COMBINATION AND MONITORING METHOD FOR MONITORING THE QUALITY STATUS OF A THERMALLY SENSITIVE ARTICLE

专利摘要:
time-temperature indicator and a monitoring method for monitoring the quality status of a thermally sensitive article. the present invention relates to a time-temperature indicator for monitoring the quality status of a thermally sensitive article and a monitoring method. the present invention also relates to a method of preparing the time-temperature indicator and to a thermally sensitive article using the time-temperature indicator. the time-temperature indicator according to the present invention comprises two laminated layers, which are physically separated, that is, a function indication layer and an adsorption function layer. the two laminated layers are stored and transported separately, and combined in use. therefore, the time-temperature indicator of the present invention can be stored and transported at room temperature, which reduces the costs of using the time-temperature indicator.
公开号:BR112013033371B1
申请号:R112013033371-5
申请日:2012-06-26
公开日:2020-10-06
发明作者:Zongwu Deng；Xiaofang Ying；Xiaoju Shi
申请人:Suzhou Qualimark Technology Co., Ltd；
IPC主号:

专利说明:

Technical Field
[001] The present invention relates to a time-temperature indicator for the purpose of monitoring the quality status of a thermally sensitive article and a monitoring method for monitoring the quality status of a thermally sensitive article. In particular, the present invention relates to the preparation of a time-temperature indicator using a volatile dye. The time-temperature indicator, through the color change resulting from the volatilization of the volatile dye, indicates whether a thermally sensitive article deteriorates or fails due to the influence of temperature or exposure to a temperature for too long. BACKGROUND OF THE TECHNIQUE
[002] Some articles that are very sensitive to temperature, such as most vaccines, biological products, bioactive samples, some medicines and the like, as well as fresh foods, such as fresh milk, dairy product, fresh meat, fish fresh and similar, need to be transported and stored at low temperature. For a long time, it is a main method to ensure the safety of these articles / products, especially medicines or foods, to label the expiration period, the quality guarantee period or the fresh preservation period. However, these methods can rarely suggest whether medicines or foods that need to be stored and transported at a low temperature have been exposed to a temperature above the transport temperature and safe storage for too long a time. The safe use and use of various heat-sensitive articles can best be ensured by using a simple economical method to accurately indicate whether heat-sensitive articles, such as fresh food, vaccines (usually between 2 ° C and 8 ° C ° C), and similar bioactive samples need low storage temperature, deteriorate, fail or lose activity during storage or transport, once safe storage and transport temperature is exceeded.
[003] In 1990, the World Health Organization (WHO) began to pay attention to the problem that vaccines are overheated during cold chain storage and transport, as this will lead to a decrease in the immunological effect of vaccines , reducing vaccine protection for children. Subsequently, WHO drew attention to the development of a marker that is easy to use and inexpensive, in order to adequately reflect the thermal history of vaccines leaving the factory after manufacture, being transported and stored for the purpose of reaching end users. The essential requirements for marking are as follows: 1. it can give an accurate indication to restrict the use of heated vaccines, 2. it has a small volume, and it can be pasted in a vaccine vial, ampoule or injector 3. it is stable and reliable throughout the process from production to actual use, 4. It is suitable for mass production, is economical and meets the global demand for vaccines from the United Nations International Children's Emergency Fund.
[004] In 1996, the company Temptime (the predecessor of which it is Lifelines), in the United States of America, developed a brand that for the first time can meet the requirements of WHO, and the brand is applied to vaccines against polio produced through three vaccine manufacturers, namely GlaxoSmithKline, Sanofi- Pasteur and Novartis. The brands supplied by Temptime are classified into three categories according to their function. The first is the Critical Temperature Indicator (CTI), which immediately changes color when the set temperature value is exceeded. The second is a Critical Temperature-Time Indicator (CTTI), the color change of which is delayed to some extent, and which changes color after exposure to a temperature above the set value for several minutes or tens of minutes. The third is known as the Time-Temperature Indicator (TTI), which has a longer response time, in which the temperature sensor material changes color after receiving a certain amount of heat, and this type of mark is a suitable mark for the thermal history of vaccines.
[005] Currently, there are hundreds of patents related to time and temperature indicators in the world. These patented technologies can be classified into mechanical type, chemical type, enzyme reaction type, microorganism type, polymer type, electronic chemical type, diffusion type and the like according to the product's operating principles. These technologies are mainly based on mechanical property, electrical property, diffusion property, bioenzyme reaction, polymerization and the like of materials. There are basically three types of TTI brands that are more mature and already commercialized: type of polymer, type of enzymatic reaction and type of diffusion.
[006] The type of polymer is developed by the company Temptime, in the United States of America, and is based mainly on that a colored polymer is produced by the polymerization of addition of 1,4 in the solid state of a substituted diacetylene derivative . The rate of polymerization increases as the temperature rises, and the polymer produced causes the darker color to continue. By comparing with the color of an environment, it is indicated whether the vaccines have been overheated. It is necessary to track and synthesize the appropriate monomer for such a brand, and the brand needs to be stored at -18 ° C or below after its production, which obviously increases the cost of using the brand.
[007] The early indicator of the enzyme-like reaction is essentially a type of pH indicator, which indicates the evolution of temperature or the heating history by measuring the color change caused by the change in the pH value of the medium, which is caused by the proton H + released from the catalyzed hydrolysis of the enzyme through the lipid substrate. Enzymatic hydrolysis becomes faster as the temperature rises, and thus the rate of proton release also becomes faster. A typical is a Vitsab ring indicator developed by a Swedish company.
[008] A typical time-temperature indicator product of the previous diffusion type is the Mark 3M monitor indicator produced by the company 3M, in the United States of America, which is based on the diffusion of the dye on a string, and the temperature indicating response time and interval, which depends on the type of dyes. Another form of diffusion type indicator is prepared by coating a porous substrate with a material with a specific melting point. The optical refraction indices of the substrate and the material are close to each other. When the material melts at a temperature above the specific temperature and diffuses to the porous substrate, the transmittance of the substrate increases after the air in the substrate pores is exhausted, and in this way, a color change is achieved, which shows the heating process.
[009] Currently, WHO classifies almost twenty vaccines in 4 categories according to their stability: the most unstable vaccines, unstable vaccines, stable vaccines and highly stable vaccines and, therefore, proposes the technical requirements for the indicators of time and corresponding temperature. The established technical standards thus take the properties of state of the art indicator products into account, but do not depend on the thermal stability of vaccines per se completely. In fact, among twenty vaccines, which require cold chain storage and transport and need to be monitored throughout the process, each vaccine has different stability. An ideal time-temperature indicator should be an individualized time-temperature indicator that adequately reflects the thermal stability of the indicated product, that is, the rate of color change and the effect of its temperature kept so consistent as possible with the product failure process.
