CN112578067A - Method for measuring content of glucose in star-shaped PLGA - Google Patents
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- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 title claims abstract description 45
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 title claims abstract description 39
- 239000008103 glucose Substances 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 23
- 150000002500 ions Chemical class 0.000 claims abstract description 16
- 238000004949 mass spectrometry Methods 0.000 claims abstract description 5
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- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 4
- 238000005516 engineering process Methods 0.000 claims abstract description 4
- 238000010829 isocratic elution Methods 0.000 claims abstract description 4
- 238000004811 liquid chromatography Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 13
- 239000012488 sample solution Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 3
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- 238000004445 quantitative analysis Methods 0.000 description 2
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- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- HPPONSCISKROOD-OYLNGHKZSA-N acetic acid;(2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-y Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 HPPONSCISKROOD-OYLNGHKZSA-N 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
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- 238000012377 drug delivery Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229960001494 octreotide acetate Drugs 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
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- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
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- 229960000434 triptorelin acetate Drugs 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8624—Detection of slopes or peaks; baseline correction
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
- G01N2030/885—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds involving polymers
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- Physics & Mathematics (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
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Abstract
The invention relates to a method for determining the content of glucose in star-shaped PLGA by adopting an LC-MS/MS method. The method adopts a liquid chromatography and mass spectrometry combined technology, and the chromatographic detection condition is that a mobile phase adopts 75% acetonitrile water solution of 0.1% ammonia water for isocratic elution, wherein the flow rate is 0.4 mL/min‑1Column temperature 35 ℃ column Xbridge @ Amide (250 mm. times.4.6 mm, 5 μm) was used. The mass spectrum detection conditions are that a negative ion scanning mode is adopted, the ion source temperature is 300 ℃, the spraying voltage is 45psi, the ion spraying voltage is 3500V, and the ion pairs m/z are monitored to be 179.0/89.1, 179.0/59.2 and 179.0/71.1. The method has high accuracy and simple operation, fills the gap of the existing research on the content of trace glucose in the star-shaped PLGA, can influence the molecular weight distribution of the star-shaped PLGA by controlling the amount of the glucose, and realizes that the size of the molecular weight can be adjusted to meet different clinical medication requirements.
Description
Technical Field
The invention relates to a content determination method, in particular to a method for determining the content of glucose in star-shaped PLGA by adopting an LC-MS/MS method.
Background
In recent years, biodegradable high molecular polymer materials have been hot spots of research at home and abroad, and PLGA has received much attention due to its good biocompatibility, biodegradability and high safety. In the pharmaceutical field, PLGA has been approved by FDA as a slow release carrier for microspheres and implants, has the advantages of prolonging drug release time and achieving targeted drug delivery, and can significantly improve drug efficacy and reduce drug toxicity, showing a very broad development prospect. Currently, representative slow-release microsphere products on the market include daphne (triptorelin acetate for injection), shanning (octreotide acetate for injection) and the like.
PLGA is mostly synthesized by mixing glycolide and lactide in different proportions and then ring-opening polymerization under the action of an initiator. In the preparation process, when the functionality of hydroxyl in the initiator is 1 or 2 (long-chain alkyl alcohol, glycolic acid, lactic acid, ethylene glycol, etc.), the resulting PLGA is a linear structure; when the hydroxyl functionality is 3 or greater (glycerol, pentaerythritol 2 alcohol, glucose, etc.), the resulting PLGA is a star-shaped structure. PLGA has different structures and different degradation performances, thereby influencing the slow release effect of the preparation. Compared with linear PLGA, the star-shaped PLGA shows obvious advantages of lower solution viscosity, higher drug loading rate, encapsulation rate and the like when being used as a drug carrier. In addition, the literature reports that the star-shaped PLGA used for the microsphere preparation can obviously improve the burst release phenomenon and ensure the stability of the release behavior of the microsphere to a certain extent.
