CN103555810A - Medicine microbe inspection double-filter-membrane filtration method - Google Patents
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- UWBXIFCTIZXXLS-UHFFFAOYSA-L disodium;2,3,4,5-tetrachloro-6-(2,4,5,7-tetraiodo-3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 UWBXIFCTIZXXLS-UHFFFAOYSA-L 0.000 description 3
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Abstract
The invention relates to a medicine microbe inspection double-filter-membrane filtration method. Two filter membrane layers are adopted: the pore size of the first filter membrane layer can be 5-10 mu m, 10-20 mu m, 20-30 mu m or 30-50 mu m, and the first filter membrane layer is used for entrapping high-polymer matrixes, particles, fibers, medicine residues and other insoluble substances; and the pore size of the second filter membrane layer is not greater than 0.45 mu m, and the second filter membrane layer is used for entrapping microbes. The method can effectively prevent the filter membranes from blockage, is beneficial to eliminating the antibacterial activity of the test sample, and avoids damage of polluting microbes in the test sample. The medicines, which can not be effectively inspected by the existing methods, can be inspected by the method provided by the invention. Abundant test data proves that the method is convenient and feasible and has effective results.
Description
Technical field
The present invention relates to medicine Micro biological Tests field, be specifically related to a kind of two membrane filtration methods of medicine Micro biological Tests.
Background technology
Microbial contamination is the one of the main reasons that causes adverse drug events, stops contaminated medicine and comes into the market, significant for the life security that ensures patient.In medicine Micro biological Tests link, can detect the microorganism in microcosm, the method for inspection is most important.Membrane filtration technology is medicine Micro biological Tests field, for a kind of important technology of attached collection microorganism.For the medicine that has anti-microbial activity, need to adopt membrane filtration process, fully eliminate the anti-microbial activity of medicine, be beneficial to dormancy in medicine or faulted condition microorganism recovery, breed and detect.But there is certain defect in this technology at present: in some drugs test liquid, contain carbomer, derivatived cellulose, colloid silicon, calcium soap and insoluble drugs residue etc.; in process of the test, often can stop up filter membrane (in national standard, regulation filter membrane aperture is not more than 0.45 μ m), cause test to continue.
At present, for such medicine, there is no highly effective Micro biological Tests method.In the country of medicine industry prosperity, for such sample, implement production process more and control.In China, because present stage that national conditions are limit also cannot imitate, existing national standard is still usingd final detection result as the whether qualified foundation of product.But, because method exists defect, cause part to be subject to the medicine detected result of microbial contamination, particularly low-level pollution qualified, flow into clinically, cause serious threat to patient's healthy or even life security.
Summary of the invention
The object of the present invention is to provide a kind of two membrane filtration methods of medicine Micro biological Tests, adopt two-layer filtering membrane, the first layer filter membrane insoluble substances such as macromole matrix, particle, fiber and medicine residue that are used for damming, second layer filter membrane is used for holding back microorganism, can effectively prevent that filter membrane from stopping up, be beneficial to the bacteriostatic activity of eliminating trial-product, avoid contaminating microorganisms in trial-product to sustain damage.
The technical solution adopted for the present invention to solve the technical problems is: the two membrane filtration methods of medicine Micro biological Tests, comprise the following steps:
1) trial-product that step is got specified amount is routinely prepared into test liquid, test liquid is passed through to the first layer membrane filtration, hold back the insoluble substances such as macromole matrix, particle, fiber and medicine residue, test liquid continues, by second layer filter membrane, to hold back microorganism potential in test liquid;
2) with washing fluid, the first layer and second layer filter membrane are rinsed, washing fluid is identical with test liquid by filter membrane mode, washing fluid is eluted to second layer filter membrane by the microorganism that may adhere on the first layer filter membrane, the material with anti-microbial activity simultaneously adhering on the two-layer filter membrane of wash-out;
3) according to check object, the first layer and second layer filter membrane are accessed respectively in corresponding substratum, cultivate;
4), according to cultivation results, according to existing Chinese Pharmacopoeia or other countries' standard-required, carry out result judgement.
Particularly, in checkout procedure, test liquid will, by the first layer and the second layer, be total to two-layer filtering membrane.
Particularly, according to needs or the test liquid characteristic of check object, in step 2) increase separately afterwards the flushing dose to second layer filter membrane washing fluid, fully to eliminate existing of antibacterial substance on second layer filter membrane.
Particularly, described the first layer filter membrane is divided into four kinds by pore size: 5 μ m～10 μ m, 10 μ m～20 μ m, 20 μ m～30 μ m and 30 μ m～50 μ m.
Particularly, described the first layer filter membrane is a kind of in above-mentioned four kinds.
