Analysis method of elements in leaching liquor, standard stock solution and internal standard element stock solution

Abstract

The invention discloses a method for analyzing elements in a leaching solution, a standard stock solution and an internal standard element stock solution, and the method comprises the following steps: preparing a matrix solution, preparing the standard stock solution, preparing the internal standard element stock solution, preparing a standard solution, a calibration blank solution and a sample solution, and finally testing the calibration blank solution, the calibration blank solution and the sample solution in sequence by ICP-MS (Inductively Coupled Plasma Mass Spectrometry). The types and the contents of the elements in the sample solution are obtained. By reasonably preparing the types of the elements in the standard solution and the internal standard solution and utilizing semi-quantitative analysis of ICP-MS, rapid screening of the elements can be realized, the content of 58 elements can be reported, the adding standard recovery rate of each element is 50-300%, although the accuracy is slightly lower than that of a quantitative detection method (the recovery rate is 70-150%), the method can be used for rapidly detecting the content of 58 elements. However, the content detection result still has reference, the detection efficiency is high, and the risk of missing detection of potential harmful elements caused by only paying attention to related and key elements in related laws and regulations in the prior art can be effectively avoided.

Description

Technical Field

[0001] The invention relates to the field of biomedical analysis and detection, and in particular to an analysis method for elements in an extract, a standard stock solution and an internal standard element stock solution. Background Art

[0002] When medical devices are in constant contact with the human body and play a role, or interact with other media in use (such as liquid medicine, blood, etc.), some chemical substances will be released. These chemical substances are collectively referred to as leachable substances. Leachable substances generally include sterilization residues, processing residues, degradation products, solvents, monomers and additives in materials (including stabilizers, antioxidants, plasticizers, colorants), etc. While medical devices play a diagnostic and therapeutic role, leachable substances also pose a safety hazard to the human body in the short or long term, so it is necessary to conduct a risk assessment of the leachable substances of medical devices.

[0003] Although leachable studies can best represent the amount of exposure to users during actual use, due to practical limitations (including the diversity and complexity of clinical contact routes and usage methods, ethical issues in clinical sample collection, etc.), it is difficult to conduct a true leachable study for most devices. Therefore, in some cases, it is appropriate to use an extraction test instead of a leachable study.

[0004] The commonly used detection of elements in extractables at present mainly involves quantitative detection of elements involved in ICH Q3D and elements that may be introduced into the material of the device. However, the quantitative method has a large workload and low efficiency. If more elements need to be tested, considering the interference between elements and the complexity of the sample matrix, multiple method sequences may be required to meet the needs of quantitative testing. In addition, there are many types of medical devices and their usage is complicated. The quantitative method only focuses on key elements, which may lead to the omission of some elements, thereby causing safety risks. It is not suitable for rapid screening of elements in medical device extracts. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide an analysis method for elements in an extract and a standard stock solution and an internal standard element stock solution, which can realize rapid detection of inorganic element types in a medical device extract.

[0006] In order to solve the above technical problems, the present invention provides a method for analyzing elements in an extract, comprising the following steps:

[0007] S1. Prepare a matrix solution that matches the medical device extract;

[0008] S2. Prepare a standard stock solution containing 31 inorganic elements, namely Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Hg, Te, Hf, Sm and Ce; the concentration of Hg is less than that of the other 30 elements;

[0009] S3. Prepare internal standard element stock solution, which contains five inorganic elements, namely Sc, Ga, In, Tb and Re;

[0010] S4. Prepare a standard solution: take an appropriate amount of the standard stock solution prepared in S2, the internal standard element stock solution prepared in S3, and the matrix solution in S1, and mix them to obtain a standard solution;

[0011] S5. Prepare a calibration blank solution: Take the internal standard element stock solution prepared in S3 and the matrix solution in S1, mix them to obtain a calibration blank solution, the concentration of the internal standard element in the calibration blank solution is the same as the concentration of the internal standard element in the standard solution prepared in S4;

[0012] S6. Prepare a sample solution by mixing an appropriate amount of the medical device extract and the internal standard element stock solution prepared in S3 to obtain a sample solution, wherein the concentration of the internal standard element in the sample solution is the same as the concentration of the internal standard element in the standard solution prepared in S4;

[0013] S7. Using ICP-MS, the calibration blank solution prepared in S5, the standard solution prepared in S4, and the sample solution prepared in S6 are tested in sequence to obtain the concentration of each element in the sample solution;

[0014] S8. Calculate the element content in the medical device extract.

