CN106771015A - A kind of method and system of prediction/detection stability of drug products and its application - Google Patents
A kind of method and system of prediction/detection stability of drug products and its application Download PDFInfo
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Abstract
The invention discloses the method and system of prediction/detection stability of drug products, the medicine is polypeptide liquid drug, and the change of the medicine viscosity with temperature is detected using rheometer, obtains transition temperature, and stability of drug products is judged with this.System of the invention, including for detecting the rheometer of the change curve of the medicine viscosity with temperature；Data processing unit for being obtained transition temperature based on the change curve, the transition temperature is compared with the data in database, obtains the stability test result of the medicine；With the data display unit of the stability test result for showing the medicine.The method of the present invention and system, can investigate to medicine in a short time, predict/detect its stability, and result resulting after SEC HPLC detections stability is completely the same after placed three months in 25 DEG C with medicine.The method of the present invention and system are used for prescription screening, the time cost needed for can substantially reducing monoclonal antibody recipe development.
Description
Technical field
The present invention relates to biological technical field, it is related to a kind of method and system of prediction/detection stability of drug products and its answers
With, more particularly in a kind of utilization rheometer short time investigate stability of drug products method and its in monoclonal antibody prescription screening should
With.
Background technology
Nowadays, the commanding elevation that bio-pharmaceuticals industry has been contended for markets as pharmaceutical field, including monoclonal antibody, recombinant protein, epidemic disease
Seedling, blood product, polypeptide drugs and bio-extract etc..And monoclonal antibody is used as representative therein, even more numerous pharmacy corporations causes
The object of power research and development.Monoclonal antibody medicine is normally manufactured as liquid drugs injection or powder-injection, and the latter is the quilt in the case where the former is unstable
The formulation of consideration.Either which kind of, its composition is by monoclonal antibody main ingredient and some other auxiliaries with protective effect
Into, the purpose for adding auxiliary material mainly maintains the stability of preparation as much as possible.
Preparation stability refers to the ability that preparation keeps physics, chemistry, biology and microbiological property, by stability
The rule that the formulation properties of experiment investigation medicine (such as temperature, humidity, light) under difficult environmental conditions are changed over time, with
The stability trend of understanding and prediction preparation.The stability testing method of medicine has three kinds：Long term test, accelerated test and influence
Factorial experiments.In the formal study on the stability of product, generally using above two kinds, long term test will sample close to actual
Stored in the environment of storage requirement, sampled on time, according to the term of validity for investigating result formulation sample.Meanwhile, in order to be able to shorter
Steady quality situation of the time interior prediction product under normal temperature condition, so as in time by improving prescription, production technology or packaging
Condition improves drug quality stability, it will usually synchronous to carry out accelerated test.Even accelerated test, needed for it most in short-term
Between be also up to three months, it is and usual, at the initial stage of drug research, based on not known about to medicine, substantial amounts of lab scale experiment need to be done
Progressively to recognize the characteristic of medicine, in this process, needing also exist for substantial amounts of stability test, to carry out preliminary screening unstable
Prescription, this when, common accelerated test will seem very time-consuming and poorly efficient.Influence factor experiment is recipe development rank
A kind of stability prediction method that section is commonly used, required time is shorter than accelerated test, but specific required time is because of sample
And it is different, several weeks are as short as, it is long to one or two months；And prescription screening is carried out with the method, it is typically only capable to predict single factor test (such as oxygen
Change, freeze thawing, stirring) to the stability of sample, comprehensive stability can not be predicted.If various factors is investigated simultaneously, then can make
It is various into detection project and measuring samples quantity, or experimental design and the situation for analyzing complex.
At present, this area is still needed the method for exploitation short time interior prediction/detection stability of drug products, acceleration preparation screening, soon
Speed evaluates preparation.
The content of the invention
It is an object of the invention to provide one kind using rheometer short time interior prediction/detection polypeptide liquid drug stabilization
The method and system of property and its application.
A kind of the first aspect of the present invention, there is provided the method for prediction/detection stability of drug products, methods described includes following step
Suddenly：
I () provides candidate drug, the medicine is polypeptide liquid drug；
(ii) change of the medicine viscosity with temperature is detected using rheometer, transition temperature is obtained；
(iii) transition temperature obtained based on step (ii) judges stability of drug products.
In another preference, the transition temperature is the turning point correspondence that the viscosity measured using rheometer is steeply risen
Temperature, the turning point be second dervative summit, onset points or range estimation point.
