d under the tunable light source that intensity of illumination is 4500 ± 500Lx, the gained color sample is deepened.
Sample (S31-S33) is placed in Kaifeng: get 30 of martial prowess Pharmaceutical SW07040341 qualified samples, 10d is placed in Kaifeng.
Different condition sterilization sample (S34, S40-S42, S48, S50): get 180 in FF070620 batch of sample, per 30 respectively at 100 ℃ of flowing steam sterilization 10min, 100 ℃ of flowing steam sterilization 30min, 100 ℃ of flowing steam sterilization 45min, 100 ℃ of flowing steam sterilization 60min, 115.2 ℃ of high pressure (10lbf/in2) sterilization 10min, 115.2 ℃ of high pressure (10lbf/in2) sterilization 40min.
The sterilization sample that excessively is heated (S35, S46, S48): get 90 in SW07040341 batch of sample of martial prowess Pharmaceutical, per 30 respectively at 121 ℃ of high pressure (15lbf/in2) sterilizations 30min, 126 ℃ of high pressure (20lbf/in2) sterilization 15min, 126 ℃ of high pressure (20lbf/in2) sterilization 30min.
For react the information of all kinds of samples comprehensively, this research at first by conventional physico-chemical analysis method (" 2005 editions Chinese medicine ruless of preparations of Chinese pharmacopoeia are checked a down regulation), is checked all of pH value, visible foreign matters, particulate matter and the Chinese medicine related substance (protein, tannin, resin, oxalates etc.) of each batch sample.
The result shows, the detection method of rules of preparations only can detect the failed test sample of character generation significant change, as: expired sample (S19, S20) produces tangible turbidity sediment material, high temperature accelerated test sample slightly turbidity sediment occurs, illumination accelerated test color sample is deepened, Kaifeng placement sample (S31-S33) becomes turbid, and excessively is subjected to heat sterilization sample (S48) to produce flocculent deposit.
The rules of preparations inspection still can not effectively detect the failed test sample that no obvious character changes: S26, S29, S30, S34, S41 and S50 etc.Therefore need by other means if will detect this type of sample.
Instrument, material and test method
Instrument and equipment: the little calorimeter of TAM Air that Sweden Thermometric company produces, LKB-2277 biological heat activity monitor system; The double single face clean work station of SW-CJ-2FD type, Suzhou elite equipment company limited; The desk-top constant temperature oscillator of TH2-22 type, granary, Jiangsu testing equipment factory.
Strains tested: coli strain (Escherichia coli CCTCC 44 301) is provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
The L.B culture medium: peptone 10g, yeast extract 5g, NaCl 5g, be dissolved in the 1000mL distilled water, packing behind the accent pH=7.2,121.1 ℃ of autoclaving 15min place standby in 4 ℃ of refrigerators.
Relevant sterility test material: liquid-transfering gun (Drugonmed 0～5000 μ L).
1. inoculation
Under the aseptic condition, get 100 μ l low-temperature preservations the 3rd generation the escherichia coli mother solution, add in the L.B culture medium of 50ml, counting, regulating and making its concentration is 1 * 10
6Cell/ml.
2. the preparation of blank solution
Add 5ml and contain colibacillary L.B culture medium solution in ampoule bottle, 37 ℃ of homothermic micro-calorimeters are put in sealing, obtain blank solution (KB).
3. the preparation of sample solution
Under the aseptic condition, accurately add in ampoule bottle that 5mL is above-mentioned to contain colibacillary L.B culture medium solution, add 150 μ L Yinzhihuang Injection sample to be measured then, add a cover bottle stopper, at 37 ℃ of low speed jolting 10min, make the abundant mixing of medicinal liquid and culture medium, obtain sample solution.
4. instrument precision experiment
Drawing germ-carrying L.B culture medium 5ml adds respectively in the special-purpose ampoule bottle of 8 microcalorimetries, place 37 ℃ of homothermic micro-calorimeters, with 8 colibacillary thermal power-time graphs of passage of data acquisition software track record instrument, when curve returned baseline again, experiment finished.Extract the biological heat kinetic parameter: the first trophophase peak time T
1M and peak value P
1M, the second trophophase peak time T
2M and peak value P
2M (seeing Fig. 1 b) carries out statistical analysis, calculates each time test RSD value, sees Table 1.
Each parameter list of table 1 eight passage escherichia coli thermal power-time graphs
Result: the major parameter T of escherichia coli thermal power-time graph
1M, T
2M, P
1M, P
2M, RSD show that all less than 3.00% instrument has good stable.