[0010] Thus, in the art there is still a need for a time-temperature indicator and method in order to monitor the thermal history of heat-sensitive articles, which are used for the purpose of monitoring the storage and transport of sensitive articles to heat, and to accurately indicate whether a thermally sensitive article has failed or deteriorated. Summary of the Invention
[0011] An objective of the present invention is to provide a time-temperature indicator for the purpose of monitoring the condition of a thermally sensitive article, which is used for the purpose of monitoring the thermal history of a thermally sensitive article and which indicates whether the thermally sensitive article has failed or deteriorated.
[0012] Another objective of the present invention is to provide a method for the preparation of a time-temperature indicator for the purpose of monitoring the quality status of a thermally sensitive article.
[0013] Yet another objective of the present invention is to provide a method for monitoring the quality status of a thermally sensitive article.
[0014] The present invention has discovered that a laminate structure is formed as follows: fixing the volatile species that have some color (referred to in the present invention as volatile dye) for a thermally sensitive article, in the volatile dye fixing a layer of adsorption material which can absorb the dye, and by sealing the layer of volatile paint and the layer of adsorption material on the thermally sensitive article with a sealing layer, during storage and transportation, the volatile dye absorbs heat and volatilizes, and then it is absorbed by means of the absorbent material layer, the color of the volatile paint layer becomes lighter due to heat absorption volatilization, and the amount of volatilization of the dye is closely related to its thermal history. On the one hand, the amount of volatilization of the dye increases in the same way that time extends to a temperature. On the other hand, the volatilization rate increases as the temperature increases. The process of changing the quality of a thermally sensitive article has similar characteristics, that is, the quality of a thermally sensitive article that deteriorates in the same way that time extends to a temperature, and the failure or deterioration of an article thermally sensitive occurs after being extended for a period of time, as the temperature increases, the rate of deterioration in the quality of a thermally sensitive article increases, and the time to failure or deterioration is shortened. For a specific thermally sensitive article, the type and quantity of the dye can be selected, and / or other methods can be combined in order to adjust the volatilization rate of the dye, so that the color change response of the layer of ink for thermal history is close to or identical to the response to the change in quality of the thermally sensitive article for thermal history. Therefore, it can be easily determined whether a thermally sensitive article is in the shelf life or shelf life, that is, whether a thermally sensitive article does not deteriorate or simply by changing the color of the paint layer. Based on the above discovery, the present invention is achieved.
[0015] Therefore, the first aspect of the present invention provides a time-temperature indicator for the purpose of monitoring the condition of a thermally sensitive article, which comprises two portions of laminate, that is, an indication function layer and a layer adsorption function, which are physically independent of each other before use, where:
[0016] the indication function layer comprises:
[0017] a first layer of substrate material;
[0018] a layer of volatile paint coated on one side of the first layer of substrate material, in which the difference between the activation energy of the volatilization process of the volatile paint layer and that the process of changing the quality of the thermally sensitive article is in a predetermined range, and
[0019] a first layer of release protection film, which covers the layer of volatile paint, where the first layer of substrate material and the first layer of release of the film are larger than the layer of volatile paint in dimension, and the volatile ink layer is sealed between the first layer of substrate material and the first film release layer;
[0020] the function of the adsorption layer comprises:
[0021] a second layer of substrate material;
[0022] a layer of absorption material coated on one side of the second layer of substrate material, wherein the layer of absorption material is larger than the layer of volatile paint in dimension;
[0023] an adhesive layer, which is coated over the second layer of substrate material and surrounds the periphery of the adsorption material layer, and
[0024] a second layer of release protection film, which covers the adhesive layer and the layer of adsorption material.
[0025] According to the first aspect of the present invention, when used, the time-temperature indicator in the state of use is formed as follows: the removal of the first film release layer and the second film release layer , aligning the absorption material layer with the volatile ink layer, and sealing the volatile ink layer and the adsorption material layer between the first substrate layer and the second substrate layer, and firmly holding the time indicator - temperature in the thermally sensitive article.
[0026] The second aspect of the present invention provides a thermally sensitive article using the time-temperature indicator according to the first aspect of the present invention.
[0027] The third aspect of the present invention provides a method of preparing a time-temperature indicator for the purpose of monitoring the quality status of a thermally sensitive article, comprising the following steps:
[0028] providing a first substrate material;
[0029] coating one side of the first substrate material with a layer of volatile paint in order to form a layer of volatile paint, in which the difference between the energy of activation of the volatilization process of the volatile paint layer and the process of changing the quality of the thermally sensitive article is at a predetermined interval;
[0030] covering the volatile paint layer with a first film release layer in order to form an indication function layer;
[0031] and
[0032] providing a second substrate material;
[0033] coating one side of the second substrate material with an adsorption material in order to form a layer of adsorption material;
[0034] wherein the layer of absorbent material is larger than the layer of volatile paint in dimension;
[0035] coating the periphery of the layer of absorption material on the second layer of substrate material with an adhesive layer, and
[0036] covering the adhesive layer and the adsorption material layer with a second film release layer and sealing the adsorption material layer between the substrate material layer and the second film release layer in order to form a function adsorption layer.
[0037] The fourth aspect of the present invention provides a method for monitoring the quality status of a thermally sensitive article, comprising the following steps:
[0038] providing a thermally sensitive article, wherein the duration that the thermally sensitive article remains in the effective quality state at temperature T1 is t1;
[0039] in one or more areas of the thermally sensitive article fixing:
[0040] a volatile paint layer, which has a final color difference C1 after time t1 at temperature T1;
[0041] a layer of adsorption material, which irreversibly adsorbs the volatilized dye from the volatile paint layer;
[0042] a layer of sealing film, which is larger than the layer of absorption material and the layer of volatile paint in dimension, and hermetically fixes the layer of absorption material and the layer of volatile paint on the thermally sensitive article ;
[0043] practically treat the thermally sensitive article after fixing the sealing film;
[0044] observe or determine the actual color difference C2 of the volatile paint layer after being practically treated;
[0045] comparing the actual color difference C2 with the final color difference C1 of the volatile paint layer, where if the actual color difference C2 of the volatile paint layer is greater than the final color difference C1, it is indicated that the thermally sensitive article remains in an effective state of quality, if the actual color difference C2 of the volatile paint layer is less than that of the final color difference C1, it is indicated that the thermally sensitive article fails.
[0046] According to the method of the fourth aspect of the present invention, the fixing sequence of the volatile paint layer and the absorption material layer are not limited, that is, the volatile paint layer can be fixed first, and then the absorption material layer and also the adsorption material layer can be attached first, and then the volatile paint layer. Brief Description of Drawings
[0047] Figure 1 is a diagram of the structure of a time-temperature indicator prepared according to an example of the present invention.