In another preference, methods described also includes step (iv)：The stability of drug products result that step (iii) is obtained
SEC-HPLC testing results are contrasted before and after being placed three months in 25 DEG C of accelerated test casees with medicine, so as to judged result
Verified.
In another preference, the polypeptide liquid drug is protide liquid preparation.
In another preference, the protide liquid preparation is monoclonal antibody liquid preparation.
In another preference, the monoclonal antibody liquid preparation is included：
I () concentration is the Anti-X activity of 25mg/ml-180mg/ml；
(ii) the histidine buffer system of 10-40mM；
(iii) the antibody stabilization agent of 100-250mM；
(iv) second stabilizer of 0-15mM, and
The surfactant of (v) 0-0.1wt%.
Wherein, the pH of the preparation is 5-8, preferably 5.4-7.7.
In another preference, the histidine buffer system includes histidine and histidine monohydrochloride.
In another preference, the antibody stabilization agent is trehalose, sucrose, sorbierite, lactose, arginine or its group
Close.
In another preference, second stabilizer is methionine, thiosulfate or its combination.
In another preference, the surfactant is polysorbas20, Tween 80, PLURONICS F87 or its combination.
In another preference, the initial sweep temperature of the rheometer is 0-50 DEG C.
In another preference, the shear rate of the rheometer is 0-200 1/s.
In another preference, the heating rate of the rheometer is 1-20 DEG C/min.
In another preference, the gap between the rheometer fixture and sample plate of the rheometer is 100-500 μm.
The second aspect of the present invention, there is provided a kind of method of prediction described in implementation first aspect/detection stability of drug products
System, including：
A () rheometer, the rheometer is used to detect the change curve of the medicine viscosity with temperature, the medicine is many
Peptides liquid drug；
B () data processing unit, the data processing unit is used to obtain transition temperature based on the change curve, by institute
State transition temperature to compare with the data in database, obtain the stability test result of the medicine；
(c) data display unit, the stability test result for showing the medicine.
In another preference, the initial sweep temperature of the rheometer is 0-50 DEG C.
In another preference, the shear rate of the rheometer is 0-200 1/s.
In another preference, the heating rate of the rheometer is 1-20 DEG C/min.
In another preference, the gap between the rheometer fixture and sample plate of the rheometer is 100-500 μm.
In another preference, the polypeptide liquid drug is protide liquid preparation.
In another preference, the protide liquid preparation is monoclonal antibody liquid preparation.
In another preference, the monoclonal antibody liquid preparation is included：
I () concentration is the Anti-X activity of 25mg/ml-180mg/ml；
(ii) the histidine buffer system of 10-40mM；
(iii) the antibody stabilization agent of 100-250mM；
(iv) second stabilizer of 0-15mM, and
The surfactant of (v) 0-0.1wt%.
Wherein, the pH of the preparation is 5-8, preferably 5.4-7.7.
In another preference, the histidine buffer system includes histidine and histidine monohydrochloride.
In another preference, the antibody stabilization agent is trehalose, sucrose, sorbierite, lactose, arginine or its group
Close.
In another preference, second stabilizer is methionine, thiosulfate or its combination.
In another preference, the surfactant is polysorbas20, Tween 80, PLURONICS F87 or its combination.
The third aspect of the present invention, there is provided the systematic difference described in first aspect, for screening polypeptide liquid drug.
In another preference, the polypeptide liquid drug is protide liquid preparation.
In another preference, the protide liquid preparation is monoclonal antibody liquid preparation.
In another preference, the monoclonal antibody liquid preparation is included：
I () concentration is the Anti-X activity of 25mg/ml-180mg/ml；
(ii) the histidine buffer system of 10-40mM；
(iii) the antibody stabilization agent of 100-250mM；
(iv) second stabilizer of 0-15mM, and
The surfactant of (v) 0-0.1wt%.
Wherein, the pH of the preparation is 5-8, preferably 5.4-7.7.
In another preference, the antibody stabilization agent is trehalose, sucrose, sorbierite, lactose, arginine or its group
Close.
In another preference, the histidine buffer system includes histidine and histidine monohydrochloride.
In another preference, second stabilizer is methionine, thiosulfate or its combination.
In another preference, the surfactant is polysorbas20, Tween 80, PLURONICS F87 or its combination.