Particularly, described the first layer filter membrane can select the filter membrane stack of two or more different pore size to use.
Particularly, described second layer filter membrane requires aperture to be not more than 0.45 μ m according to national standard.
The present invention has following beneficial effect: the two membrane filtration methods of medicine Micro biological Tests of the present invention, adopt two-layer filtering membrane, according to filter membrane different pore size and material, dam respectively insoluble substance or the microorganisms such as macromole matrix, particle, fiber and medicine residue, prevent that filter membrane from stopping up, be beneficial to the bacteriostatic activity of eliminating trial-product, avoid contaminating microorganisms in trial-product to sustain damage.To current methods, can not realize the medicine of effective check, can adopt the inventive method to test, through great number tested data, prove, present method is simple and feasible, and result is effective.
Embodiment
Be below specific embodiments of the invention, technical scheme of the present invention is done to further description, but protection scope of the present invention is not limited to these embodiment.Every do not deviate from the change of the present invention design or be equal to substitute include within protection scope of the present invention.
The two membrane filtration methods of medicine Micro biological Tests, comprise the following steps:
1) trial-product that step is got specified amount is routinely prepared into test liquid, test liquid is passed through to the first layer membrane filtration, hold back the insoluble substances such as macromole matrix, particle, fiber and medicine residue, test liquid continues, by second layer filter membrane, to hold back microorganism potential in test liquid;
2) with washing fluid, the first layer and second layer filter membrane are rinsed, washing fluid is identical with test liquid by filter membrane mode, washing fluid is eluted to second layer filter membrane by the microorganism that may adhere on the first layer filter membrane, the material with anti-microbial activity simultaneously adhering on the two-layer filter membrane of wash-out;
3) according to check object, the first layer and second layer filter membrane are accessed respectively in corresponding substratum, cultivate;
4), according to cultivation results, according to existing Chinese Pharmacopoeia or other countries' standard-required, carry out result judgement.
Particularly, in checkout procedure, test liquid will, by the first layer and the second layer, be total to two-layer filtering membrane.
Particularly, according to needs or the test liquid characteristic of check object, in step 2) increase separately afterwards the flushing dose to second layer filter membrane washing fluid, fully to eliminate existing of antibacterial substance on second layer filter membrane.
Particularly, described the first layer filter membrane is divided into four kinds by pore size: 5 μ m～10 μ m, 10 μ m～20 μ m, 20 μ m～30 μ m and 30 μ m～50 μ m.
Particularly, described the first layer filter membrane is a kind of in above-mentioned four kinds.
Particularly, described the first layer filter membrane can select the filter membrane stack of two or more different pore size to use.
Particularly, described second layer filter membrane requires aperture to be not more than 0.45 μ m according to national standard.
Embodiment 1
The ganciclovir ophthalmic gel sterility test of take test is example.
1. substratum and reagent: THIOGLYCOLLIC ACID salt broth, improvement Martin substratum, nutrient broth medium, nutrient agar, Rose Bengal Sodium nutrient agar, 0.1% peptone buffer agent, Calcium Chloride Powder Anhydrous.
2. test sample: ganciclovir ophthalmic gel.
3. experimental strain: subtilis [CMCC (B) 63501], escherichia coli [CMCC (B) 44102], streptococcus aureus [CMCC (B) 26003]; Clostridium sporogenes [CMCC (B) 64941], Candida albicans [CMCC (F) 98001], aspergillus niger [CMCC (F) 98003] provide by Chinese food medicine identification research institute.
4. bacterium solution preparation: escherichia coli, streptococcus aureus, subtilis adopt nutrient broth medium, clostridium sporogenes adopts THIOGLYCOLLIC ACID salt broth, cultivates 18～24 hours for 30～35 ℃; Candida albicans adopts improvement Martin substratum, cultivates 24～48 hours for 20～25 ℃; Aspergillus niger adopts Sabouraud's dextrose agar slant medium, cultivates 5～7 days for 20～25 ℃.By the above-mentioned test organisms suspension of pharmacopeia regulation preparation, make final weaker concn all be less than 100cfumL
-1.
5. sterility test test
Chinese Pharmacopoeia requires the filter membrane aperture of sterility test application should be not more than 0.45 μ m, and carbomer gel cannot pass through this aperture filter membrane, therefore, can not adopt the method for the rear direct filtration of trial-product dilution.Some divalence particle, strongly hydrophilic ionogen etc. can make carbomer gel flocculate, therefore, can consider first carbomer gel to be precipitated, and separation, then test.Make the medium of carbomer gel precipitation can not cause damage to microorganism in trial-product, consider various influence factors, selective chlorination calcium is tested.