5. stability of instrument experiment
According to the method described above, use the same passage record of micro-calorimeter thermokinetics curve, extract the biological heat kinetic parameter: the first trophophase peak time T
1M and peak value P
1M, the second trophophase peak time T
2M and peak value P
2M carries out statistical analysis, calculates each time test RSD value, sees Table 2.
Each parameter list of table 2 single channel escherichia coli biological heat power-time graph
Result: the major parameter T of escherichia coli thermal power-time graph
1M, T
2M, P
1M, P
2M, RSD show that all less than 3.00% the precision of instrument is good.
6. measure each sample thermal power-time graph
Respectively above-mentioned blank solution and sample solution are put into 37 ℃ of homothermic micro-calorimeters, with data acquisition software track record bacteria growth process thermal power-time graph, when curve returned baseline again, experiment finished.
Gather the thermal power-time graph (see figure 2) of each sample, the curve of blank solution and each sample solution is compared, the result shows:
(1) the pattern basically identical of the biological heat living features collection of illustrative plates of the qualified Yinzhihuang Injection sample of martial prowess (SW), Taihang (TH), two crane (SH) Pharmaceutical shows that the quality of the Yinzhihuang Injection of each manufacturer production has higher concordance and stability;
(2) compare with blank sample, each producer's qualified samples is to colibacillary P
2M increases significantly, to P
1M decreases, to T
1M, T
2The time of occurrence of m is all obviously delayed, and prolongs the bacterial growth cycle, increases maximum caloric value;
(3) compare with blank sample, each rotten sample is to T
1M, T
2M all shifts to an earlier date to some extent, to P
1The m influence is not remarkable, to P
2M decreases and is the most obvious with S29 (high temperature acceleration sample), and gross calorific power is decreased;
(4) compare with blank sample, each sample of Yinzhihuang Injection all can weaken escherichia coli and become feeble and die plateau, dwindles the width (T of half maximum heat production power
H) and reduce by half maximum heat production power caloric value (Q
H);
(5) the biological characteristic collection of illustrative plates obvious difference of rotten sample and qualified samples, can obviously be examined knowledge, its reason may have certain inhibitory action earlier to escherichia coli for the Yinzhihuang Injection qualified samples, treat to increase rapidly after bacterial strain conforms, reduce rising then earlier so qualified samples shows as heat production power; And injection material base or microbial environment change in each rotten sample, and bacteriostasis reduces and more adapts to the escherichia coli growth, so biological profile figure shows as first trophophase in advance, and totally back decline rapidly of the system material consumption for the treatment of.
In sum, can draw as drawing a conclusion: compare with the thermal power-time graph of blank solution, what the peak time of the first and second maximum heat production power was delayed in the sample solution is qualified samples, and what described peak time shifted to an earlier date is failed test sample.
7. sample clustering analysis
In order to verify above-mentioned conclusion, gather the biological heat living features collection of illustrative plates of each sample, extract the thermokinetic parameters of each characteristic spectrum, and be the cluster index with each parameter, adopt SAS8.0 software to carry out the sample clustering analysis, cluster analysis result is seen Fig. 3.
Cluster analysis result shows: (1) Yinzhihuang Injection qualified samples is at first poly-to be a class, illustrates that the stability of each sample room is better; (2) blank sample is poly-separately is a class, shows that medicine is comparatively obvious to the influence of model organism; (3) different sterilising conditions samples and all kinds of rotten sample are poly-one by one is a class, and has and mix, and illustrates that each sterilising conditions is bigger to sample effects, sterilize insufficient then poly-with the sample of not sterilizing be a class, excessively sterilize then and the polymerization of rotten oxidation deterioration sample; (4) the illumination acceleration is bigger to the quality influence of sample, and the biological heat living features collection of illustrative plates that high temperature quickens sample takes place more obviously to change, and shows that biological heat living features collection of illustrative plates is higher to the identification ability of sample.
The result of comprehensive cluster analysis proves whether detection method of the present invention exists microorganism or other biological sensitizer in the judgement sample quickly and accurately, can become feasible means for detection.
8. discriminant analysis
Gather the biological heat living features collection of illustrative plates of each sample, extract the thermokinetic parameters of each characteristic spectrum, adopt SAS8.0 software to qualified samples (S01, S02, S03, S04, S05, S06, S07, S08, S09, S10), rotten sample (S26, S29, S30, S31, S32, S33, S34, S35) carries out discriminant analysis, set up discriminant equation, process and the results are shown in Table 3A～B.