[0048] Figure 2A is a schematic diagram of the use and process of changing the color of a time-temperature indicator prepared according to an example of the present invention. Figure 2B is a schematic diagram of the use and process of changing the color of a time-temperature indicator prepared according to an example of the present invention.
[0049] Figure 3 is a schematic diagram of the use and process of changing the color of a time-temperature indicator prepared with dye A as the volatile ink in example 1 of the present invention.
[0050] Figures 4A and 4B show the color change rate of a time-temperature indicator prepared with dye A as the volatile ink in example 2 of the present invention at different temperatures.
[0051] Figure 5 shows the activation energy of the color change process of a time-temperature indicator calculated with the color difference AE * ab = 10 as the end point of the color change, where the time indicator -temperature is prepared with dye A as the volatile dye in example 2 of the present invention.
[0052] Figure 6 shows that the color-changing response of a time-temperature indicator is almost completely consistent with the changing activity of a hepatitis B vaccine (Hep-B), in which the time- temperature is prepared with a dye like the volatile dye and designed for the hepatitis B vaccine (Hep-B) in Example 2 of the present invention.
[0053] Figure 7 shows the initial saturation of the indicator and the color change process, at the same temperature, in which the indicator is prepared with a dye like the volatile dye through the use of different concentrations of dye (ie dye ) and the same amount of ink in example three of the present invention.
[0054] Figure 8 shows that the time that the indicator passes to reach the end is in linear relationship with the amount of volatile dye printed per unit area, in which the indicator is prepared with a dye such as the volatile dye by means of different concentrations of ink and the same amount of ink in example 3 of the present invention.
[0055] Figure 9 shows the color difference of a time-temperature change indicator over time at 50 ° C, where the time-temperature indicator is prepared with the three compounds of formula I (dye A, dye B and dye C, respectively) as the thermally sensitive material thereof in example 4 of the present invention.
[0056] Figure 10 shows the color difference change of an indicator over time, at the same temperature, in which dye A is printed as the volatile dye, and cyclohexane, dichloromethane, methyl acetate, ethanol and ethyl acetate are used respectively as the solvent in example 5 of the present invention.
[0057] Figure 11 shows the relationship between the change in color difference of an indicator and the time of 80 ° C, in which the indicator is prepared by means of the appropriate addition of EC binder (cellulose acetate) in the organic solution of a dye in example 6 of the present invention.
[0058] Figure 12 shows the difference in color change in the layer indicating function of a time-temperature indicator over time, in which the time-temperature indicator is prepared with dye B, such as the volatile dye through selection and use of three different adsorption materials in example 7 of the present invention.
[0059] The terms and reference numbers used in the present invention are summarized as follows:
[0060] indication function layer 1, volatile paint layer 15,
[0061] adsorption function layer 2, reference color layer 16,
[0062] thermally sensitive article 3, first release layer of film 17,
[0063] substrate material layer 10, substrate material layer 20,
[0064] second film release layer 23, adsorption material layer 21,
[0065] adhesive layer 12, adhesive layer 22,
[0066] film seal layer 13, film release layer 23,
[0067] sealing adhesive layer 14, insulation layer 24. Description of Modalities
[0068] The first aspect of the present invention provides a time-temperature indicator for the purpose of monitoring the quality status of a thermally sensitive article.
[0069] In one embodiment, the time-temperature indicator of the present invention comprises two laminated portions, that is, an indication function layer and an adsorption function layer, which are physically independent of each other before use, in what;
[0070] the indication function layer comprises:
[0071] a first layer of substrate material;
[0072] a layer of volatile paint, which is coated in one or more zones on one side of the first layer of substrate material; and
[0073] a first film release layer, which is coated over the volatile paint layer, wherein the first substrate material layer and the first film release layer are larger than the dimension volatile paint layer, and the volatile ink layer is sealed between the first layer of substrate material and the first release layer of the film;
[0074] in which the difference between the activation energy of the volatilization process of the volatile paint layer and the process of changing the quality of the thermally sensitive article is in a predetermined range;
[0075] the function of the adsorption layer comprises:
[0076] a second layer of substrate material;
[0077] a layer of adsorption material, which is coated on one side of the second layer of substrate material, wherein the layer of absorption material is larger than the layer of volatile paint in dimension;
[0078] an adhesive layer, which is coated over the second layer of substrate material, and surrounds the periphery of the adsorption material layer, and
[0079] a second layer of release protection film, which covers the adhesive layer and the layer of adsorption material.
[0080] In use, a time-temperature indicator in the state of use is formed as follows: the removal of the first release layer of the film and the second release layer of the film, the alignment of the layer of absorption material with the volatile paint layer, and sealing of the volatile paint layer and the adsorption material layer between the first substrate layer and the second substrate layer.
[0081] The first layer of substrate of the time-temperature indicator is firmly bonded to the thermally sensitive article. Before using the thermally sensitive article, the layer of adsorption material is separated from the layer of volatile paint, and then the color of the paint layer is observed or measured.
[0082] Preferably, after the time-temperature indicator of the present invention has previously been subjected to the same treatment as the process in which the thermally sensitive article fails or deteriorates, the color difference of the volatile paint layer is measured with a colorimeter, and this color difference value is defined as the final color difference. Before the thermally sensitive article, with the time-temperature indicator of the present invention is to be used, the actual color difference of the volatile paint layer is measured. If the actual color difference of your volatile paint layer is greater than the final color difference, it is indicated that this thermally sensitive article has not failed or deteriorated and is in a usable state. If the actual color difference of your volatile paint layer is less than or equal to the final color difference, it is indicated that this thermally sensitive article has already failed or deteriorated. Wherein, the colorimeter can be any commercially available colorimeter.
[0083] Preferably, after the final color difference has been measured, a reference color marking, with the final color difference, is prepared with a non-volatile dye or pigment. Before the thermally sensitive article, with the time-temperature indicator of the present invention is to be used, the color of the volatile ink layer is observed visually and in relation to the reference color label. If the color of the volatile ink layer is darker than the reference color marking, it is indicated that this thermally sensitive article has not failed or deteriorated and is in a usable state. If the color of the volatile paint layer is lighter than or equal to that of the reference color marking, it is indicated that this thermally sensitive article has already failed or deteriorated and is not useful for use.
[0084] For example, if a thermally sensitive article will deteriorate or not after time t1 at temperature T1, then the time-temperature indicator of the present invention can be subjected to a treatment for time t1 at temperature T1, and the color difference of the volatile paint layer after treatment is recorded as the final color difference. If the time interval t1 is too long, the final color difference can also be measured with the test acceleration known to a person skilled in the art.
