An evaluation method for oxygen absorbers added to infusion and peritoneal dialysis fluid products

Abstract

The present invention discloses an evaluation method for oxygen absorbers added to infusion solutions and peritoneal dialysis fluid products. The method is divided into five steps. Different types of oxygen absorbers, medicines and packaging products used for medicines are systematically investigated in an all-round manner, and the most suitable types of oxygen absorbers for different medicines are determined. The evaluation method can be extended to the evaluation of oxygen absorbers suitable for other types of medicines such as precious Chinese medicinal materials and nutrient solution medicines. At the same time, selective recommendation guidance is provided to enterprises based on test data, filling the gap in evaluation methods in the current field.

Description

Technical Field

[0001] The present invention relates to the technical field of oxygen absorbent selection and evaluation, and in particular to a method for evaluating an oxygen absorbent added to infusion and peritoneal dialysis fluid products. Background Art

[0002] The clinical use of large infusion products such as multi-layer co-extruded infusion bags and multi-layer co-extruded peritoneal dialysis bags is huge, and the annual use of multi-chamber infusion bags and peritoneal dialysis fluid has increased rapidly in recent years. However, due to the weak barrier capacity of traditional multi-layer co-extruded infusion bags and multi-layer co-extruded peritoneal dialysis bags to oxygen, the current packaging of high-risk products such as plastic-packaged infusions and peritoneal dialysis fluids is mostly packaged by adding oxygen absorbers outside the inner bag of the product and adding external barrier bags, etc., due to the oxygen sensitivity of the product itself and the large volume of the product, to ensure the stability of the product and to ensure that the product is not affected by external oxygen and drug denaturation occurs. The content of clinical multi-chamber infusion bags is diverse. Once the inevitable risks of clinical use such as failure of oxygen absorbers and migration of harmful substances occur, the consequences are serious; such problems have caused many units to take a cautious or evasive attitude in the basic research on special oxygen absorbers, especially after comprehensively considering many factors such as experimental design research funds, technical personnel reserves, research duration and economic benefits. This attitude of ignoring risks and being indifferent will lead to the involvement of a large number of patients; the lack of a risk warning system will lead to a variety of emergency incidents related to pharmaceutical packaging materials, such as the chromium-exceeding toxic capsule incident, the plasticizer incident, the Xinfu incident, etc. in recent years.

[0003] Given the huge annual consumption of multi-chamber infusion bags and peritoneal dialysis fluid, the probability of occurrence of low-probability risk events will be magnified and cannot be ignored. In actual applications, there is a lack of research on the suitability of oxygen absorbers and infusion bags and peritoneal dialysis fluid products. In the selection of oxygen absorbers for their products, companies generally do not conduct systematic research, but only focus on whether the oxygen absorbers absorb oxygen, but do not conduct detailed evaluations of their principles, physical and chemical properties, etc., and there are no relevant standards for the suitability of oxygen absorbers for reference. Not to mention that after the oxygen absorbers have been denatured by oxygen absorption, some oxygen absorbers have obviously changed color or exuded. Whether these situations will affect the safety of infusion and peritoneal dialysis fluid products, or whether the two have interacted with each other and affected the stability of the product itself, etc.

[0004] Therefore, technicians in this field are committed to developing an evaluation method for oxygen absorbers added to infusion and peritoneal dialysis fluid products to address the deficiencies of the above-mentioned prior art. Summary of the invention

[0005] In view of the above-mentioned defects of the prior art, the technical problem to be solved by the present invention is that there is currently no systematic evaluation of the applicability, physical and chemical properties, safety and other issues of oxygen absorbers in infusion bags and peritoneal dialysis fluid products.