(1) at first each sample is carried out progressively discriminant analysis, the result shows: progressively the discriminant analysis process is introduced variables D (T successively
2M), J (T
1), A (T
1M), M (Q
H), E (P
2M), B (P
1M), when being selected in B, square (the Average SquaredCanonical Correlation) of average canonical correlation coefficient increases little, so reject variable B, its dependent variable is set up discriminant coefficient and had remarkable statistical significance;
(2) introduce parameter D, J, A, M, when E sets up discriminant function because heterogeneity of variance, so set up quadric discriminant function, but this function False Rate is higher, so screen variable successively; As introducing D, J, when A sets up discriminant function, homogeneity of variance is set up linear discriminant function, and identification effect significantly improves, so select it.
Table 3 is based on the qualified and rotten sample discriminant analysis of colibacillary Yinzhihuang Injection
Table 3A is discriminant analysis progressively
Stepwise?Selection?Summary
Table 3B discriminant function coefficient table
(3) according to discriminant function coefficient (seeing Table 3B), set up quadric discriminant function:
Qualified=0.07T
2M+0.07T
1-0.04T
1M-2056.54 (discriminant equation 1)
Rotten=0.03T
2M+0.03T
1-0.01T
1M-420.19 (discriminant equation 2)
(4) discriminant equation is used
With each sample parameter information substitution discriminant equation 1 and 2 respectively, contrast two discriminant equation result of calculation numerical value, sample is declared in the bigger group of numerical value (seen Table 4).
Table 4 escherichia coli are to the differentiation result of each sample of Yinzhihuang Injection
The result shows: is model organism 1), adopts this discriminant equation that sample is had and examine the knowledge ability preferably with escherichia coli, and can each rotten sample of complete inspection (S26, S29-S35, S41, S42, S44, S46, S48, S50); 2) difference is between (592.89 ± 40.73) as a result for this discriminant equation of qualified samples substitution, two equations, and rotten sample difference range is between (637.10 ± 40.19), and two to differentiate intervals overlapping to some extent; 3) two equation results of failed test sample are divided into positive negative value, and qualified samples two equation results be on the occasion of, two groups of data are all more stable; The above factor of integrated survey can obtain sensitivity, correct differentiation result.
Embodiment 3 is based on the biological heat living features collection of illustrative plates research of staphylococcus aureus
Instrument, material and test method
Instrument and equipment: the little calorimeter of TAM Air that Sweden Thermometric company produces, LKB-2277 biological heat activity monitor system; The double single face clean work station of SW-CJ-2FD type, Suzhou elite equipment company limited; The desk-top constant temperature oscillator of TH2-22 type, granary, Jiangsu testing equipment factory.
Strains tested: staphylococcus aureus strains (Staphylococcus aureus, CMCC (b) 26 003) is provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Nutrient broth medium: peptone 10g, Carnis Bovis seu Bubali cream 5g, NaCl 5g, be dissolved in the 1000mL distilled water, packing behind the accent pH=7.2,121.1 ℃ of autoclaving 15min place standby in 4 ℃ of refrigerators.
Relevant sterility test material: liquid-transfering gun (Drugonmed 0～5000 μ L).
1. inoculation
Under the aseptic condition, get the 3rd cash equivalent Staphylococcus aureus mother solution of 100 μ l low-temperature preservations, add in the nutrient broth medium of 100ml, counting, regulating and making its concentration is 0.5 * 10
6Cell/ml.
2. the preparation of blank solution
Add the nutrient broth medium solution that 10ml contains staphylococcus aureus in ampoule bottle, 37 ℃ of homothermic micro-calorimeters are put in sealing, obtain blank solution (KB).
3. the preparation of sample solution
Under the aseptic condition, in ampoule bottle, accurately add the above-mentioned nutrient broth medium solution that contains staphylococcus aureus of 10mL, add the yellow injection sample of 100 μ L mattress Cape jasmine to be measured then, add a cover bottle stopper, put 37 ℃ of low speed jolting 10min, make the abundant mixing of medicinal liquid and culture medium, obtain sample solution.
4. measure each sample thermal power-time graph
Respectively above-mentioned blank solution and sample solution are put into 37 ℃ of homothermic micro-calorimeters, with data acquisition software track record bacteria growth process thermal power-time graph, when curve returned baseline again, experiment finished.
Gather the thermal power-time graph (seeing Fig. 4,5) of each sample, the curve of blank solution and each sample solution is compared, the result shows:
(1) the pattern basically identical of the biological heat living features collection of illustrative plates of each producer's Yinzhihuang Injection qualified samples, and different degree prolongs the bacterial growth cycle; (2) S19, S20, S27, S28 significantly change the antibacterial first trophophase collection of illustrative plates, improve maximum heat production power, increase the first trophophase caloric value; (3) rotten sample S32, S33, S34, S35 significantly change the hot living features collection of illustrative plates of model organism, significantly improve maximum heat production power of second trophophase and maximum caloric value, prolong the bacterial growth cycle, show that serious rotten sample can obviously change the growth metabolism of model organism, can obviously examine knowledge by biological heat living features collection of illustrative plates.
