CN102166216A - Lactulose oral solution and quality control method thereof - Google Patents
Lactulose oral solution and quality control method thereof Download PDFInfo
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Abstract
The invention discloses a lactulose oral solution. Every 1000 ml solution is prepared by the following ingredients: 667 g lactulose, 0.004 g sunset yellow, 0.0001 g banana essence, 1 g sodium benzoate and the balance of water. The formula is simple without producing new related substances. The invention also discloses a quality control method of the lactulose oral solution, which adopts a commonly used HPLC-differential refraction detector method for determining, and the method is strong in specificity, high in sensitivity, good in accuracy, and simple, convenient and fast.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of medicine that is used for the treatment of chronic functional constipation and falls blood ammonia, be specifically related to a kind of lactulose oral administration solution and method of quality control thereof.
Background technology
Lactulose has another name called isomerized lactose, and is soluble in water.Its molecular formula is C
11H
22O
11, molecular weight is 342.30.
Lactulose is a kind of disaccharidase, and the glucose in the lactose molecule is replaced by fructose, is lactulose, and its sugariness is a little more than lactose.There is not lactulose in occurring in nature, and it belongs to the disaccharidase of synthetic, but all contains a spot of lactulose in milk that boils and condensed milk.
Lactulose oral administration solution (Lactulose Oral Solution) is the clear and bright thick liquid of pale brown color.Main component is a lactulose, and related substance comprises lactose, Tagatose, table lactose, galactose, fructose.Wherein the related substance in the lactulose oral administration solution is bigger to its Safety Effect, such as: the lactulose oral administration solution can not anti-receptor should not be taken galactose the careful usefulness of diabetics, and the person should be forbidden can not to tolerate the lactose.Lactulose oral administration solution its prescription and technology aborning should be avoided the increase of related substance as far as possible, and should set up the drug quality that the strict quality method guarantees the lactulose oral administration solution.
The quality standard of 2010 editions two middle lactulose oral administration solutions of Chinese Pharmacopoeia, related substance inspection item is: the need testing solution of getting under the assay item is a need testing solution; It is an amount of to get in addition lactulose, fructose, galactose, lactose reference substance respectively, accurate claim fixed, add the dissolving of acetonitrile-water (1: 1) solution and quantitatively dilution make the mixed solution that contains 3.2mg, 0.4mg, 4.8mg, 4mg among every 1ml, product solution in contrast.According to the chromatographic condition under the assay item, precision is measured reference substance solution and each 20 μ l of need testing solution, injects chromatograph of liquid respectively, the record chromatogram.In the chromatogram of need testing solution,, with calculated by peak area, contain fructose, galactose and lactose and must not cross 1.0%, 12.0% and 9.0% of lactulose labelled amount respectively by external standard method if any the chromatographic peak of fructose, galactose, lactose; With respect to about 0.9 place of fructose peak retention time if any chromatographic peak (Tagatose) or with respect to about 0.9 place of lactulose peak retention time if any chromatographic peak (according to a lactose), with lactulose calculated by peak area in the reference substance solution, must not cross 3.0% and 7.0% of lactulose labelled amount by external standard method respectively.
Wherein assay item chromatographic condition is: with aminopropyl silane group silica gel is filler; With acetonitrile-phosphate buffer (get sodium dihydrogen phosphate 115g, be dissolved in the 1000ml water) (84: 16) is mobile phase; Measure with differential refraction detector, column temperature and detection cell temperature are 40 ℃, and flow velocity is per minute 1.5ml.It is an amount of to get lactulose, fructose, galactose, lactose reference substance respectively, add the dissolving of acetonitrile-water (1: 1) solution and make the mixed solution that contains 40mg, 0.4mg, 4.8mg, 4mg among every 1ml, measure 20 μ l, inject chromatograph of liquid, the peak sequence of each component is followed successively by fructose, galactose, lactulose and lactose, the signal to noise ratio of fructose chromatographic peak should be greater than 10, and the peak-to-peak separating degree of lactulose peak and lactose should be greater than 2.0.
This related substance inspection method can not be carried out detection by quantitative to the related substance of all lactulose, has potential safety hazard, and lactulose peak and the peak-to-peak separating degree of lactose be difficult to reach 2.0, and condition is relatively harsher.