[0006] To achieve the above object, the present invention provides a method for evaluating an oxygen absorber added to infusion solutions and peritoneal dialysis solutions, the method comprising the following steps:

[0007] Step 1, examine the composition of the oxygen absorbent and oxygen absorption quality indicators;

[0008] Step 2: Classify the infusion bags and peritoneal dialysis bags to be evaluated, and examine the barrier capacity and oxygen permeability of the products;

[0009] Step 3: Conduct an adaptability experiment;

[0010] Step 4, examine the effect of oxygen absorbent denaturation on the infusion bag;

[0011] Step 5: Analyze the data and draw conclusions;

[0012] Further, for step 1, the composition of the oxygen absorber is investigated by using an X-ray fluorescence analyzer and a scanning electron microscope to analyze the elemental composition of different types of oxygen absorbers; the oxygen absorption quality index is investigated by using a residual oxygen meter to measure the oxygen absorption capacity, total oxygen absorption amount, and oxygen absorption time of the oxygen absorber; the oxygen absorption quality index is investigated by using an optical microscope to observe the internal structure of the oxygen absorber and compare the changes in the internal structure before and after oxygen absorption; based on the composition of the oxygen absorber and the data related to the oxygen absorption quality index, the oxygen absorber is screened and evaluated for use in adaptability experiments;

[0013] Further, for step 2, the basis for classifying the evaluated infusion bags and peritoneal dialysis bags is the functional efficacy of the infusion bags and peritoneal dialysis bags; the investigation of the barrier capacity is carried out by using an oxygen permeator and a moisture permeator to measure the barrier capacity of the inner and outer bags of the infusion bags and peritoneal dialysis bags; the investigation of the oxygen permeability is carried out by using a residual oxygen meter to measure the residual oxygen inside the infusion bags and peritoneal dialysis bags;

[0014] Further, for step 3, the adaptability experiment combines different oxygen absorbers with different types of infusion bags and peritoneal dialysis bags to examine their compatibility and adaptability;

[0015] Further, for step 4, the effect of the oxygen absorber on the infusion bag after denaturation needs to be investigated by absorbing oxygen into the oxygen absorber, and performing migration experiments on various components to determine the effect of the oxygen absorber on various packaging bags after denaturation;

[0016] Further, for step 5, the physical and chemical properties, applicability and safety of the oxygen absorbent are evaluated and analyzed through the data of steps 1 to 4;

[0017] By adopting the above scheme, the evaluation method of an oxygen absorber added to infusion and peritoneal dialysis fluid products disclosed in the present invention has the following advantages:

[0018] (1) The present invention provides an evaluation method for oxygen absorbers added to infusion solutions and peritoneal dialysis solutions. The method examines the barrier properties of the drug packaging itself, the oxygen concentration of the drug itself, and the influence of component forward migration. The method comprehensively evaluates and considers the adaptability of the oxygen absorber and drug packaging, and provides selective recommendations and guidance for enterprises.

[0019] (2) The present invention provides an evaluation method for oxygen absorbers added to infusion and peritoneal dialysis fluid products. The common components and properties of different oxygen absorbers are systematically studied, and the types of oxygen absorbers with good applicability to peritoneal dialysis fluid drugs and injection solutions are obtained. At the same time, the evaluation method can also be extended to the evaluation of oxygen absorbers suitable for other types of drugs such as precious Chinese medicinal materials and nutrient solution drugs, and has good applicability.

[0020] In summary, the present invention discloses an evaluation method for oxygen absorbers added to infusion and peritoneal dialysis fluid products, which systematically conducts a comprehensive investigation of different types of oxygen absorbers, medicines and packaging products used for medicines, and determines the most suitable types of oxygen absorbers for different medicines. The evaluation method can be extended to the evaluation of oxygen absorbers suitable for other types of medicines such as precious Chinese medicinal materials and nutrient solution medicines. At the same time, selective recommendation guidance is provided to enterprises based on test data, filling the gap in evaluation methods in the current field.

[0021] The concept, specific technical scheme and technical effects of the present invention will be further described below in conjunction with specific implementation methods to fully understand the purpose, characteristics and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The present invention is a schematic diagram of the steps of a method for evaluating an oxygen absorber added to infusion and peritoneal dialysis fluid products. DETAILED DESCRIPTION

[0023] The following introduces several preferred embodiments of the present invention to make its technical content clearer and easier to understand. The present invention can be embodied in many different forms of embodiments, which are exemplary descriptions, and the protection scope of the present invention is not limited to the embodiments mentioned in the text.

[0024] If there are experimental methods without specific conditions, they are usually implemented according to conventional conditions, such as those in the relevant instructions or manuals.