The method for investigating preparation stability in a short time that the present invention is provided, using the temperature scanning function of rheometer,
Attempt to find an obvious turning point in the viscosity with temperature scanning curve of sample, the judgement for being used as sample stability refers to
Mark, and filtered out in a short time with this and stablize preferable sample.And the result screened using the method, exist with medicine
Result resulting after SEC-HPLC detections stability is completely the same after being placed three months in 25 DEG C.Rheometer is used in the present invention
Stability of drug products can be in a short time investigated, for prescription screening, preparation screening can be accelerated, Fast Evaluation preparation, significantly
Time cost needed for reducing recipe development.
The features described above that the present invention is mentioned, or the feature that Examples below is mentioned can be in any combination.This case specification institute
The all features for disclosing can be used in combination with any combinations thing form, and each feature disclosed in specification can be by any offer
The alternative characteristics substitution of identical, impartial or similar purpose.Therefore except there is special instruction, disclosed feature is only impartial or phase
Like the general example of feature.As space is limited, no longer tire out one by one herein and state.
Brief description of the drawings
Fig. 1 is to detect the viscosity with temperature variation diagram of sample 1 using rheometer.
Specific embodiment
Present inventor develops a kind of utilization and is examined in the rheometer short time first by extensively and in depth studying
The method for examining stability of drug products.An obvious turning point is found in the viscosity with temperature scanning curve of sample, as sample
The Judging index of stability, and filter out the preferable sample of stability in a short time with this.And filtered out using the method
The result come, result resulting after SEC-HPLC detection stability is complete after being proved to be placed three months in 25 DEG C with medicine
Unanimously.Stability of drug products can in a short time be investigated using rheometer in the present invention, for prescription screening, list is greatly reduced
Time cost needed for anti-recipe development, on this basis, completes the present invention.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip
Part such as Sambrook et al., molecular cloning：Laboratory manual (New York:Cold Spring Harbor Laboratory
Press, 1989) described in condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and
Number is percentage by weight and parts by weight.
Unless otherwise defined, all specialties used in text and scientific words and meaning familiar to one skilled in the art institute
Justice is identical.Additionally, during any method similar to described content or impartial and material all can be applied to the inventive method.Wen Zhong
Described preferable implementation only presents a demonstration with material and is used.
Universal method
Rheometer is detected
The stability of sample is analyzed using rheometer, viscosity with temperature change scanning is carried out, the turnover for steeply rising is found
Point (onset points), every group of sample detects average afterwards twice that respectively the average value as characterizes sample stabilization in the present invention
The index of property.
The function of changing into the scanning viscosity with temperature of rheometer in experiment, and series of parameters is set, mainly include：
I () initial sweep temperature is 0-50 DEG C；
(ii) shear rate is 0-200 1/s；
(iii) heating rate is 1-20 DEG C/min；
(iv) gap between rheometer fixture and sample plate is 100-500 μm.
Embodiment 1
Component and content formulated as shown in table 1.
Fig. 1 is the rheometer scanning curve of sample 1, wherein, use stream for typical by what small triangle was coupled together
Become the curve of the viscosity with temperature change of instrument scanning, be denoted as curve 1；By blockage couple together for the second order of curve 1 is led
Number curve, is denoted as curve 2；When Article 3 is the Onset values of system formation curve 1, the back-up curve for automatically generating.
In transition temperature when taking, respectively can using the range estimation turnover value of curve 1, the vertex value of curve 2 and through point
The Onset values that system is automatically generated after analysis.Tried one's best in order to reduce human error, during value selection after both.Show value is in figure
The Onset values for detecting sample 1 second, the Onset values with first time detection sample are averaged, and obtain the turnover temperature of sample 1
Degree.
Table 1
| Anti-X activity | 132.1mg/ml |
| Histidine salt | 20mM |
| Trehalose | 80mg/ml |
| Polysorbas20 | 0.06% |
| Methionine | 10 |
| pH | 6.7 |
| Transition temperature 1 | 72.083 |
| Transition temperature 2 (such as Fig. 1) | 72.766 |
| Transition temperature average value | 72.424 |
Embodiment 2
Component and content formulated as shown in table 2.
Table 2
| Anti-X activity | 129.2mg/ml |
| Histidine salt | 20mM |
| Trehalose | 80mg/ml |
| Polysorbas20 | 0.06% |
| Methionine | 10 |
| pH | 5.5 |
| Transition temperature 1 | 68.834 |
| Transition temperature 2 | 68.596 |
| Transition temperature average value | 68.715 |
Embodiment 3
Component and content formulated as shown in table 3.