Chinese Journal of Pharmaceuticals, 2010,41 (6), author: Shao Hong, exercise question: the high performance anion exchange chromatography method of lactulose and related substance is measured in the lactulose oral administration solution, a kind of inspection method of lactulose oral administration solution related substance is disclosed in one literary composition, 5 kinds of related substances that this method adopts high performance anion exchange chromatography (HPAEC)-integration ampere detector method to measure the lactulose in the lactulose oral administration solution simultaneously and may exist.This method specificity is strong, highly sensitive, and is easy to be quick.But this method adopts anion-exchange chromatography, owing to anion-exchange chromatography is of little use, and the price height, be not suitable for applying.
Summary of the invention
The invention provides a kind of lactulose oral administration solution, in every 1000ml solution, be grouped into by following one-tenth: lactulose 667g, sunset yellow 0.004g, flavoring banana essence 0.0001g, sodium benzoate 1g, surplus is a water.
This prescription is simple, and sample stability and mouthfeel are good, can not produce new related substance.
The present invention also provides a kind of preparation method of lactulose oral administration solution, may further comprise the steps:
(1) weighing: take by weighing lactulose solution (being converted to lactulose solution according to the lactulose of recipe quantity feeds intake), sunset yellow, flavoring banana essence, sodium benzoate;
(2) preparation: with sunset yellow, after flavoring banana essence, sodium benzoate dissolve fully with suitable quantity of water, add lactulose solution and mix, add suitable quantity of water again and be settled to scale, after stirring, sampling detects the intermediate quality;
(3) fill: after the intermediate detection is qualified, carry out fill (60ml/ bottle), packing.
This technology is simple, and energy consumption is low, has reduced production cost, the lactulose oral administration solution good stability of preparing, the basic no change of related substance.
The present invention further provides a kind of method of quality control of lactulose oral administration solution, include related substance quantitative check and assay, its concrete grammar is as follows:
Assay is measured according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D);
Chromatographic condition and system suitability test ZORBAX Carbohydrate Analysis Columns (carbohydrate analysis column), with 0.01mol/L disodium phosphate soln-acetonitrile (20: 80) is mobile phase, column temperature and differential refraction detector temperature are 40 ℃, number of theoretical plate calculates by the lactulose peak should be not less than 3000, and the lactulose peak should be respectively greater than 1.5 and 2.0 with table lactose and the peak-to-peak separating degree of lactose;
Algoscopy is measured this product 3ml (being equivalent to lactulose 2g approximately) with inner capacities pipet precision, put in the 50ml measuring bottle, with an amount of acetonitrile-water (1: 1) flushing inner capacities pipet, washing liquid is incorporated in the measuring bottle, add acetonitrile-water (1: 1) and be diluted to scale, shake up, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram; It is an amount of that in addition precision takes by weighing Tagatose, fructose, galactose, table lactose, lactulose, lactose reference substance, dissolve and make the solution that contains 1.6mg, 0.4mg, 6.4mg, 3.2mg, 40mg and 4.8mg among every 1ml respectively approximately with acetonitrile-water (1: 1), shake up, measure with method, press external standard method with calculated by peak area, promptly;
Related substance is calculated by the result who records under the assay item, the peak area of known each impurity and the peak area ratio of corresponding reference substance solution are, content with respect to lactulose, contain Tagatose and must not cross 3%, contain fructose and must not cross 1%, contain galactose and must not cross 10%, contain the table lactose and must not cross 5%, contain lactose and must not cross 7%.
This method adopts HPLC-differential refraction detector method commonly used to measure, and this method specificity is strong, highly sensitive, accuracy is good, and easy to be quick, all impurity of lactulose can both detect by qualitative, quantitative, the Control of Impurities limit obviously improves than pharmacopeia in 2010, can control drug quality effectively accurately.
Description of drawings
Fig. 1: the application's related substance HPLC collection of illustrative plates
Fig. 2: the analysis of results table of the application's related substance HPLC collection of illustrative plates
Fig. 3: 2010 editions official method related substance HPLC collection of illustrative plates
Fig. 4: 2010 editions official method related substance HPLC collection of illustrative plates analysis of results table
The specific embodiment
The present invention is further illustrated below in conjunction with specific embodiment, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.Adjuvant in following examples can be replaced with pharmaceutically acceptable similar adjuvant, perhaps reduces, increases.