In the existing microsphere products, the Shangning for treating acromegaly in the market of Norhua is star-shaped PLGA prepared by taking glucose as an initiator, and the long-acting slow-release effect is realized. At present, the main identification methods of the star-shaped PLGA prepared by taking glucose as an initiator are glucose identification reaction and nuclear magnetic resonance carbon spectrum. The prerequisite for the glucose identification reaction to be trusted is that there is no free glucose in the synthesis product that is not bound to a covalent bond that would interfere with the result. The characterization of the star-shaped PLGA currently stays in the stage of only proving the existence of covalently bonded glucose in the star-shaped PLGA, and the quantitative analysis research on the content of glucose in the star-shaped PLGA is in the basic blank. However, for star-type PLGA, the amount of glucose has a direct influence on the molecular weight, and microspheres prepared from PLGA with different molecular weight distributions have different release characteristics, thereby affecting the degradation rate and the like.
Disclosure of Invention
Aiming at overcoming the defects of the existing detection method, the invention carries out deep research aiming at the defects of the prior art and provides a qualitative and quantitative analysis method for trace glucose in medicinal carrier star-shaped PLGA by utilizing LC-MS/MS technology.
The method adopts a liquid chromatography and mass spectrometry combined technology, and the chromatographic detection condition is that a mobile phase adopts 75% acetonitrile water solution of 0.1% ammonia water for isocratic elution, wherein the flow rate is 0.4 mL/min-1Column temperature 35 ℃ column Xbridge @ Amide (250 mm. times.4.6 mm, 5 μm) was used.
The mass spectrum detection conditions are that a negative ion scanning mode is adopted, the ion source temperature is 300 ℃, the spraying voltage is 45psi, the ion spraying voltage is 3500V, and the ion pairs m/z are monitored to be 179.0/89.1, 179.0/59.2 and 179.0/71.1.
Star-shaped PLGA is prepared from ring-opened Lactide (LA) and Glycolide (GA) monomers of glucose under the catalysis of stannous octoate. The star-shaped PLGA can be hydrolyzed under alkaline conditions, ester bonds are broken, and an initiator glucose can be dissociated. The free glucose of the hydrolyzed PLGA can be detected by an LC-MS/MS method, and the quantity of the star-shaped PLGA and the free glucose is determined. The star-shaped PLGA is hydrolyzed in a sodium hydroxide solution with the concentration of 0.1-1M for 4-48 hours at the temperature of 20-50 ℃, and preferably in a sodium hydroxide solution with the concentration of 0.5M for 20 hours at room temperature.
The LC-MS/MS analysis method can detect whether the glucose residue added in the synthesis process exists in the sample, and proves that the glucose which reacts comes from the glucose combined by covalent bonds in the sample, so that the interference is avoided, and the accuracy of the result is ensured. The method for determining the content of the trace glucose in the star-shaped PLGA by using the LC-MS/MS has high accuracy and simple operation, fills the gap of the current research on the content of the trace glucose in the star-shaped PLGA, influences the molecular weight distribution of the star-shaped PLGA by controlling the amount of the glucose, and realizes that the size of the molecular weight is adjusted to meet different clinical medication requirements. According to the primary methodology verification result, the method has good specificity, repeatability, precision and higher recovery rate, can effectively distinguish linear and star-shaped PLGA which is synthesized by taking glucose as an initiator, and can be used for the quality research work of the medicine which takes the star-shaped PLGA as a carrier.
Drawings
FIG. 1 is a spectrum of glucose control solution
FIG. 2 shows hydrolysis detection spectra under alkaline condition of star PLGA
FIG. 3 hydrolysis detection spectrum of linear PLGA under alkaline condition
Detailed Description
1. Experimental materials and instruments
DL-lactide, glycolide (Jinan Dai handle bio-technology Co., Ltd.); glucose (Tianjin Bodi chemical Co., Ltd.); stannous octoate (national drug group chemical agents limited); 1260 liquid chromatograph (Agilent, usa); liquid phase mass spectrometry (liquid phase 1290, mass 6740, Agilent, usa); XBridge @ Amide column (Waters corporation, USA).
2. Method and results
2.1 detection conditions
Chromatographic conditions are as follows: using chromatographic column XBridge @ Amide (250mm × 4.6mm, 5 μm), the mobile phase is 75% acetonitrile water solution containing 0.1% ammonia water, isocratic elution is carried out, the flow rate is 0.4mL min-1The column temperature was 35 ℃.
Mass spectrum conditions: the ion source temperature was 300 ℃, the spray voltage was 45psi, the ion ejection voltage was 3500V, and the ion pairs m/z were monitored at 179.0/89.1, 179.0/59.2, and 179.0/71.1 using a negative ion scan mode.