[0085] The reference color marking can be separated from the indication function layer and the adsorption function layer, or combined in the indication function layer. Preferably, the reference color marking is arranged adjacent the layer of volatile ink. Here, any viable mark can be used, for example, the reference color marking is arranged side by side with the volatile ink layer, or arranged around the volatile ink layer, or the like. Most preferably, after coating the volatile ink layer, a reference color layer is coated near or around it, and this reference color layer functions as the reference color marking. More preferably, after coating the volatile ink layer and coating a layer of reference color near or around it, the volatile ink layer and the reference color layer are sealed between the first substrate layer and the first film release layer. Before the thermally sensitive article is used, the color of the volatile ink layer is visually compared to that of the reference color marking (i.e., reference color layer), and it is therefore determined whether the thermally sensitive article fails or it doesn't deteriorate.
[0086] More preferably, the first layer of substrate material, in itself, is prepared as the reference color marking.
[0087] The thermally sensitive article is selected from vaccines, biological articles, bioactive samples, medicines, food or drinks. Preferably, the thermally sensitive article is an article that needs to be stored and / or transported at a temperature in the range of -40 ° C to 50 ° C, preferably from -30 ° C to 40 ° C, preferably from - 30 ° C to 30 ° C, preferably from -20 ° C to 20 ° C, preferably from -20 ° C to 10 ° C, preferably from -10 ° C to 10 ° C, preferably from 0 ° C at 10 ° C, as well as from 2 to 8 ° C. For example, it can be any item that needs to be stored and / or transported at a temperature in the range of 2 ° C to 8 ° C recorded in volumes of one, two and three of the "Chinese pharmacopoeia", 2005 or 2010 edition The thermally sensitive article that includes, but is not limited to: vaccines, such as thermally unstable vaccines, such as polio vaccine, typhoid vaccine, hepatitis B vaccine and the like; biological articles, such as human immunoglobulin, porcine human anti-immunoglobulin T lymphocytes, and the like; bioactive samples, such as plasma, blood, serum and the like; medications, such as the injection of posterior pituitary, ethylene and stannous chloride for injection and the like; foods, such as fresh meat, fresh fish and the like; drinks such as fresh milk, dairy products, yogurt, pasteurized milk and the like.
[0088] In the present invention, the difference between the activation energy of the volatilization process of the volatile paint layer and the activation energy of the quality variations or failure process of the thermally sensitive article is in a predetermined range, and preferably, the difference is in the range of ± 10 kJ / mol, more preferably ± 5 kJ / mol. Preferably, the energy for activating the volatilization process of the volatile paint layer is 60 to 140 kJ / mol. The activation energy of the volatilization process of the volatile ink layer described in the present invention refers to the apparent activation energy of the time-temperature indicator of the present invention in use during the volatilization process of the volatile ink layer.
[0089] Preferably, the volatile ink layer is in a solid or liquid state, at a temperature in the range 0 to 80 ° C, more preferably, in the solid state at a temperature in the range 0 to 50 ° C.
[0090] In the present invention, the volatile dye is not particularly limited, and any volatile dye that may come to achieve the objective of the present invention can be used. Preferably, the volatile dye is at least one selected from azo dyes, anthraquinone dyes, compounds of formula I and derivatives thereof, or a combination thereof, in which compounds of formula I have the following formula:

[0091] where,
[0092] R1 is selected from the group consisting of hydrogen, halogen, straight or branched C1-6, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl and the like; C1-6 linear or branched, alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like; -COR2, - COOR2;
[0093] R2 is selected from the group consisting of hydrogen, C1-6 straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl , isopentyl, neopentyl, n-hexyl and the like; C1-6 linear or branched alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, hexylamino and the like.
[0094] More preferably, the volatile dye is selected from the compound of formula I.
[0095] Preferably, the volatile paint layer also contains one or more volatilization additives. In the present invention, the volatilization additive is not particularly limited, and any volatilization additive, which may come to achieve the objective of the present invention can be used, as long as it can adjust the volatilization rate of the volatile dye of the present invention. The volatilization additive in the present invention can accelerate or delay the volatilization of the volatile dye. Preferably, the volatilization additive is one or more of those selected from the following volatile compounds:
[0096] linear alkanes, branched alkanes, cycloalkanes, aromatic hydrocarbons, such as hexane, heptane, octane or the isomer thereof, cyclohexane, heptane, cyclopentane, naphthalene, anthracene and the like;
[0097] linear or branched or aromatic or cyclic alcohols, such as butantetraol, lauryl alcohol, tridecanol, tetradecanol, pentecanol, hexadecanol, stearyl alcohol and the like;
[0098] linear or branched or cyclic or aromatic carboxylic acids, such as maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid and the like;
[0099] amino acids, such as aminobenzoic acid, leucine, phenylalanine and the like;
[00100] esters;
[00101] sulfones, such as diphenyl sulfone, diphenyl disulfone, di benzyl sulfone, dibutyl sulfone and the like;
[00102] and various volatile natural materials, including naphthalene, camphor and the like;
[00103] Preferably, the volatile paint layer also contains one or more solvents. In the present invention, the solvent is not particularly limited, and any solvent that can achieve the purpose of the present invention can be used. Preferably, the solvent is one or more selected from the group consisting of water, hexane, cyclohexane, tetrahydrofuran, benzene, dimethyl-benzene, methanol, ethanol, isopropyl alcohol, 2-butanol, acetone, diethyl ether , methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane and dichloroethane.
[00104] In the present invention, the type of the adsorption material is not particularly limited, and any adsorption material that can achieve the purpose of the present invention can be used. Preferably, the adsorption material of the present invention irreversibly adsorbs the volatilized dye from the volatile paint layer, and more preferably, the adsorption rate at which the adsorption material adsorbs the volatile volatile dye from the volatile paint layer. it is much higher than the volatilization rate of volatile dye. When the adsorption rate at which the adsorption material adsorbs the volatile volatile dye from the volatile dye layer is much higher than the volatilization rate of the volatile dye, the dye absorption rate is substantially volatile only related to the volatilization rate. Therefore, the rate of volatilization of the dye is only influenced by means of temperature, but not, for example, by the factor that is blocked by the saturated vapor and / or quasi-saturated vapor produced by its volatilization, and the like. As the amount of dye volatilization is only influenced by temperature and time, the color change due to volatilization may reflect the thermal history of the time-temperature indicator, more precisely, in order to monitor the thermal history of an article thermally sensitive more accurately. Certainly, if it is necessary for the layer of adsorption material to limit the volatilization of the volatile paint layer in order to reduce its volatilization rate, the adsorption material with relatively low absorption rate can also be used. In one embodiment, the adsorption material includes, but is not limited to, oily or aqueous glue, commercial adhesive paper, adhesive tape and the like.