[0025] like Figure 1As shown, the evaluation method of the oxygen absorber added to the infusion and peritoneal dialysis fluid products of the present invention is specifically implemented as follows:

[0026] Experimental materials: Inorganic series oxygen absorbers ① Iron series oxygen absorbers (iron powder, sodium chloride, starch) ② Hydrogenation catalyst type deoxidizer;

[0027] Organic series oxygen absorbers ①Ascorbic acid oxygen absorbers (ascorbic acid AA and copper sulfate CuSO4) ②Coupled enzyme oxygen absorbers (glucose and glucose oxidase) ③Unsaturated fatty acid oxygen absorbers (oleic acid, linoleic acid added with oleic acid metal salt catalysts, calcium hydroxide and other alkaline coagulants);

[0028] Example: Evaluation method of oxygen absorbers added to infusion and peritoneal dialysis fluid products

[0029] Step 1, investigate the composition of oxygen absorbers, select 5 batches of medicinal oxygen absorber samples, of which 3 batches are iron-based oxygen absorbers and 2 batches are organic-based oxygen absorbers; use an X-ray fluorescence analyzer to determine the elemental composition of the oxygen absorbers; the test results of the 5 batches of samples tested this time are shown in Tables 1-5; Iron-based oxygen absorbers: the iron content exceeds 45%, and the main elements are iron, silicon, aluminum and other elements; Organic-based oxygen absorbers: the content of each element in each type of oxygen absorber is different, and the main elements are sodium, silicon, calcium, iron, sulfur and other elements;

[0030] Table 1 Elemental composition of oxygen absorbent 1

[0031]

[0032]

[0033] Table 2 Element composition of oxygen absorbent 2

[0034] Compound formula Concentration Unit Na 0.457 ％ Mg 0.033 ％ Al 1.033 ％ Si 4.446 ％ P 0.011 ％ S 0.095 ％ Cl 0.826 ％ K 0.312 ％ Ca 0.422 ％ Cr 0.061 ％ Mn 0.197 ％ Fe 91.956 ％ Co 0.130 ％ Zn 0.010 ％ Mo 0.011 ％

[0035] Table 3 Element composition of oxygen absorbent 3

[0036]

[0037]

[0038] Table 4 Element composition of oxygen absorbent 4

[0039] Compound formula Concentration Unit Na 0.238 ％ Mg 0.353 ％ Al 0.246 ％ Si 0.222 ％ P 0.046 ％ S 0.011 ％ Cl 0.702 ％ Ca 97.239 ％ Mn 0.882 ％ Fe 0.029 ％ Zn 0.007 ％ Sr 0.024 ％

[0040] Table 5 Element composition of oxygen absorbent 5

[0041]

[0042]

[0043] The oxygen absorption capacity of oxygen absorbers was investigated. The experimental samples were 5 bottles of medical oxygen absorbers, all of which were iron-based oxygen absorbers, of which 3 batches were used in amino acid (15) peritoneal dialysis fluid, 1 batch was used in fat emulsion amino acid (17) glucose (11%) injection, and 1 batch was used in medium- and long-chain fat emulsion amino acid (16) glucose (16%) injection;

[0044] For the determination of residual oxygen content: put the oxygen absorbent and the wetted cotton (soaked in 10ml water) into a barrier protection bag, heat seal, sterilize at 121℃ for 15 minutes, put it at room temperature, insert a three-way tube needle into the barrier protection bag, and inject 500ml, 1000ml, 1500ml, and 2000ml of air respectively. Pull it out quickly after injection and seal it to prevent gas leakage; place it at 25℃±2℃ for 20 hours; use a residual oxygen meter to measure the residual oxygen concentration in the barrier protection bag; the test results of the three batches of samples are shown in Table 6;

[0045] Table 6 Residual oxygen content test results of pharmaceutical oxygen absorbers

[0046]