1, prescription:
Lactulose solution (in lactulose) 667g
Sunset yellow 0.004g
Flavoring banana essence 0.0001g
Sodium benzoate 1g
Add water and be settled to 1000ml
2, processing step:
(1) weighing: take by weighing lactulose solution (being converted to lactulose solution according to the lactulose of recipe quantity feeds intake), sunset yellow, flavoring banana essence, sodium benzoate;
(2) preparation: with sunset yellow, after flavoring banana essence, sodium benzoate dissolve fully with suitable quantity of water, add lactulose solution and mix, add suitable quantity of water again and be settled to scale, after stirring, sampling detects the intermediate quality;
(3) fill: after the intermediate detection is qualified, carry out fill (60ml/ bottle), packing.Carry out quality examination according to following quality standard
This product is the aqueous solution of lactulose.Contain lactulose (C
12H
22O
11) should be 90.0%～110.0% of labelled amount.
[character] this product is yellow to pale brown color clarification thick liquid.
[discriminating]
(1) gets this product 5% aqueous solution, slowly splash among the warm alkaline cupric tartrate test solution 5ml, promptly generate the red precipitation of Red copper oxide.
(2) in the chromatogram that writes down under the assay item, the retention time of need testing solution main peak should be consistent with the retention time of lactulose reference substance solution main peak.
[inspection]
The relative density of relative density this product (two appendix VI of Chinese Pharmacopoeia version in 2005 A) should be 1.260～1.390.
PH value should be 3.0～7.0.After contacting 15 minutes, measure (two appendix VI of Chinese Pharmacopoeia version in 2005 H) with electrode.
Related substance is calculated by the result who records under the assay item, the peak area of known each impurity and the peak area ratio of corresponding reference substance solution are, content with respect to lactulose, contain Tagatose and must not cross 3%, contain fructose and must not cross 1%, contain galactose and must not cross 10%, contain the table lactose and must not cross 5%, contain lactose and must not cross 7%.
Residue on ignition is got this product 1.0g, checks in accordance with the law and leaves over (two appendix VIII of Chinese Pharmacopoeia version in 2005 N) residue and must not cross 0.3%.
Heavy metal is got the residue of leaving under the residue on ignition item, checks to contain (two appendix VIII of Chinese Pharmacopoeia version in 2005 H, first method) heavy metal and must not cross 20/1000000ths in accordance with the law.
Other should meet every regulation relevant under the oral solution item (two appendix I of Chinese Pharmacopoeia version in 2005 O) and must not detect Salmonella.
[assay] measured according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test ZORBAX Carbohydrate Analysis Columns (carbohydrate analysis column), with 0.01mol/L disodium phosphate soln-acetonitrile (20: 80) is mobile phase, column temperature and differential refraction detector temperature are 40 ℃, number of theoretical plate calculates by the lactulose peak should be not less than 3000, and the lactulose peak should be respectively greater than 2.0 and 2.5 with table lactose and the peak-to-peak separating degree of lactose.
Algoscopy is measured this product 3ml (being equivalent to lactulose 2g approximately) with inner capacities pipet precision, put in the 50ml measuring bottle, with an amount of acetonitrile-water (1: 1) flushing inner capacities pipet, washing liquid is incorporated in the measuring bottle, add acetonitrile-water (1: 1) and be diluted to scale, shake up, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram; It is an amount of that in addition precision takes by weighing Tagatose, fructose, galactose, table lactose, lactulose, lactose reference substance, dissolve and make the solution that contains 1.6mg, 0.4mg, 6.4mg, 3.2mg, 40mg and 4.8mg among every 1ml respectively approximately with acetonitrile-water (1: 1), shake up, measure with method.Press external standard method with calculated by peak area, promptly.
Blood ammonia and caccagogue fall in [classification]
[specification] 60ml:40.02g
[storage] shading, sealing is preserved
[effect duration] 24 months
Experimental condition: place 40 ± 2 ℃ of temperature, in the medicine stability experimental box of humidity 75 ± 5%, projects such as the character of investigation this product, relative density, pH value, related substance, content.Result of the test is summarized as follows:
Illustrate: on behalf of Tagatose, G-T, TG-T represent fructose, BA-T to represent galactose, BR-T representative table lactose, R-T to represent lactose.