[00105] In the present invention, the materials of the first layer of substrate material and the second layer of substrate material are not particularly limited, and any substrate material, which can achieve the objective of the present invention can be used. The same material or different materials can be used for the first layer of substrate material and the second layer of substrate material. Preferably, the first layer of substrate material together with the first layer of release protective film seals the volatile paint layer, the layer of substrate material together with the second seal of the release film layer of the adsorption material. Preferably, the first layer of substrate material has a laminated structure, and an adhesive sealing layer, an adhesive layer and a third film release layer are composed in sequence on the face opposite the layer of volatile paint on the layer of substrate material. In use, the third film release layer is removed first, and the adhesive layer of the first layer of substrate material is glued to the thermally sensitive layer. Then, the first film release layer and the second film release layer are removed, the adsorption material layer is aligned with the volatile paint layer, and the absorption material layer and the volatile paint layer are removed. sealed in the thermally sensitive article.
[00106] Preferably, the time-temperature indicator further comprises an insulation layer, and in use this insulation layer is located between the volatile paint layer and the adsorption material layer. Before use, this insulation layer is located between the volatile paint layer and the first film release layer, or between the absorption material layer and the second film release layer. This insulation layer can be used for the purpose of adjusting the volatilization rate of the volatile dye in the volatile paint layer. This insulation layer can be beneficial for separating the volatile paint layer and the adsorption material layer. In the present invention, the material of the insulation layer is not particularly limited, and any material can be used as long as it can achieve the purpose of the present invention. Non-limiting examples include non-woven cloth, P6 nylon net, P66 nylon net and the like. When observing or determining the color or color difference of the volatile paint layer, this insulation layer together with the adsorption material layer is separated from the volatile paint layer.
[00107] The film release layer of the present invention is not particularly limited, and any film release layer, which can achieve the purpose of the present invention can be used. It can be understood that the film release layer of the present invention can be easily selected by means of persons skilled in the art according to the description of the present invention. In the present invention, the first, second and third film release layers have no volatile dye adsorption effect. The material used in the film release layer can be widely selected, and non-limiting examples include paper, wax paper, and polymer film, such as polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene terephthalate glycol and the like.
[00108] Without limiting himself to any theory, the inventor of the present invention believes that the rate of change of the deterioration or failure process of the thermally sensitive article that follows the Arhenius equation, that is,
, where, k is the rate of change of the deterioration or failure process of the thermally sensitive article, T is the absolute temperature (K), E is the activation energy of the process in which the thermally sensitive article deteriorates or fails, R is the ideal gas constant, and A is a constant.
[00109] Likewise, not being limited to any theory, the inventor of the present invention considers that the volatilization rate of the volatile dye layer according to the present invention, follows the Arrhenius equation, that is,
The volatilization rate of the volatile paint layer according to the present invention can be adjusted to a rate close to the rate of change of the deterioration or failure process of the thermally sensitive article by selecting the type of volatile dye and the quantity thereof. or the addition of a volatilization additive. In this way, the thermal history of the deterioration or failure process of the thermally sensitive article is precisely indicated, through the fading rate of the volatile dye. The rate of color fading has a positive correlation with its rate of volatilization, so that the rate of color fading has a positive correlation with the rate of change of process deterioration or failure of the thermally sensitive article.
[00110] In another embodiment, the first layer of substrate has one or more transparent zones. When the time-temperature indicator is to be used, a time-temperature indicator in the state of use is formed as follows: removal of the first film release layer and the second film release layer, 0 layer alignment absorption material with the volatile paint layer, and sealing of the volatile paint layer and the adsorption material layer between the first substrate layer and the second substrate layer. The second layer of substrate is glued to the thermally sensitive article. Before using the thermally sensitive article, the color depth or color difference of the volatile paint layer is observed or measured, directly, by means of a transparent zone. Preferably, the first substrate layer itself is transparent, and when using the time-temperature indicator, the second substrate layer is glued to the thermally sensitive article. Before using the thermally sensitive article, the color change of the volatile paint layer is observed or measured through the first layer of transparent substrate. In fact, as the color of the volatile paint layer can be directly observed, the thermally sensitive article can be selected at any time to remove the thermally sensitive article that has failed or deteriorated, reducing unnecessary storage and transportation. As the thermally sensitive article is generally stored and transported at a low temperature, it can, of course, reduce storage and transportation costs in order to reduce unnecessary storage and transportation. In another aspect, the user can choose to use the thermally sensitive article with a lighter color, which has not deteriorated or not, in order to reduce the possibility of deterioration or failure of the thermally sensitive article.
[00111] In the present invention, the materials of the first layer of substrate material and the second layer of substrate material are not particularly limited, and any substrate material, which can achieve the objective of the present invention can be used. The same material or different materials can be used for the first layer of substrate material and the second layer of substrate material. Preferably, the first layer of substrate material together with the first layer of release protective film seals the volatile paint layer, the layer of substrate material together with the second seal of the release film layer of the adsorption material. Preferably, the second layer of substrate material has a laminated structure, and an adhesive sealing layer, an adhesive layer and a fourth film release layer are composed in sequence on the face opposite to the layer of volatile paint on the layer of substrate material. In use, the fourth film release layer is removed first, and the adhesive layer of the second layer of substrate material is glued to the thermally sensitive layer. Then, the first film release layer and the second film release layer are removed, the adsorption material layer is aligned with the volatile paint layer, and the absorption material layer and the volatile paint layer are removed. sealed in the thermally sensitive article.
[00112] Like other characteristics and their description and variations in this modality are the same or similar to the previous modality, they are not repeated in the present invention. For example, the volatile paint layer, the descriptions of the absorption material layer, the insulation layer, the first film release layer, the second film release layer and the reference color marking, in this modality are the same or similar to those of the previous modality, in this modality, the difference in color or color intensity of the paint layer is volatile observed or measured in the same way or similar to the previous modality, in this modality, the way to determine if the article thermally sensitive fails or deteriorates is the same or similar to the previous modality. All the same or similar parts are not repeated in the present invention.
[00113] This can reduce costs and increase the accuracy of monitoring the thermal history of the thermally sensitive article to use the time-temperature indicator provided by means of the first aspect of the present invention. The customized time-temperature indicator can be developed for several thermally sensitive articles, selecting the appropriate volatile dye, volatilization additive, solvent and quantity. In particular, for a specific thermally sensitive article, the activation energy of their deterioration or failure process and each of the parameters in the Arrhenius equation can be determined through an experiment. Then, each of the parameters of the volatile ink layer in the Arrhenius equation is adjusted so that the next or equal to that of the specific thermally sensitive article, selecting the appropriate volatile dye, volatilization additive, solvent and the amount thereof, in Then, a time-temperature indicator that accurately monitors the thermal history of this specific thermally sensitive article can be obtained, which cannot be achieved in the prior art.