[0047] For the determination of oxygen absorption time: put the oxygen absorbent and the wetted cotton (soaked with 10ml water) into a barrier protection bag, heat seal, sterilize at 121℃ for 15 minutes, put it at room temperature, insert a three-way tube needle into the barrier protection bag, inject 1000ml of air respectively, pull it out quickly after injection, seal it to prevent gas leakage; put it in an environment of 25℃±2℃; measure the time when the residual oxygen concentration reaches less than 0.1%; the test results of 3 batches of samples are shown in Table 7;

[0048] Table 7 Oxygen absorption time test results of pharmaceutical oxygen absorbers

[0049] Sample No. Air volume Residual oxygen concentration (%) Time (h) 1 1000ml 0 20 2 1000ml 0 20 3 1000ml 0 20

[0050] The above test verifies that it is reasonable and feasible to monitor the oxygen absorption capacity of iron-based oxygen absorbers by placing them in 1000ml of air at 25℃±2℃ for 20h;

[0051] Step 2, the three-layer co-extruded infusion bag and the outer barrier bag are subjected to physical and chemical performance inspection using a water vapor permeation tester, a gas permeation rate tester, a pharmaceutical packaging tear force tester, a liquid chromatograph, a microscopic infrared, a universal material testing machine, a gas chromatograph, and an atomic absorption spectrophotometer; the inspection standard refers to the "National Pharmaceutical Packaging Material Standard" three-layer co-extruded infusion film (I), bag YBB00102005-2015 inspection, and relevant enterprise standards; the inspection items include but are not limited to appearance identification, sterilization adaptability test, use adaptability test, physical property test, metal element content, dissolution test, biological test, solvent residue test, and caprolactam content determination;

[0052] In order to control the mixing of metal elements in catalysts and production equipment during the production of inner bags (bags made of polypropylene / polypropylene / polypropylene three-layer co-extruded dialysis membranes through heat sealing) that are in direct contact with the drug solution, targeted inspections are carried out on toxic and harmful metals; and the situation of infusion is simulated to monitor the amount of dissolved substances to ensure the safety and effectiveness of the drug solution; targeted tests are carried out to control the seepage of harmful metal ions in water-soluble extracts, which is different from heavy metal inspections; due to the large amount of infusion, in order to effectively control these ions within the safe dosage range, the main metal ions inspected are: barium ions, copper ions, cadmium ions, lead ions, tin ions, chromium ions, and aluminum ions; the water vapor permeation rate, bag water loss rate, oxygen permeation rate, nitrogen permeation rate, carbon dioxide permeation rate and other test items are used to examine the material's barrier capacity to water vapor, oxygen, nitrogen, and carbon dioxide; the barrier capacity of the outer barrier bag is good, and the barrier capacity of the three-layer co-extruded infusion bag is relatively general; combined with the test data, both types of samples meet the requirements;

[0053] Step 3, combining the type of medicinal oxygen absorber and the physical and chemical properties of the infusion bag and the peritoneal dialysis fluid outer barrier bag, conduct adaptability tests on them according to the requirements; since the peritoneal dialysis fluid exchanges solutes and water with the plasma components in the capillaries on the other side of the peritoneum after being infused into the abdominal cavity, the metabolites and excess water retained in the body are removed, and at the same time, the dialysate is used to supplement the body's necessary substances to achieve the purpose of renal replacement or supportive treatment; the tryptophan and other substances in its formula are easily oxidized and decomposed, and its stability during production and storage is greatly affected by the oxygen content in the drug solution; therefore, the amino acid (15) peritoneal dialysis fluid adopts the packaging form of adding oxygen absorbers to improve product quality and maintain drug stability, and the iron-based oxygen absorbers meet the physical and chemical properties of the peritoneal dialysis fluid and its outer barrier bag;

[0054] For injections such as sodium bicarbonate injection, in order to keep the pH value of the solution within a certain reasonable range, ascorbic acid oxygen absorbers that release carbon dioxide while absorbing oxygen are used;

[0055] Step 4, investigate the effect of oxygen absorbent denaturation on infusion bag; the product of iron oxygen absorbent is generally Fe(OH)3, which is commonly known as rust, but in fact rust is composed of α-FeO(OH) and β-FeO(OH) hydrate, so the chemical formula should be expressed as Fe2O3·3H2O; the product after oxygen absorption denaturation is highly safe, so it is a kind of oxygen absorbent that is widely used at present, mainly used for most liquid preparations, such as injection, nutrient solution, peritoneal dialysis solution, prefilled syringe, eye drops, etc.;