The preparation of test liquid: get 15 of trial-products, with the aseptic peptone buffer agent dilution of 50mL0.1%, then add 10% aseptic calcium chloride solution to dissolve, limit edged jolting, now divalent ion and carboxylate radical are in conjunction with forming insoluble salt, produce gradually a large amount of flockss, no longer increase to precipitation capacity, use the about 80mL of calcium chloride solution.
Get above-mentioned test liquid and filter, test liquid is first by the first layer filter membrane (aperture 20 μ m～30 μ m), and flocks is trapped; Then test liquid is by second layer filter membrane (aperture should be not more than 0.45 μ m), and the microorganism in test liquid is trapped.Adopt washing fluid, according to test liquid pass-through mode, two-layer filter membrane is rinsed, total flushing dose is 500ml.Respectively 100ml THIOGLYCOLLIC ACID salt broth and improvement Martin substratum are added in corresponding filter cylinder.
Result judgement: should first meet Chinese Pharmacopoeia result judgment principle.After cultivating, if (nutrient solution muddiness more than the first layer filter membrane is that particulate matter, throw out etc. cause to the nutrient solution clarification between the whole clarification of nutrient solution or the first layer, second layer filter membrane, as truly have suspicious, the test of should transferring), sentence trial-product up to specification; If nutrient solution is whole muddy, sentence trial-product against regulation.Cultivation results is in Table 1.
Table 1 Sterility Test Methods the result
Test organisms is well-grown in each culture tube, and two membrane filtration methods can effectively be eliminated the effect of fungistat in trial-product, by Chinese Pharmacopoeia version requirement in 2010, can be used for the sterility test test of ganciclovir ophthalmic gel.
Embodiment 2
Take FUFANG HUANGLIANSU PIAN limit test of microbe as example.
1. instrument BSC-1500IIA2-X biologic cleanliness safety cabinet; MJ-250I mold incubator, GHP-9270 water isolation type constant incubator; SartoriusCP225D electronic balance; YT-X301 type limit test of microbe instrument.
2. trial-product FUFANG CHUANXINLIAN PIAN.
3. bacterial classification subtilis (Bacillus subtilis) [CMCC (B) 63501]; Escherichia coli (Escherichia coli) [CMCC (B) 44102]; Streptococcus aureus (Staphylococcus aureus) [CMCC (B) 26003]; Candida albicans (Candida albicans) [CMCC (F) 98001]; Aspergillus niger (Aspergillus niger) [CMCC (F) 98003] is all from Chinese pharmaceutical biological product calibrating research institute medical science DSMZ, and above bacterial classification is all used the 3rd generation bacterial classification that goes down to posterity.
4. substratum nutrient agar, lot number 101021; Rose Bengal Sodium nutrient agar, lot number 1001122pH7.0 sodium-chlor-peptone buffer agent, lot number 110421; All be purchased from Beijing San Yao scientific and technological development company, substratum is through sensitivity test, and result is up to specification.
5. bacterium solution preparation escherichia coli, streptococcus aureus, subtilis adopt nutrient broth medium, and clostridium sporogenes adopts THIOGLYCOLLIC ACID salt broth, cultivate 18～24 hours for 30～35 ℃; Candida albicans adopts improvement Martin substratum, cultivates 24～48 hours for 20～25 ℃; Aspergillus niger adopts Sabouraud's dextrose agar slant medium, cultivates 5～7 days for 20～25 ℃.By the above-mentioned test organisms suspension of pharmacopeia regulation preparation, make final weaker concn all be less than 100cfumL
-1.
6. trial-product 10g is got in test liquid preparation, adds the aseptic sodium-chlor-peptone buffer agent of pH7.0 to 100ml, and Syrup-homogenizing instrument is fully damaged, mix trial-product, as the test liquid of 1: 10.
Bacterium, mould and yeast counting: get the test liquid 1ml of 1: 10, with the dilution of the aseptic sodium-chlor of 100mlpH7.0-peptone buffer agent.Test liquid filters through the first layer filter membrane (aperture 30 μ m～50 μ m), and a large amount of insoluble drugs residues are by the first layer membrane retention.Then, test liquid continues to cross rate by second layer filter membrane (aperture should be not more than 0.45 μ m), and in trial-product, microorganism is trapped.By said process, the first and second metafiltration films are rinsed, each flushing dose is 100ml, and total flushing dose is 200ml.Then, take off the first layer filter membrane, continue second layer filter membrane to rinse, flushing dose is 100ml.Get second layer filter membrane, bacterium faces up to be affixed on nutrient agar flat board or Rose Bengal Sodium nutrient agar flat board and cultivates.