Chromatographic condition determines in the quality standard
Instrument: Tianjin, island LC-10A high performance liquid chromatograph
Chromatographic column: Agilent ZORBAX Carbohydrate Analysis Columns, 250*4.6mm, 5um.
Detector: differential refraction detector
Column temperature: 40 ℃
Mobile phase: 0.01mol/L disodium phosphate soln-acetonitrile (20: 80)
Diluent: 50% acetonitrile solution
The specificity test
The interference of retarder thinner and adjuvant to measuring
This product is that lactulose solution is prepared from through oral administration solution preparation technology, in whole process engineering, add adjuvants such as sunset yellow, flavoring banana essence, sodium benzoate, retarder thinner, blank adjuvant, reference substance solution, material solution and sample solution are investigated by high performance liquid chromatography.Result of the test sees the following form
Adjuvant and related impurities chromatographic retention in the lactulose oral administration solution
| Items | Diluent | Blank adjuvant | Tagatose | Fructose | Galactose | The table lactose | Lactulose | Lactose |
| Retention time min | 3.7 | - | 9.9 | 11.1 | 14.5 | 24.9 | 28.1 | 31.0 |
The result shows that adjuvant does not disturb the mensuration of the content and the related substance of this product, and the separating degree of principal agent lactulose and adjacent impurity (table lactose, Tagatose) is good.Destructive testing
Slight degraded takes place in the blank adjuvant impurity peaks of not degrading out, sample solution under high light, high temperature, alkali, oxidizing condition, except that existing impurity slightly increases, produce the small amount of impurities peak, can reach with main peak and have impurity and separate well; Under acid condition, the main peak degraded is comparatively serious, except that existing impurity obviously increases, produces the small amount of impurities peak, can separate well with main peak and existing impurity, illustrates that this chromatographic system can be used in the related substance inspection of this product.The system suitability test
After the specificity off-test, six kinds of reference substance mixed solutions, sample solution have been carried out the chromatographic isolation test, result of the test sees the following form
The system suitability result of the test
Conclusion: as can be seen from the test results, can access good separation between the following six kinds of reference substances of this chromatographic condition, the separating degree between main constituent lactulose and adjacent impurity peaks table lactose, the lactose reaches 1.8 and 2.5.Replica test
Get same batch sample, prepare six parts of need testing solutions and measure, result of calculation sees the following form
The replica test result
| Measure number of |
1 | 2 | 3 | 4 | 5 | 6 | On average | RSD％ |
| Tagatose (%) | 1.59 | 1.60 | 1.60 | 1.59 | 1.58 | 1.57 | 1.59 | 0.72 |
| Fructose (%) | 0.073 | 0.071 | 0.071 | 0.069 | 0.070 | 0.070 | 0.071 | 1.80 |
| Galactose (%) | 5.77 | 5.67 | 5.74 | 5.74 | 5.71 | 5.74 | 5.73 | 0.61 |
| Table lactose (%) | 1.92 | 1.98 | 1.99 | 1.96 | 1.92 | 1.94 | 1.95 | 1.57 |
| Lactulose (%) | 99.52 | 99.52 | 99.35 | 99.81 | 100.38 | 100.33 | 99.82 | 0.44 |
| Lactose (%) | 3.21 | 3.28 | 3.22 | 3.26 | 3.21 | 3.19 | 3.23 | 1.03 |
The result shows: this method good reproducibility.
Middle precision
Measure same batch of sample drug content and its related substances by two analysis personnel.
Middle Precision test result
The result shows: the result that two analysts measure same batch sample principal agent and its related substances is approaching, and the middle precision of illustration method is good.
Linear relationship is investigated
Respectively precision take by weighing Tagatose, fructose, galactose, table lactose, lactulose, lactose reference substance an amount of, add retarder thinner and make certain density solution, sample detection.