[0056] Ascorbic acid oxygen absorbers are aqueous solutions of ascorbic acid (AA) and copper sulfate (CuSO4), which can achieve the effect of deoxygenation within 3 minutes. Ascorbic acid itself is a strong reducing agent. In the presence of oxygen, it can be oxidized to form oxidized ascorbic acid (DHAA), thereby removing oxygen from the environment. Ascorbic acid is vitamin C, so the use of ascorbic acid deoxidizers is relatively safe and will not have excessive effects on infusion bags. It is mainly suitable for sodium bicarbonate injections.

[0057] Step 5: Through various tests on medicinal oxygen absorbers, infusion bags, and peritoneal dialysis fluid external barrier bags, the corresponding applicable oxidant types were determined. The results also showed that the dissolved oxygen content of the drug itself would also have a certain impact on the stability of the drug, and the heavy metal ions in the oxygen absorber had no obvious migration to the drug; this method can be applied to other types of medicinal barrier bags and Chinese medicinal material storage bags to evaluate their applicable oxygen absorbers;

[0058] By analyzing various data in the embodiment experiments, it can be known that the evaluation method of the oxygen absorber added to infusion and peritoneal dialysis fluid products of the present invention systematically conducts a comprehensive investigation of different types of oxygen absorbers, medicines and packaging products used for medicines, and determines the most suitable types of oxygen absorbers for different medicines. The evaluation method can be extended to the evaluation of oxygen absorbers suitable for other types of medicines such as precious Chinese medicinal materials and nutrient solution medicines. At the same time, selective recommendation guidance is provided to enterprises based on the test data, filling the gap in evaluation methods in the current field.

[0059] The preferred specific embodiments of the present invention are described in detail above. It should be understood that ordinary technicians in the field can make many modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A method for evaluating an oxygen absorber added to infusion solutions and peritoneal dialysis solutions, characterized in that: The method comprises the following steps: Step 1, examine the composition of the oxygen absorbent and oxygen absorption quality indicators; Step 2: Classify the infusion bags and peritoneal dialysis bags to be evaluated, and examine the barrier capacity and oxygen permeability of the products; Step 3: Conduct an adaptability experiment; Step 4, examine the effect of oxygen absorbent denaturation on the infusion bag; Step 5: Analyze the data and draw conclusions; For step 1, the composition of the oxygen absorber is investigated by using an X-ray fluorescence analyzer and a scanning electron microscope to analyze the elemental composition of different types of oxygen absorbers; the oxygen absorption quality index is investigated by using a residual oxygen meter to measure the oxygen absorption capacity, total oxygen absorption amount, and oxygen absorption time of the oxygen absorber; the oxygen absorption quality index is investigated by using an optical microscope to observe the internal structure of the oxygen absorber and compare the changes in the internal structure before and after oxygen absorption; based on the composition of the oxygen absorber and the data related to the oxygen absorption quality index, the oxygen absorber is screened and evaluated for use in the adaptability experiment; For step 2, the basis for classifying the evaluated infusion bags and peritoneal dialysis bags is the functional efficacy of the infusion bags and peritoneal dialysis bags; the investigation of the barrier capacity is carried out by using an oxygen permeator and a moisture permeator to measure the barrier capacity of the inner and outer bags of the infusion bags and peritoneal dialysis bags; the investigation of the oxygen permeability is carried out by using a residual oxygen meter to measure the residual oxygen inside the infusion bags and peritoneal dialysis bags; For step 3, the adaptability experiment combines different oxygen absorbers with different types of infusion bags and peritoneal dialysis bags to examine their compatibility and adaptability; For step 4, the effect of the oxygen absorber on the infusion bag after denaturation needs to be investigated by absorbing oxygen into the oxygen absorber, and performing migration experiments on various components to determine the effect of the oxygen absorber on various packaging bags after denaturation; For step 5, the physical and chemical properties, applicability and safety of the oxygen absorbent are evaluated and analyzed using the data from steps 1 to 4.

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