5. sample clustering analysis
In order to verify The above results, gather the biological heat living features collection of illustrative plates of each sample, extract the thermokinetic parameters of each characteristic spectrum, and be the cluster index with each parameter, adopt SAS8.0 software to carry out the sample clustering analysis, cluster analysis result is seen Fig. 6.
Cluster analysis result shows:
(1) blank sample, martial prowess Pharmaceutical Yinzhihuang Injection qualified samples are at first poly-is a class, show that martial prowess Pharmaceutical sample is less to the biological heat living features collection of illustrative plates influence of staphylococcus aureus, and sample has higher concordance and stability between each qualified batch;
(2) inventor make by oneself sample, Taihang Pharmaceutical sample, Double-Crane Pharmaceutical Co., Ltd's sample one by one with martial prowess Pharmaceutical Yinzhihuang Injection sample collection, show with the staphylococcus aureus to be the sample that the hot living features collection of illustrative plates of model organism can clearly be distinguished different manufacturers, simultaneously, the inventor makes sample by oneself does not have evident difference to the influence of the hot living features collection of illustrative plates of staphylococcus aureus and the Yinzhihuang Injection of other manufacturer production;
(3) to gather in distance farthest with other sample be a class to rotten sample, shows with the staphylococcus aureus to be that the hot living features collection of illustrative plates of model organism can significantly be distinguished qualified and rotten sample.
The result of comprehensive cluster analysis proves whether detection method of the present invention exists microorganism or other biological sensitizer in the judgement sample quickly and accurately, can become feasible means for detection.
6. discriminant analysis
Gather the biological heat living features collection of illustrative plates of each sample, extract the thermokinetic parameters of each characteristic spectrum, adopt SAS8.0 software to qualified samples (S01, S03, S05, S07, S08, S09), rotten sample (S32, S33, S34, S35) carries out discriminant analysis, set up discriminant equation, process and the results are shown in Table 5A～B.
(1) at first each sample is carried out progressively discriminant analysis, the result shows: progressively the discriminant analysis process is introduced variable G (Q successively
T), F (K
2), M (Q
H), H (T
T), when being selected in H, square (the Average Squared Canonical Correlation) of average canonical correlation coefficient increases little, so reject variable H, its dependent variable is set up discriminant coefficient and is had remarkable statistical significance.So introducing parameter G, F, M set up discriminant function;
Table 5 is based on the qualified and rotten sample discriminant analysis of Yinzhihuang Injection of staphylococcus aureus
Table 5A is discriminant analysis progressively
Stepwise?Selection?Summary
Table 5B discriminant function coefficient table
(2) according to discriminant function coefficient (seeing Table 5B), set up the linear discriminant equation:
Qualified=0.01Q
T+ 2140594.24K
2-180.71 (discriminant equations 3)
Rotten=0.02Q
T+ 6148131.71K
2-0.01Q
H+ 1277.25 (discriminant equations 4)
(3) discriminant equation is used
With each sample parameter information substitution discriminant equation 3 and 4 respectively, contrast two discriminant equation result of calculation numerical value, sample is declared in the bigger group of numerical value (seen Table 6).
The result shows: is model organism 1), adopts this discriminant equation that sample is had and examine the knowledge ability preferably with the staphylococcus aureus, and can each rotten sample (S32-S35) of complete inspection;
2) this discriminant equation is made sample (S23, S24, S25) by oneself to expired sample (S19, S20) and inventor and is produced erroneous judgement, and prompting is unsuitable for the discriminant analysis that expired sample and inventor are made by oneself sample under this method condition; So this research does not adopt staphylococcus aureus to make the model organism that sample biological characteristic collection of illustrative plates is checked by oneself as the inventor;
3) with this discriminant equation of qualified samples substitution, two groups of result differences are remarkable, and both differences are between (690.43 ± 185.06), and rotten sample difference range is between (302.49 ± 20.71), two differentiate interval zero lap, show that this method is higher to the degree of corroboration of two class samples.