[00114] The time-temperature indicator provided by means of the first aspect of the present invention directly determines whether the thermally sensitive article does not deteriorate or fail by changing the color of the volatile paint layer, which is simple and easy to apply. More time-temperature indicator in the state of the art can only be stored at a low temperature. The temperature time indicator of the present invention skillfully adopts the structure so that the indicating function layer and the adsorption function layer are stored separately and combined in use, so that the time-temperature indicator of the present invention can stored at normal temperature, reducing the cost of using the indicator.
[00115] The time-temperature indicator provided by means of the first aspect of the present invention is achieved through a new theory of color change of the indicator. Different from the indicators of the type of polymer, the type of enzymatic reaction and the type of diffusion, the present invention achieves color change, using the volatilization property of the material through a process of transferring the volatilization-adsorption dye. After the approval of a new theory, low-cost materials can be selected and used, while the selection range is very wide, and the overall cost for preparing the indicator is reduced.
[00116] When the first layer of substrate material has one or more transparent zones or the first layer of material, in itself is transparent, the color of the volatile ink layer can be observed, in a direct way, through the first layer of substrate material. In this way, the user can select and use the thermally sensitive article according to the color of the volatile paint layer, and filter the thermally sensitive article that has deteriorated or failed during storage and transportation, so that the efficiency of use is obviously increased and storage and transportation costs are reduced.
[00117] In use, the time-temperature indicator according to the present invention is attached to the thermally sensitive article packaging container, and can certainly be attached to the thermally sensitive article, in any convenient way. The accessory described in the present invention can be in any possible form, such as gluing. For example, the time-temperature indicator can be affixed, for example, to the outer surface of the primary package (or the minimum package, such as a vaccine vial) of vaccines, drugs and the like, such as the outer surface of a vaccine or medicine bottle cup that is provided with a glass bottle, or the outer surface of a flexible plasma or milk bag, which is provided with a soft pouch.
[00118] The second aspect of the present invention provides a thermally sensitive article using the temperature indicator according to the first aspect of the present invention. The thermally sensitive article is as described in the first aspect of the present invention.
[00119] The third aspect of the present invention provides a method of preparing a time-temperature indicator for the purpose of monitoring the quality status of a thermally sensitive article.
[00120] In one embodiment, the method of the third aspect of the present invention comprises the following steps:
[00121] providing a first layer of substrate material;
[00122] coating one or more zones on one side of the first layer of substrate material with a layer of volatile paint in order to form a layer of volatile paint, in which the difference between the activation energy of the volatilization process the volatile paint layer and the change in the quality process or failure of the thermally sensitive article is of a predetermined interval;
[00123] covering the layer of volatile paint with a first release film, wherein the first layer of release film together with the first seals of layers of substrate material, the layer of volatile paint between them, for the purpose to form an indication function layer;
[00124] and
[00125] providing a second layer of substrate material;
[00126] coating one side of the second layer of substrate material with an adsorption material for the purpose of forming a layer of adsorption material, wherein the layer of absorption material is larger than the layer of volatile paint in dimension ;
[00127] coating an adhesive layer around the layer of absorption material in the second layer of the substrate material; and
[00128] covering the adhesive layer and the adsorption material layer with a second film release layer and sealing the adsorption material layer between the second substrate material layer and the second film release layer for the purpose of form a function adsorption layer;
[00129] In use, a time-temperature indicator is formed as follows: removing the first release film and second release film, aligning the adsorption function layer with the volatile paint layer, gluing the first layer of substrate firmly glued on the thermally sensitive article, and seal the layer of volatile paint, together with the layer of adsorption material between the first layer of substrate material and the second layer of substrate material.
[00130] The separate indication function layer and the adsorption function layer are obtained using the preparation method above. Therefore, the indication function layer and the time-temperature indicator adsorption function layer of the present invention can be stored and transported at normal temperature, which is difficult to achieve in the prior art time-temperature indicator. In use, they are combined for the purpose of forming the time-temperature indicator of the present invention, glued to the thermally sensitive article, and subjected to storage and transportation, together with the thermally sensitive article. The time-temperature indicator can accurately control the thermal history of the thermally sensitive article, and accurately determine the status of the quality thermally sensitive article.
[00131] Preferably, after the time-temperature indicator of the present invention has been previously subjected to the same process as the process in which the thermally sensitive article fails or deteriorates, the color difference when the thermally sensitive article fails or deteriorates is measured with a colorimeter, and recorded as the final color difference. Before the thermally sensitive article is used, the layer of adsorption material is separated from the layer of volatile paint, the actual color difference from the volatile paint layer is measured with a colorimeter, and the actual color difference is compared to the difference in final color. If the actual color difference is greater than the final color difference, the thermally sensitive article that has not failed or deteriorated, and is in a state of usable quality. If the actual color difference is less than the final color difference, the thermally sensitive article has failed or deteriorated, and is in a state of useless quality.
[00132] Preferably, after the time-temperature indicator of the present invention has been previously subjected to the same process as the process in which the thermally sensitive article fails or deteriorates, the color difference when the thermally sensitive article fails or deteriorates is measured and recorded as the final color difference. A reference color marking having the final color difference is prepared with a non-volatile dye or a non-volatile pigment. Before the thermally sensitive article is used, the layer of adsorption material is separated from the layer of volatile paint, the actual color of the layer of volatile paint is observed visually, and the actual color is compared with the reference color marking. If the actual color is darker than the reference color marking, the thermally sensitive article has not failed or deteriorated, and is in a state of usable quality. If the actual color is lighter than or equal to that of the reference color marking, the thermally sensitive article has failed or deteriorated, and is in a state of useless quality.
[00133] The reference color marking can be independent of the indication function layer and the adsorption function layer. Preferably, the reference color marking is included in the indication function layer. Preferably, after coating the volatile ink layer, a non-volatile dye or non-volatile pigment having the final color difference is coated around the volatile ink layer in order to form the reference color marking. The reference color marking can be arranged in the vicinity of the volatile ink layer in any possible way, for example, the reference color marking is arranged side by side with the volatile ink layer, or arranged around the ink layer volatile, or the like. More preferably, the first layer of substrate material, in itself, is prepared as the reference color marking.
[00134] For example, if a thermally sensitive article will deteriorate or not, after time t1 at temperature T1, then the time-temperature indicator of the present invention is subjected to a treatment for time t1 at temperature T1, and the color difference of the volatile dye layer after treatment is recorded as the final color difference.