Table 3
| Anti-X activity | 142.4mg/ml |
| Histidine salt | 20mM |
| Trehalose | 80mg/ml |
| Polysorbas20 | 0.06% |
| Methionine | 0 |
| pH | 5.4 |
| Transition temperature 1 | 69.847 |
| Transition temperature 2 | 66.822 |
| Transition temperature average value | 68.334 |
Embodiment 4
Component and content formulated as shown in table 4.
Table 4
Embodiment 5
Component and content formulated as shown in table 5.
Table 5
| Anti-X activity | 132.6mg/ml |
| Histidine salt | 20mM |
| Trehalose | 80mg/ml |
| Polysorbas20 | 0.06% |
| Methionine | 0 |
| pH | 6.2 |
| Transition temperature 1 | 70.638 |
| Transition temperature 2 | 72.609 |
| Transition temperature average value | 71.623 |
Embodiment 6
Component and content formulated as shown in table 6.
Table 6
Embodiment 7
Component and content formulated as shown in table 7.
Table 7
| Anti-X activity | 135.4mg/ml |
| Histidine salt | 20mM |
| Trehalose | 80mg/ml |
| Polysorbas20 | 0.06% |
| Methionine | 0 |
| pH | 6.1 |
| Transition temperature 1 | 70.085 |
| Transition temperature 2 | 68.007 |
| Transition temperature average value | 69.046 |
Embodiment 8
Component and content formulated as shown in table 8.
Table 8
| Anti-X activity | 145.5mg/ml |
| Histidine salt | 20mM |
| Trehalose | 80mg/ml |
| Polysorbas20 | 0.06% |
| Methionine | 10 |
| pH | 6.2 |
| Transition temperature 1 | 69.335 |
| Transition temperature 2 | 69.336 |
| Transition temperature average value | 69.335 |
Comparative example
Accelerated stability test
8 groups of samples of embodiment 1-8 are placed in 25 DEG C of accelerated stability test case, each sampling one is entered after three months
Row SEC-HPLC detects that detection method is as follows：
1. chromatographic condition
Chromatographic column：TSKgel G3000SWXL
Flow velocity：0.5ml/min
Wavelength：280nm
Column temperature：25℃
Mobile phase：200mmol/L NACL+25mmol/L phosphate, pH6.0
2. blank：Mobile phase
3. process：Take sample and be directly injected into chromatograph, chromatogram is recorded, by area normalization method result of calculation.
SEC results during the T=0 for measuring and the SEC results after being placed 3 months in 25 DEG C.
Table 9 shows the transition temperature and use SEC-HPLC that eight groups of sample rheometers measure
9 eight groups of sample rheometer testing results of table and SEC-HPLC testing results compare
The transition temperature numerical value measured by rheometer from table 9 can be seen that several groups of stabilizations of formulation samples prepared
Property is variant, wherein the 5th group of sample transition temperature highest, stability is best.
From the point of view of SEC purity results when T=0, the poorer sample of stability, purity (such as 2,3 groups, several groups of samples higher
The purity difference of product is mainly relevant with preparation prescription), but from from the perspective of stability, the time of 3 months, stability difference
Sample purity have dropped 6% or so, and the sample (5 groups) of good stability only have dropped 0.08%.
Knowable to testing result, scanned with rheometer come the stability that is characterized of transition temperature, with sample at 25 DEG C
The SEC stability results that middle storage is detected before and after 3 months are completely the same：Transition temperature is higher, and sample stability is better, and sample is pure
Degree fall off rate is slower.This explanation, rheometer can in a short time investigate polypeptide, particularly egg as one kind completely
In vain, the more particularly instrument of the stability of monoclonal antibody.Typically for same compounding medicine into liquid preparation, transition temperature gets over
Height, stability is better.
Sample is detected using rheometer, from start to warm up time of the scanning to needed for the end of scan usually a few minutes to
1.5 hours.Such as, according to 1-20 DEG C of heating rate scope/min of the invention, 70 DEG C or so of transition temperature, if past 10 DEG C of pusher
(i.e. 80 DEG C) are used as final temperature, then each sample is 4-80 from time of the scanning to needed for the end of scan is started to warm up
Minute.Specifically, heating rate is set to 10 DEG C/min, and each sample obtains collection of illustrative plates by then only needing 8 minutes.Along with operating
The time of cooling and loading, each sample at most 12 minutes in journey.It can be seen that, polypeptide can in a short time be investigated using rheometer
The stability of class, particularly albumen, more particularly monoclonal antibody.