The linear equation A=162396.14C+1655.5674 of Tagatose
The linear equation A=153710.69C+181.33256 of fructose
The linear equation A=169600.76C-14050.816 of galactose
The linear equation A=150500.56C-3169.1053 of table lactose
The linear equation A=181527.87C-41929.201 of lactulose
The linear equation A=155363.64C-17495.863 of lactose
Conclusion: by above experimental data as can be known, Tagatose sample introduction concentration is good linear relationship with peak area between 0.16466mg/ml～1.6466mg/ml; Fructose sample introduction concentration is good linear relationship with peak area between 0.01708mg/ml～0.4271mg/ml; Galactose sample introduction concentration is good linear relationship with peak area between 0.648mg/ml～6.480mg/ml; Table lactose sample introduction concentration is good linear relationship with peak area between 0.3269mg/ml～3.2690mg/ml; Lactulose sample introduction concentration is good linear relationship with peak area between 4.1271mg/ml～41.2712mg/ml; Lactose sample introduction concentration is good linear relationship with peak area between 0.992mg/ml～4.960mg/ml.The mensuration concentration of each component of this product all can satisfy the regulation of the above range of linearity.Quantitative limit and detectability
The result of detectability and quantitative limit
Conclusion: six kinds of sugar (differential refraction detector) under this testing conditions all can satisfy the sensitivity requirement of mensuration.
Accuracy
Lactulose recovery test result
Fructose recovery test result
Tagatose recovery test result
Table lactose recovery test result
Galactose recovery test result
Lactose recovery test result
The stability test of reference substance solution
Get the reference substance solution of new system, place under room temperature, sample introduction is measured respectively at 0,2,4,6, during 8h, the record chromatogram, and result of the test sees the following form
The stability test of reference substance solution
| Time (h) | 0 | 2 | 4 | 6 | 8 | On average | RSD％ |
| Tagatose (A) | 266102 | 263945 | 266676 | 268552 | 271046 | 267264 | 1.00 |
| Fructose (A) | 88053 | 88805 | 88315 | 88620 | 88555 | 88470 | 0.33 |
| Galactose (A) | 1152252 | 1150523 | 1161859 | 1151049 | 1167173 | 1156571 | 0.65 |
| Table lactose (A) | 365485 | 365477 | 368729 | 369242 | 371349 | 368056 | 0.69 |
| Lactulose (A) | 6901363 | 6931091 | 7031967 | 6931638 | 6966150 | 6952442 | 0.72 |
| Lactose (A) | 1039851 | 1040147 | 1025216 | 1036343 | 1003418 | 1028995 | 1.51 |
Conclusion: reference substance solution is stable in 8 hours.
The stability test of sample solution
It is an amount of to get the lactulose oral administration solution, makes need testing solution by aforementioned preparation method, place under the room temperature, respectively 0,2,4,6,8h hour measures each peak area, investigates sample solution stability.Result of the test sees the following form
The stability test of sample solution
| Time (h) | 0 | 2 | 4 | 6 | 8 | On average | RSD％ |
| Tagatose (A) | 98218 | 99045 | 99864 | 99879 | 99315 | 99264 | 0.69 |
| Fructose (A) | 6674 | 6514 | 6676 | 6671 | 6650 | 6637 | 1.05 |
| Galactose (A) | 348269 | 343972 | 345662 | 347069 | 346236 | 346242 | 0.46 |
| Table lactose (A) | 115285 | 115260 | 115135 | 114392 | 115669 | 115148 | 0.41 |
| Lactulose (A) | 6476588 | 6427732 | 6477129 | 6472683 | 6488955 | 6462617 | 0.38 |
| Lactose (A) | 318768 | 315165 | 315102 | 315276 | 317874 | 316437 | 0.55 |
Conclusion: need testing solution is stable in 8 hours.
Serviceability test
Result of the test show the organic facies ratio 75%～85%, in 0.9ml/min～1.1ml/min scope, main peak separates well with adjacent impurity column temperature at 35 ℃～45 ℃, flow velocity, the main peak post is imitated high, good tolerance.
This Control of Impurities method and 2010 editions official method contrast tests
This method adopts HPLC-differential refraction detector method commonly used to measure, this method specificity is strong, highly sensitive, accuracy is good, and easy to be quick, the Control of Impurities limit obviously improves than pharmacopeia in 2010, the application's related substance HPLC collection of illustrative plates is seen accompanying drawing 1, the analysis of results table of the application's related substance HPLC collection of illustrative plates sees that 2,2010 editions official method related substances of accompanying drawing HPLC collection of illustrative plates sees that 3,2010 editions official method related substances of accompanying drawing HPLC collection of illustrative plates analysis of results table sees accompanying drawing 4.