[00135] The thermally sensitive article is selected from vaccines, biological articles, bioactive samples, medicines, food or drinks. Preferably, the thermally sensitive article is an article that needs to be stored and / or transported at a temperature in the range of -40 ° C to 50 ° C, preferably from -30 ° C to 40 ° C, preferably from - 30 ° C to 30 ° C, preferably from -20 ° C to 20 ° C, preferably from -20 ° C to 10 ° C, preferably from -10 ° C to 10 ° C, preferably from 0 ° C at 10 ° C, as well as from 2 ° C to 8 ° C. For example, it can be any item that needs to be stored and / or transported at a temperature in the range of 2 ° C to 8 ° C recorded in volumes of one, two and three of the "Chinese pharmacopoeia", 2005 or 2010 edition The thermally sensitive article that includes, but is not limited to: vaccines, such as thermally unstable vaccines, such as polio vaccine, typhoid vaccine, hepatitis B vaccine and the like; biological articles, such as human immunoglobulin, porcine human anti-immunoglobulin T lymphocytes, and the like; bioactive samples, such as plasma, blood, serum and the like; medications, such as the injection of posterior pituitary, ethylene and stannous chloride for injection and the like; foods, such as fresh meat, fresh fish and the like; beverages, such as fresh milk, milk product, yogurt, pasteurized milk and the like.
[00136] In the present invention, the difference between the activation energy of the volatilization process of the volatile paint layer and the activation energy of the variations of the failing or deteriorating quality process of the thermally sensitive article is in a predetermined range, and preferably , the difference is in the range of ± 10 kJ / mol, more preferably ± 5 kJ / mol. Preferably, the energy for activating the volatilization process of the volatile paint layer is 60 to 140 kJ / mol. The activation energy of the volatilization process of the volatile ink layer described in the present invention refers to the apparent activation energy of the time-temperature indicator of the present invention in use during the volatilization process of the volatile ink layer.
[00137] Preferably, the volatile ink layer is in a solid or liquid state, at a temperature in the range 0 to 80 ° C, more preferably, in the solid state at a temperature in the range 0 to 50 ° C.
[00138] In the present invention, the volatile dye is not particularly limited, and any volatile dye that can achieve the purpose of the present invention can be used. Preferably, the dye is volatile, at least one selected from azo dyes, anthraquinone dyes, compounds of formula I and derivatives thereof, or a combination thereof, wherein the compounds of formula I have the following formula :

[00139] where,
[00140] R1 is selected from the group consisting of hydrogen, halogen, C1-6 straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n -pentyl, isopentyl, neopentyl, n-hexyl and the like; C1-6 linear or branched alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like; -COR2, -COOR2;
[00141] R2 is selected from the group consisting of hydrogen, C1-6 straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl , isopentyl, neopentyl, n-hexyl and the like; C1-6 linear or branched alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, hexylamino and the like.
[00142] More preferably, the volatile dye is selected from the compound of formula I.
[00143] Preferably, the volatile paint layer also contains one or more volatilization additives. In the present invention, the volatilization additive is not particularly limited, and any volatilization additive, which can achieve the objective of the present invention, can be used. The volatilization additive in the present invention can accelerate or delay the volatilization of the volatile dye. Preferably, the volatilization additive is one or more selected from the following volatile compounds:
[00144] linear alkanes, branched alkanes, cycloalkanes, aromatic hydrocarbons, such as hexane, heptane, octane or the isomer thereof, cyclohexane, heptane, cyclopentane, naphthalene, anthracene and the like;
[00145] linear or branched or aromatic or cyclic alcohols, such as butantetraol, lauryl alcohol, tridecanol, tetradecanol, penta-decanol, hexadecanol, stearyl alcohol and the like;
[00146] linear or branched or cyclic, or aromatic carboxylic acids, such as maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid and the like;
[00147] amino acids, such as aminobenzoic acid, leucine, phenylalanine and the like;
[00148] esters;
[00149] sulfones, such as diphenyl sulfone, diphenyl disulfone, di benzyl sulfone, dibutyl sulfone and the like;
[00150] and various volatile natural materials, including naphthalene, camphor and the like;
[00151] Preferably, the volatile paint layer also contains one or more solvents. In the present invention, the solvent is not particularly limited, and any solvent that can achieve the purpose of the present invention can be used. Preferably, the solvent is one or more selected from the group consisting of water, hexane, cyclohexane, tetrahydrofuran, benzene, dimethyl-benzene, methanol, ethanol, isopropyl alcohol, 2-butanol, acetone, diethyl ether , methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane and dichloroethane.
[00152] Preferably, the volatile ink layer is formed on the first layer of substrate material, after mixing the volatile dye, additive and solvent volatilization. The coating method is not particularly limited, and any coating method can be used as long as the layer of volatile paint is formed. For example, any method known for the purpose of forming the coating, such as spraying, printing, smearing and the like, can be used.
[00153] Preferably, the adsorption material of the present invention irreversibly adsorbs the volatilized dye from the volatile paint layer, and more preferably, the adsorption rate at which the adsorption material adsorbs the volatilized volatile dye from the layer of volatile ink is much higher than the volatilization of the volatile dye rate. When the adsorption rate at which the adsorption material adsorbs the volatile volatile dye from the volatile dye layer is much higher than the volatilization rate of the volatile dye, the dye absorption rate is substantially volatile only related to the volatilization rate. Therefore, the rate of volatilization of the dye is only influenced by means of temperature, but not by, for example, the factor that is blocked by the saturated vapor and / or quasi-saturated vapor produced through its volatilization, and the like. As the amount of dye volatilization is only influenced by temperature and time, the thermal history of the temperature time indicator can reflect more accurately. Certainly, if this is necessary, in order to reduce the volatilization rate of the volatile paint layer, the adsorption material with relatively low adsorption rate, such as the adsorption material, in which the dye absorption rate is lower than the volatilization rate of the dye, it can also be used. In the present invention, the type of the adsorption material is not particularly limited, and any adsorption material that can achieve the purpose of the present invention can be used. In one embodiment, the adsorption material includes, but is not limited to, oily or aqueous glue, commercial adhesive paper, adhesive tape and the like.
[00154] In the present invention, the materials of the first layer of substrate material and the second layer of substrate material are not particularly limited, and any substrate material, which can achieve the objective of the present invention can be used. The same material or different materials can be used for the first layer of substrate material and the second layer of substrate material. Preferably, the first layer of substrate material together with the first layer of release protective film seals the volatile paint layer, the layer of substrate material together with the second seal of the release film layer of the adsorption material. Preferably, the first layer of substrate material has a laminated structure, and an adhesive sealing layer, an adhesive layer and a third film release layer are composed in sequence on the face opposite the layer of volatile paint on the layer of substrate material. In use, the third film release layer is removed first, and the adhesive layer of the first layer of substrate material is glued to the thermally sensitive layer. Then, the first film release layer and the second film release layer are removed, the adsorption material layer is aligned with the volatile paint layer, and the absorption material layer and the volatile paint layer are removed. sealed in the thermally sensitive article.