The all documents referred in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after above-mentioned instruction content of the invention has been read, those skilled in the art can
Made various changes or modifications with to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. the method for a kind of prediction/detection stability of drug products, it is characterised in that the described method comprises the following steps：
I () provides candidate drug, the medicine is polypeptide liquid drug；
(ii) change of the medicine viscosity with temperature is detected using rheometer, transition temperature is obtained；
(iii) transition temperature obtained based on step (ii) judges stability of drug products.
2. the method for claim 1, it is characterised in that methods described also includes step (iv)：Step (iii) is obtained
Stability of drug products result and medicine placed three months in 25 DEG C of accelerated test casees before and after SEC-HPLC testing results carry out it is right
Than so as to be verified to judged result.
3. the method for claim 1, it is characterised in that the polypeptide liquid drug is protide liquid preparation.
4. the method as described in claim 1 or 3, it is characterised in that the protide liquid preparation is monoclonal antibody liquid preparation.
5. the method for claim 1, it is characterised in that the initial sweep temperature of the rheometer is 0-50 DEG C；And/or
The shear rate of the rheometer is 0-200l/s；And/or
The heating rate of the rheometer is 1-20 DEG C/min；And/or
Gap between the rheometer fixture and sample plate of the rheometer is 100-500 μm.
6. a kind of system for predicting/detecting the method for stability of drug products described in implementation claim 1, it is characterised in that the system
System includes：
A () rheometer, the rheometer is used to detect the change curve of the medicine viscosity with temperature, the medicine is polypeptide
Liquid drug；
B () data processing unit, the data processing unit is used to obtain transition temperature based on the change curve, described will turn
Pack temperature is compared with the data in database, obtains the stability test result of the medicine；
(c) data display unit, the stability test result for showing the medicine.
7. system as claimed in claim 6, it is characterised in that the initial sweep temperature of the rheometer is 0-50 DEG C；And/or
The shear rate of the rheometer is 0-200l/s；And/or
The heating rate of the rheometer is 1-20 DEG C/min；And/or
Gap between the rheometer fixture and sample plate of the rheometer is 100-500 μm.
8. system as claimed in claim 5, it is characterised in that the polypeptide liquid drug is protide liquid preparation, compared with
Goodly, the protide liquid preparation is monoclonal antibody liquid preparation.
9. the application of the system as claimed in claim 1, it is characterised in that for screening polypeptide liquid drug.
10. application as claimed in claim 9, it is characterised in that the polypeptide liquid drug is protide liquid preparation, compared with
Goodly, the protide liquid preparation is monoclonal antibody liquid preparation.
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| CN107255646A (en) * | 2017-07-11 | 2017-10-17 | 华南理工大学 | A kind of method of fast quantification Predicting Stability of Drugs |
| CN108761004A (en) * | 2018-05-21 | 2018-11-06 | 北京工商大学 | A kind of evaluation method of the rice viscosity based on frictional index |
| CN109694898A (en) * | 2019-02-20 | 2019-04-30 | 扬州倍加洁日化有限公司 | A kind of measuring method of wet tissue keeping life |
| CN113205875A (en) * | 2021-05-20 | 2021-08-03 | 中科彭州智慧产业创新中心有限公司 | Method and device for promoting traditional Chinese medicine inheritance by applying modern technology |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107255646A (en) * | 2017-07-11 | 2017-10-17 | 华南理工大学 | A kind of method of fast quantification Predicting Stability of Drugs |
| CN108761004A (en) * | 2018-05-21 | 2018-11-06 | 北京工商大学 | A kind of evaluation method of the rice viscosity based on frictional index |
| CN108761004B (en) * | 2018-05-21 | 2023-08-11 | 北京工商大学 | Evaluation method of rice viscosity based on friction index |
| CN109694898A (en) * | 2019-02-20 | 2019-04-30 | 扬州倍加洁日化有限公司 | A kind of measuring method of wet tissue keeping life |
| CN109694898B (en) * | 2019-02-20 | 2022-06-10 | 扬州倍加洁日化有限公司 | Method for measuring validity period of wet tissue product |
| CN113205875A (en) * | 2021-05-20 | 2021-08-03 | 中科彭州智慧产业创新中心有限公司 | Method and device for promoting traditional Chinese medicine inheritance by applying modern technology |
| CN113205875B (en) * | 2021-05-20 | 2023-11-10 | 中科彭州智慧产业创新中心有限公司 | Intelligent medicinal material management method and device |
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