[0015] In the present invention, by reasonably preparing the types of elements in the standard solution and the internal standard solution, and utilizing the semi-quantitative analysis of an inductively coupled plasma mass spectrometer (ICP-MS), rapid screening of elements can be achieved, the contents of 58 elements can be reported, and the spiked recovery rate of each element is between 50-300%. Although the accuracy is slightly lower than that of the quantitative detection method (the recovery rate is within the range of 70-150%), the results of the content detection are still referenceable, and the detection efficiency is high. The risk of missing detection of potential harmful elements caused by the prior art only focusing on the key elements involved in relevant laws and regulations can also be effectively avoided.

[0016] In the present invention, the selection of elements (including standard stock solutions and internal standard element stock solutions) is mainly based on the fact that in the common matrix of medical device extracts, the proportion of element types with a spike recovery rate of less than 50% is reduced to the minimum. The elements in the final standard stock solution are 31 elements of Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Hg, Te, Hf, Sm and Ce, and the elements in the internal standard element stock solution are Sc, Ga, In, Tb and Re; in the present invention, in pH2 buffer, pH10 buffer and physiological saline, the elements with a spike recovery rate of less than 50% are all 0. It should be noted that in the present invention, the main role of the internal standard element is to monitor the element intensity drift and reflect the matrix effect of the sample to be tested. For example, when the internal standard element is offset more, it indicates that the reliability of the result is reduced. It should be noted that in step S8, the element content in the medical device extract is directly given by the testing equipment. The calculation principle is that the equipment converts the concentration of each element in the measured sample solution to the concentration of the extract, and then further converts it to the concentration of the medical device. The modified conversion is completed by the equipment according to the existing technology and will not be repeated here.

[0017] In a specific embodiment, the matrix solution in S1 is selected from pH 2 buffer, pH 10 buffer, water or physiological saline. The four optional liquids selected for the matrix solution of the present invention are four matrixes commonly used for medical device extraction, and when used, it depends on the medical device extraction liquid in the specific embodiment.

[0018] In a specific scheme, in S2, standard solutions of 31 inorganic elements are mixed with 5% nitric acid to obtain a standard stock solution, wherein the element concentrations of Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Te, Hf, Sm and Ce are 5-20 times or 10 times, preferably 10 times, of the Hg element concentration, and the Hg element concentration is 0.5-5ppm or 1ppm, preferably 1ppm. It should be noted that the selection of element concentration in the stock solution mainly considers the possible concentration order of magnitude range of the element to be measured, the convenience of diluting and preparing the standard solution, and the optimal measurement range of the instrument. In addition, since Hg element residues are more common in the instrument, in order to avoid the influence of residues on subsequent tests as much as possible, the concentration of Hg element is preferably lower than that of other types of elements.

[0019] In a specific solution, the internal standard element standard solution is mixed with a 5% nitric acid solution to obtain an internal standard element stock solution, wherein the concentrations of the internal standard elements are:

[0020] Sc: 100-300ppm or 200ppm;

[0021] Ga: 100-300ppm or 200ppm;

[0022] In: 30-60ppm or 40ppm;

[0023] Re: 2-6ppm or 4ppm;

[0024] Tb: 2-6ppm or 4ppm.

[0025] It should be noted that the main considerations for selecting the element concentration in the internal standard element stock solution are the possible concentration range of the element to be measured, the convenience of dilution during subsequent use, and the optimal measurement range of the instrument.

[0026] In a specific scheme, in S4, the volume ratio of the mixed standard stock solution to the internal standard element stock solution is 1:0.5-5 or 1:1; the volume ratio of the mixed standard stock solution to the matrix solution is 1:5-20 or 1:10. It should be noted that the standard solution has no special requirements for the concentration of the elements, and the ratio relationship between the elements can be determined. In addition, the concentration of the internal standard element must be kept the same in the calibration blank solution and sample solution prepared in S5 and S6, respectively, for ease of testing and calculation.

[0027] In a specific embodiment, in S7, the elements that can be determined by ICP-MS are as follows:

[0028] Li V Ni Se No Ag Cs Nd Ho Hf Pt Bi Be Cr Cu Rs Mo Cd Ba Sm Er Dad Me Th Mg Mr Zn Sr Ru Mr Day Me Tm W Hg U Al Feb Ge Y Rh Sb Ce God Yb Ir Tl / Tea Co As Zr Pd Tea Pr Dy Sun Os Pb /

[0029] Preferably, in S7, the parameters of ICP-MS are set as follows:

[0030] Mass number range: 6-210, 230-240amu;

[0031] The detector mode is Dual mode;

[0032] The reaction mode is KED collision mode.