Claims (3)
1. lactulose oral administration solution, it is characterized in that: in every 1000ml solution, be grouped into by following one-tenth: lactulose 667g, sunset yellow 0.004g, flavoring banana essence 0.0001g, sodium benzoate 1g, surplus is a water.
2. the preparation method of the described lactulose oral administration solution of claim 1 may further comprise the steps:
(1) weighing: take by weighing lactulose solution, sunset yellow, flavoring banana essence, sodium benzoate;
(2) preparation: with sunset yellow, after flavoring banana essence, sodium benzoate dissolve fully with suitable quantity of water, add lactulose solution and mix, add suitable quantity of water again and be settled to scale, after stirring, sampling detects the intermediate quality;
(3) fill: after the intermediate detection is qualified, carry out fill, packing.
3. the method for quality control of the described lactulose oral administration solution of claim 1 includes related substance quantitative check and assay, and its concrete grammar is as follows:
Assay is according to two appendix V of Chinese Pharmacopoeia version in 2010 D high effective liquid chromatography for measuring;
Chromatographic condition and system suitability test ZORBAX Carbohydrate Analysis Columns carbohydrate analysis column, with 0.01mol/L disodium phosphate soln-acetonitrile is mobile phase at 20: 80, column temperature and differential refraction detector temperature are 40 ℃, number of theoretical plate calculates by the lactulose peak should be not less than 3000, and the lactulose peak should be respectively greater than 1.5 and 2.0 with table lactose and the peak-to-peak separating degree of lactose;
Algoscopy is measured this product 3ml with inner capacities pipet precision, be equivalent to lactulose 2g approximately, put in the 50ml measuring bottle, with an amount of acetonitrile-water flushing in 1: 1 inner capacities pipet, washing liquid is incorporated in the measuring bottle, adds acetonitrile-water and is diluted to scale at 1: 1, shakes up, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram; It is an amount of that in addition precision takes by weighing Tagatose, fructose, galactose, table lactose, lactulose, lactose reference substance, with acetonitrile-water 1: 1 dissolving and make the solution that contains 1.6mg, 0.4mg, 6.4mg, 3.2mg, 40mg and 4.8mg among every 1ml respectively approximately, shake up, measure with method, press external standard method with calculated by peak area, promptly;
Related substance is calculated by the result who records under the assay item, the peak area of known each impurity and the peak area ratio of corresponding reference substance solution are, content with respect to lactulose, contain Tagatose and must not cross 3%, contain fructose and must not cross 1%, contain galactose and must not cross 10%, contain the table lactose and must not cross 5%, contain lactose and must not cross 7%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105784868A (en) * | 2016-04-12 | 2016-07-20 | 上海必诺检测技术服务有限公司 | Method for detecting lactulose in milk |
| CN109846893A (en) * | 2018-12-27 | 2019-06-07 | 陈晓 | Lactulose is in the application for preventing or treating Postmenopausal Osteoporosis |
| CN114839299A (en) * | 2022-06-14 | 2022-08-02 | 哈药集团技术中心 | Disaccharide compound analysis method |
-
2011
- 2011-01-31 CN CN 201110032943 patent/CN102166216A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| 《中国医药工业杂志》 20100630 邵泓等 乳果糖口服液中乳果糖及有关物质的高效阴离子交换色谱法测定 , * |
| 《药物分析杂志》 20000331 周立春等 乳果糖口服液含量的HPLC测定法研究 , * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105784868A (en) * | 2016-04-12 | 2016-07-20 | 上海必诺检测技术服务有限公司 | Method for detecting lactulose in milk |
| CN109846893A (en) * | 2018-12-27 | 2019-06-07 | 陈晓 | Lactulose is in the application for preventing or treating Postmenopausal Osteoporosis |
| CN114839299A (en) * | 2022-06-14 | 2022-08-02 | 哈药集团技术中心 | Disaccharide compound analysis method |
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Application publication date: 20110831 |