2.2 preparation of the solution
Preparation of a reference solution: weighing a proper amount of glucose in a volumetric flask, and preparing a reference substance with the concentration of 0.01 mg.L < -1 >.
Preparing a test solution: and weighing a proper amount of star-shaped PLGA samples, respectively adding the star-shaped PLGA samples into pure water and a sodium hydroxide solution with the concentration of 0.5M, and hydrolyzing for 20 hours at room temperature to obtain sample solutions No. 1 and No. 2.
2.3 results of the experiment
Firstly, the concentration is 0.01 mg.L-1The glucose control solution was tested, and the peak time of glucose was 22.6min, as shown in FIG. 1.
When the No. 1 sample solution is detected, no peak is produced, which indicates that the glucose in a free state is not detected. The result shows that the star-shaped PLGA sample has no residual glucose added in the synthesis process, so that the quantitative experiment is not interfered, and the accuracy of the quantitative result is ensured. When the sample solution No. 2 is detected, 3 peaks are found in the chromatogram, and the peak-off time is respectively 19.4min,20.7min and 22.6min, as shown in FIG. 2. The results of the test of the sample No. 1 and the sample No. 2 were analyzed in combination, which indicated that there was covalently bound glucose in the sample No. 2, which was star-shaped PLGA. The results also indicate that the free glucose is detected by hydrolysis of the star PLGA sample with sodium hydroxide. In addition, since glucose in a partially free state formed by hydrolysis is easily converted into isomers such as fructose under alkaline conditions, three peaks appear in the figure. And calculating according to the peak area to obtain the content of the synthesized star PLGA glucose of 0.042%.
2.4 methodological validation
The specificity is as follows: the same amount of linear PLGA sample is taken and dissolved in sodium hydroxide solution, and hydrolyzed under the same condition, and free glucose is not detected, specifically shown in figure 3, which shows that the specificity of the method is good.
Repeatability: the total 6 parts of sample solution No. 2 are taken in parallel, and after hydrolysis, the mass spectrum peak areas are shown in the table 1. The peak area RSD of the six samples is less than 5%, and the relative retention time of the common peak and the RSD of the relative peak area are both less than 3%.
TABLE 16 replicate post hydrolysis peak area
Precision: taking the sample solution No. 2, hydrolyzing, and continuously feeding sample for 6 times, wherein the mass spectrum peak area of the continuous six-needle is shown in Table 2, and the RSD of the six-needle peak area is calculated to be less than 5%. The relative retention time of the common peak and the RSD of the relative peak area are both less than 3 percent.
TABLE 2 area of liquid peak after hydrolysis of six consecutive needles of sample
And (3) recovery rate: taking 6 parts of No. 2 sample solution in parallel, adding a certain amount of reference solution, sampling, wherein the peak areas of mass spectra of 6 parallel samples are shown in Table 3, the peak areas RSD of six samples are less than 5%, the relative retention time of common peaks and the RSD of the relative peak areas are both less than 3%, and the recovery rate is 87% -97%.
Table 3: peak area of liquid matter recovered by adding standard to 6 parallel samples
Claims (3)
1. A method for determining the content of glucose in star-shaped PLGA is characterized in that a liquid chromatography and mass spectrometry combined technology is adopted, and the chromatographic test conditions are that a mobile phase adopts 75% acetonitrile water solution of 0.1% ammonia water for isocratic elution, wherein the flow rate is 0.4 mL/min < -1 >, the column temperature is 35 ℃, and a chromatographic column Xbridge @ Amide (250mm multiplied by 4.6mm, 5 mu m) is adopted; the mass spectrometry test conditions are that the flow rate adopts a negative ion scanning mode, the ion source temperature is 300 ℃, the spray voltage is 45psi, the ion injection voltage is 3500V, and the ion pairs m/z are monitored to be 179.0/89.1, 179.0/59.2 and 179.0/71.1.
2. The method according to claim 1, wherein the star-shaped PLGA is hydrolyzed in a 0.1-1M sodium hydroxide solution at 20-50 ℃ for 4-48 hours to obtain a sample solution before the measurement.
3. The method according to claim 1 or 2, wherein the star-shaped PLGA is hydrolyzed in a 0.5M sodium hydroxide solution at room temperature for 20 hours to obtain a test solution before the measurement.
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|---|---|---|---|---|
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