[0033] In order to solve the above technical problems, the present invention also provides a standard stock solution and an internal standard element stock solution for use in an analysis method of elements in a medical device extract, characterized in that the standard stock solution contains 31 inorganic elements, namely: Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Hg, Te, Hf, Sm and Ce, wherein the concentration of Hg is less than the concentration of the other 30 elements;

[0034] The internal standard element stock solution contains five inorganic elements, namely Sc, Ga, In, Tb and Re.

[0035] Preferably, the standard stock solution is obtained by mixing standard solutions of 31 inorganic elements with 5% nitric acid, wherein the element concentrations of Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Te, Hf, Sm and Ce are 5-20 times or 10 times the concentration of Hg, and the concentration of Hg is 0.5-5ppm or 1ppm.

[0036] Preferably, the internal standard element stock solution is obtained by mixing 5 internal standard element standard solutions with 5% nitric acid, wherein the concentrations of the internal standard elements are:

[0037] Sc: 100-300ppm or 200ppm;

[0038] Ga: 100-300ppm or 200ppm;

[0039] In: 30-60ppm or 40ppm;

[0040] Re: 2-6ppm or 4ppm;

[0041] Tb: 2-6ppm or 4ppm.

[0042] The standard stock solution and internal standard element stock solution for use in the analysis method of elements in medical device extracts provided by the present invention have element types in the prepared standard solutions, and when used, the spike recovery rate is between 50-300%, which meets the use requirements of semi-quantitative / qualitative analysis, especially when the matrix solution is pH 2 buffer solution, pH 10 buffer solution and physiological saline, the elements with a spike recovery rate lower than 50% are all 0. DETAILED DESCRIPTION

[0043] The technical solution of the present invention is described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0044] Example 1 Preparation of standard stock solution and internal standard element stock solution

[0045] 1-Preparation of standard stock solution

[0046] Take Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Hg, Te, Hf, Sm and Ce inorganic element standard solutions (31 in total, commercially available) and mix them with 5% nitric acid solution to obtain a mixed standard stock solution, in which the element concentrations of Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Te, Hf, Sm and Ce are all 10 ppm, and the Hg element concentration is 1 ppm.

[0047] 2-Preparation of internal standard element stock solution

[0048] Take Sc, Ga, In, Tb and Re inorganic element standard solutions (a total of 5 types, commercially available) and mix them with 5% nitric acid solution to obtain internal standard element stock solutions, wherein the concentrations of the internal standard elements are:

[0049] Sc: 200ppm;

[0050] Ga: 200ppm;

[0051] In: 40ppm;

[0052] Re: 4ppm;

[0053] Tb: 4ppm.

[0054] Example 2 Analysis of Elements in Polyethylene Suture Extract

[0055] The polyethylene suture is extracted with water as the extraction solvent to obtain an extract. The extraction method is a conventional method and will not be described in detail here.

[0056] Prepare a standard solution: take 0.1 mL of the standard stock solution in the embodiment and 0.1 mL of the internal standard element stock solution, mix them, add the matrix solution (water) to 10 mL, and mix them evenly to obtain a standard solution, wherein the concentrations of 30 elements such as Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Te, Hf, Sm and Ce are all 100 ppb, the element concentration of Hg is 10 ppb, the element concentrations of Sc and Ga are 2 ppm, the element concentration of In is 400 ppb, and the element concentration of Re and Tb is 40 ppb.

[0057] Prepare calibration blank solution: take 0.1 mL of internal standard element stock solution, add matrix solution (water) to 10 mL, mix well to obtain calibration blank solution, wherein the element concentration of Sc and Ga is 2 ppm, the element concentration of In is 400 ppb, and the element concentration of Re and Tb is 40 ppb.

[0058] The sample solution was prepared by taking 0.03 mL of the internal standard element stock solution, adding the leaching solution to 3 mL, and mixing evenly to obtain a sample solution, wherein the element concentrations of Sc and Ga were 2 ppm, the element concentration of In was 400 ppb, and the element concentrations of Re and Tb were 40 ppb.

[0059] Use ICP-MS for elemental analysis: set the mass parameters to 6-210, 230-240 amu; the detector mode to Dual; the reaction mode to KED collision mode; measure the calibration blank sample, standard solution, and sample solution in sequence, and test them three times in parallel. Each test takes about 5 minutes.