Control bacteria examination: get the test liquid 10ml of 1: 10, by bacterium, mould and yeast counting operation method, filter test liquid, and the first and second metafiltration films are rinsed, total flushing dose is 100ml.Then, getting the first and second metafiltration films puts in 100ml cholate lactose medium and cultivates.
Method validation: carry out the proof test of method for counting colonies and Control bacteria examination method by aforesaid operations, the results are shown in Table 2 and table 3.
The checking of table 2 method of counting
Table 3 Control bacteria examination the result
At 3 times independently in parallel test, thinner control group and test group bacterium count the rate of recovery all higher than 80%, Control bacteria examination test group detects test organisms.By Chinese Pharmacopoeia version requirement in 2010, aforesaid method can be used for the limit test of microbe test of FUFANG CHUANXINLIAN PIAN.
Claims (7)
1. the two membrane filtration methods of medicine Micro biological Tests, is characterized in that, comprise the following steps:
1) trial-product that step is got specified amount is routinely prepared into test liquid, test liquid is passed through to the first layer membrane filtration, hold back the insoluble substances such as macromole matrix, particle, fiber and medicine residue, test liquid continues, by second layer filter membrane, to hold back microorganism potential in test liquid;
2) with washing fluid, the first layer and second layer filter membrane are rinsed, washing fluid is identical with test liquid by filter membrane mode, washing fluid is eluted to second layer filter membrane by the microorganism that may adhere on the first layer filter membrane, the material with anti-microbial activity simultaneously adhering on the two-layer filter membrane of wash-out;
3) according to check object, the first layer and second layer filter membrane are accessed respectively in corresponding substratum, cultivate;
4), according to cultivation results, according to existing Chinese Pharmacopoeia or other countries' standard-required, carry out result judgement.
2. the two membrane filtration methods of medicine Micro biological Tests according to claim 1, is characterized in that, test liquid will, by the first layer and the second layer, be total to two-layer filtering membrane.
3. two membrane filtration methods of medicine Micro biological Tests according to claim 1, it is characterized in that, according to needs or the test liquid characteristic of check object, in step 2) afterwards, increase separately the flushing dose to second layer filter membrane washing fluid, fully to eliminate existing of antibacterial substance on second layer filter membrane.
4. the two membrane filtration methods of medicine Micro biological Tests according to claim 1, is characterized in that, described the first layer filter membrane is divided into four kinds by pore size: 5 μ m～10 μ m, 10 μ m～20 μ m, 20 μ m～30 μ m and 30 μ m～50 μ m.
5. the two membrane filtration methods of medicine Micro biological Tests according to claim 4, is characterized in that, described the first layer filter membrane is a kind of in above-mentioned four kinds.
6. the two membrane filtration methods of medicine Micro biological Tests according to claim 4, is characterized in that, described the first layer filter membrane can select the filter membrane stack of two or more different pore size to use.
7. the two membrane filtration methods of medicine Micro biological Tests according to claim 1, is characterized in that, described second layer filter membrane requires aperture to be not more than 0.45 μ m according to national standard.
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Cited By (5)
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| CN106834413A (en) * | 2017-01-20 | 2017-06-13 | 商丘医学高等专科学校 | A kind of medicine Micro biological Tests method |
| CN107638810A (en) * | 2016-07-20 | 2018-01-30 | 中国石油天然气股份有限公司 | Filter membrane component and there is its filter |
| CN112574863A (en) * | 2019-09-29 | 2021-03-30 | 广东体必康生物科技有限公司 | Bacteria detection method based on double-layer membrane filtration |
| CN112577793A (en) * | 2019-09-29 | 2021-03-30 | 广东体必康生物科技有限公司 | Double-layer membrane filter cup and application thereof |
| CN108350408B (en) * | 2015-08-25 | 2022-12-16 | 阿威尔斯医疗公司 | Devices, systems, and methods for detecting viable microorganisms in a fluid sample |
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| CN108350408B (en) * | 2015-08-25 | 2022-12-16 | 阿威尔斯医疗公司 | Devices, systems, and methods for detecting viable microorganisms in a fluid sample |
| CN107638810A (en) * | 2016-07-20 | 2018-01-30 | 中国石油天然气股份有限公司 | Filter membrane component and there is its filter |
| CN106834413A (en) * | 2017-01-20 | 2017-06-13 | 商丘医学高等专科学校 | A kind of medicine Micro biological Tests method |
| CN112574863A (en) * | 2019-09-29 | 2021-03-30 | 广东体必康生物科技有限公司 | Bacteria detection method based on double-layer membrane filtration |
| CN112577793A (en) * | 2019-09-29 | 2021-03-30 | 广东体必康生物科技有限公司 | Double-layer membrane filter cup and application thereof |
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| CN103555810B (en) | 2016-06-15 |
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