Table 6 staphylococcus aureus is to the differentiation result of each sample of Yinzhihuang Injection
Brief summary and discussion
Biological heat living features collection of illustrative plates check result shows:
(1) with escherichia coli be model organism, gather biological heat kinetics collection of illustrative plates, its caloric value is higher, and each trophophase is distinguished obviously, and growth curve is stable, and the discriminant equation parameter is T
2M, T
1, T
1M, Q
H, P
2M;
(2) be model organism with the staphylococcus aureus, caloric value is lower, and the differentiation of each trophophase is not obvious, and the mass change of sample is quick on the draw, and the discriminant equation parameter is Q
T, K
2, Q
H
(3) according to above-mentioned analysis, it is model organism that escherichia coli, staphylococcus aureus are adopted in this research, respectively with (T
2M, T
1M, P
2M) and (K
2, Q
T, Q
H) be the discriminant analysis parameter, adopt discriminant equation 1,2 and discriminant equation 3,4, Yinzhihuang Injection is carried out the inspection of biological heat living features collection of illustrative plates, obtain the key message of atlas analysis, see Table 7;
Table 7 biological heat living features atlas analysis key information table
Annotate: according to Fisher discriminant function discrimination principle, with each parameter information substitution discriminant equation, sample is included in the bigger group of result.
(4) by to Yinzhihuang Injection qualified samples biological characteristic atlas analysis, formulate the threshold range of each key parameter, and early warning sees Table 8 above the untoward reaction of this threshold range sample.
Each key parameter threshold value table of table 8 biological characteristic atlas analysis
Totally 50 batches of the qualified samples of this research collection and preparation Yinzhihuang Injection and particular sample, by " requirement under 2005 editions Chinese medicine injection ruless of preparations inspections of Chinese pharmacopoeia, the security inspection item, qualified samples and particular sample are checked, to draw the essential information of sample quality.The reason that two inspections detect particular sample mostly is visible foreign matters or color change, and security inspection only can detect serious rotten sample, and detector efficiency is lower.
Each inspection method to the inspection knowledge ability of particular sample is: biological characteristic collection of illustrative plates inspection＞conventional physico-chemical examination (rules of preparations)＞conventional security inspection; The obviously part failed test sample of change takes place in the character that only can detect conventional physics and chemistry-security inspection, conventional physics and chemistry-biological characteristic collection of illustrative plates inspection then can detect whole failed test samples, can realize the multiple mass-sensitive information that causes the Yinzhihuang Injection untoward reaction is carried out sensitivity, detected fast.
Claims (9)
1. the method for a fast detecting quality of anti-hepatitis-jaundice injection is characterized in that, comprises the steps:
1) under aseptic condition, with the inoculation of exponential phase of growth in culture medium;
2) add the culture medium solution that contains described bacterial strain in ampoule bottle, sealing obtains blank solution;
3) add culture medium solution and the Yinzhihuang Injection that contains described bacterial strain in ampoule bottle, sealing obtains sample solution;
4) described blank solution and sample solution are put into 37 ℃ of homothermic micro-calorimeters respectively, the thermal power-time graph of record strain growth process;
5) thermal power-time graph of described sample solution and blank solution is compared, what the peak time of the first and second maximum heat production power was delayed in the sample solution is qualified samples, and what described peak time shifted to an earlier date is failed test sample.
2. method according to claim 1 is characterized in that, also comprises after the described step 5):
6) adopt the SAS statistical software that the parameter of the thermal power-time graph of qualified sample sets and failed test sample group is carried out pattern recognition respectively, set up discriminant equation separately, the described discriminant equation of parameter substitution of the thermal power-time graph of the yellow injection of mattress Cape jasmine to be checked is calculated the result, the result value that compares gained, according to the gained result value the yellow injection of mattress Cape jasmine to be checked is declared in the bigger group of numerical value, judged the quality of the yellow injection of mattress Cape jasmine to be checked with this.
3. method according to claim 1 and 2 is characterized in that, described bacterial strain is escherichia coli or staphylococcus aureus.
4. method according to claim 1 and 2 is characterized in that, described culture medium is a nutrient broth medium: peptone 10g, Carnis Bovis seu Bubali cream 6g, NaCl 5g are dissolved in the 1000mL distilled water pH=7.2.
5. method according to claim 1 and 2 is characterized in that, described culture medium is the L.B culture medium: peptone 10g, yeast extract 5g, NaCl 5g are dissolved in the 1000mL distilled water pH=7.2.
6. method according to claim 1 and 2 is characterized in that, the concentration of described inoculation is 0.5-1 * 10
6Cell/ml.
7. method according to claim 6 is characterized in that, the concentration of described inoculation is 0.5 * 10
6Cell/ml.
8. method according to claim 1 and 2 is characterized in that, the described culture medium solution that adds in ampoule bottle is 5-10ml, and described Yinzhihuang Injection is 100-150 μ l.
9. method according to claim 3 is characterized in that, described bacterial strain is escherichia coli.
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