[0060] The quantitative limit of the device in this embodiment is shown in Table 1. The test results of the sample solution can be quickly converted to the content of each element in the device through the extraction ratio, as shown in Table 2.

[0061] Table 1

[0062]

[0063]

[0064] Table 2

[0065]

[0066]

[0067] In Table 2, “<LOQ” means below the limit of quantification or not detected.

[0068] In this embodiment, all possible elements in the medical device extract can be detected in one test, with fast detection speed and high efficiency, and the content shown in the test result is a semi-quantitative test result, which has a certain reference value.

[0069] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for analyzing elements in a medical device extract, characterized in that: The steps include: S1. Prepare a matrix solution that matches the medical device extract; S2. Prepare a standard stock solution containing 31 inorganic elements, namely Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Hg, Te, Hf, Sm and Ce; the concentration of Hg is less than that of the other 30 elements; S3. Prepare internal standard element stock solution, which contains five inorganic elements, namely Sc, Ga, In, Tb and Re; S4. Prepare a standard solution: take an appropriate amount of the standard stock solution prepared in S2, the internal standard element stock solution prepared in S3, and the matrix solution in S1, and mix them to obtain a standard solution; S5. Prepare a calibration blank solution: Take the internal standard element stock solution prepared in S3 and the matrix solution in S1, mix them to obtain a calibration blank solution, the concentration of the internal standard element in the calibration blank solution is the same as the concentration of the internal standard element in the standard solution prepared in S4; S6. Prepare a sample solution by mixing an appropriate amount of the medical device extract and the internal standard element stock solution prepared in S3 to obtain a sample solution, wherein the concentration of the internal standard element in the sample solution is the same as the concentration of the internal standard element in the standard solution prepared in S4; S7. Using ICP-MS, the calibration blank solution prepared in S5, the standard solution prepared in S4, and the sample solution prepared in S6 are tested in sequence to obtain the concentration of each element in the sample solution; S8. Calculate the element content in the medical device extract.

2. The method according to claim 1, characterized in that The matrix solution in S1 is selected from pH 2 buffer, pH 10 buffer, water or physiological saline.

3. The method according to claim 1, characterized in that In S2, standard solutions of 31 inorganic elements are mixed with 5% nitric acid to obtain a standard stock solution, wherein the element concentrations of Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Te, Hf, Sm and Ce are 5-20 times or 10 times the element concentration of Hg, and the concentration of Hg is 0.5-5ppm or 1ppm.

4. The method according to claim 1, characterized in that In S3, the internal standard element standard solution is mixed with a 5% nitric acid solution to obtain an internal standard element stock solution, wherein the concentrations of the internal standard elements are: Sc: 100-300ppm or 200ppm; Ga: 100-300ppm or 200ppm; In: 30-60ppm or 40ppm; Re: 2-6ppm or 4ppm; Tb: 2-6ppm or 4ppm.

5. The method according to claim 1, characterized in that In S4, the volume ratio of the standard stock solution to the internal standard element stock solution is 1:0.5-5 or 1:1; the volume ratio of the standard stock solution to the matrix solution is 1:5-20 or 1:

10.

6. The method according to claim 1, characterized in that In S7, the elements that can be measured by ICP-MS are as follows:

7. The method according to claim 7, characterized in that In S7, the parameters of ICP-MS were set as follows: Mass number range: 6-210, 230-240amu; The detector mode is Dual mode; The reaction mode is KED collision mode.

8. A standard stock solution and an internal standard element stock solution for use in an analysis method of elements in a medical device extract, characterized in that: The standard stock solution contains 31 inorganic elements, namely: Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Hg, Te, Hf, Sm and Ce, wherein the concentration of Hg is less than that of the other 30 elements; The internal standard element stock solution contains five inorganic elements, namely Sc, Ga, In, Tb and Re.

9. The standard stock solution as claimed in claim 8, characterized in that The standard stock solution is obtained by mixing standard solutions of 31 inorganic elements with 5% nitric acid, wherein the element concentrations of Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, Zn, Te, Hf, Sm and Ce are 5-20 times or 10 times the element concentration of Hg, and the concentration of Hg is 0.5-5ppm or 1ppm.

10. The method according to claim 8, characterized in that The internal standard element stock solution is obtained by mixing 5 internal standard element standard solutions with 5% nitric acid, wherein the concentrations of the internal standard elements are: Sc: 100-300ppm or 200ppm; Ga: 100-300ppm or 200ppm; In: 30-60ppm or 40ppm; Re: 2-6ppm or 4ppm; Tb: 2-6ppm or 4ppm.

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