[00155] Preferably, the time-temperature indicator further comprises an insulation layer, and this insulation layer is located between the layer of volatile paint and the layer of adsorption material. In use, this insulation layer is located between the volatile paint layer and the first film release layer, or between the absorbent material layer and the second film release layer. This insulation layer can be used for the purpose of adjusting the volatilization rate of the volatile dye in the volatile paint layer. In the present invention, the material of the insulation layer is not particularly limited, and any material can be used as long as it can achieve the purpose of the present invention. Non-limiting examples include non-woven cloth, P6 nylon net, P66 nylon net and the like. When observing or determining the color or color difference of the volatile paint layer, this insulation layer together with the adsorption material layer is separated from the volatile paint layer. For example, the insulation layer can be coated after the coating of the volatile paint layer is coated, and then the first release film layer is coated. Alternatively, the insulating layer is coated after coating the absorbent material layer, and then the second release film layer is coated.
[00156] In another embodiment, the method of the third aspect of the present invention comprises the following steps:
[00157] providing a first layer of substrate material;
[00158] coating one or more zones on one side of the first layer of substrate material with a layer of volatile paint in order to form a layer of volatile paint, in which the difference between the activation energy of the volatilization process the volatile paint layer and that the change in the quality process or failure of the thermally sensitive article is of a predetermined interval;
[00159] covering the layer of volatile paint with a first release film, in which the first layer of release film together with the first seals of layers of substrate material, the layer of volatile paint between them, for the purpose to form an indication function layer;
[00160] and
[00161] providing a second layer of substrate material;
[00162] coating one side of the second layer of substrate material with an adsorption material for the purpose of forming a layer of adsorption material, wherein the layer of absorption material is larger than the layer of volatile paint in dimension ;
[00163] coating an adhesive layer around the layer of absorbent material in the second layer of the substrate material; and
[00164] covering the adhesive layer and the adsorption material layer with a second film release layer and sealing the adsorption material layer between the second substrate material layer and the second film release layer for the purpose of form a function adsorption layer.
[00165] In use, a time-temperature indicator is formed as follows: removing the first release film and second release film, aligning the adsorption function layer with the volatile paint layer, pasting the second layer of substrate firmly glued on the thermally sensitive article, and seal the layer of volatile paint, together with the layer of adsorption material between the first layer of substrate material and the second layer of substrate material.
[00166] Preferably, the first substrate layer has one or more transparent zones, and the color of the volatile ink layer can be measured or observed across the area. Most preferably, the first layer of substrate is itself transparent, and the color of the volatile paint layer can be measured or observed through the first layer of transparent substrate.
[00167] The film release layer of the present invention is not particularly limited, and any film release layer, which can achieve the purpose of the present invention, can be used. It can be understood that the film release layer of the present invention can be easily selected by means of persons skilled in the art according to the description of the present invention. In the present invention, the first, second, third and fourth release layer of the film have no volatile dye adsorption effect. The material used in the film release layer can be widely selected, and non-limiting examples include paper, wax paper, and polymer film, such as polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene glycol terephthalate and the like.
[00168] Like other characteristics and their description and variations in this modality are the same or similar to those of the previous modality, they are not repeated in the present invention. For example, the volatile paint layer, the descriptions of the absorption material layer, the insulation layer, the first film release layer, the second film release layer and the reference color marking, in this modality are the same or similar to those of the previous modality, in this modality, the difference in color or color intensity of the volatile paint layer is observed or measured in the same way or similar to the previous modality, in this modality, the way to determine if the thermally sensitive article fails or deteriorates is the same or similar to the previous modality. All the same or similar parts are not repeated in the present invention.
[00169] The fourth aspect of the present invention provides a method for detecting the quality status of a thermally sensitive article, and in one embodiment, the method of the fourth aspect of the present invention comprises the following steps:
[00170] providing a thermally sensitive article, which deteriorates or fails after time t1, at a desired treatment temperature T1;
[00171] fix the following layers in one or more areas of the thermally sensitive article:
[00172] a volatile ink layer, in which the difference between the activation energy of the volatilization process of the volatile ink layer and the deterioration and failure of the thermally sensitive article process is in a predetermined range;
[00173] a layer of adsorption material, which irreversibly adsorbs the volatilized dye from the volatile paint layer;
[00174] a layer of sealing film, which is larger than the layer of absorption material and the layer of volatile paint in dimension, and hermetically bonds the layer of absorption material and the layer of volatile paint on the thermally sensitive article ;
[00175] treat the thermally sensitive article fixed with the sealing film practically;
[00176] remove the layer of adsorption material;
[00177] observe or determine the actual color difference C2 for the volatile paint layer that has been practically treated;
[00178] in which the final color difference of the volatile paint layer after time t1 at temperature T1 is C1;
[00179] compare the actual color difference C2 with the final color difference C1 of the volatile paint layer, where if the actual color difference C2 of the volatile paint layer is greater than the final color difference C1, which is indicated so that the thermally sensitive article remains in a state of effective quality; if the actual color difference C2 of the volatile paint layer is less than the difference of the final color C1, it is indicated that the thermally sensitive article has already failed or deteriorated.
[00180] Preferably, before attaching the layer of volatile paint, a layer of substrate material is attached to the thermally sensitive article.
[00181] Preferably, an insulation layer is fixed between the volatile paint layer and the adsorption material layer.
[00182] In another embodiment, the method of the fourth aspect of the present invention comprises the following steps:
[00183] providing a thermally sensitive article, which deteriorates or fails after time t1, at a desired treatment temperature T1;
[00184] fix the following layers in one or more areas of the thermally sensitive article:
[00185] the layer of adsorption material;
[00186] volatile paint layer;
[00187] layer of transparent sealing film;
[00188] wherein, the irreversible adsorption material layer adsorbs the volatilized dye from the volatile paint layer, and the difference between the energy of activation of the volatilization process of the volatile paint layer and that the deterioration or failure of the process of thermally sensitive article is of a predetermined range;
[00189] treat the thermally sensitive article fixed with the sealing film practically;
[00190] observe or determine the actual color difference C2 for the volatile paint layer that has been practically treated;
[00191] in which the final color difference of the volatile paint layer after time t1 at temperature T1 is C1;
[00192] comparing the actual color difference C2 with the final color difference C1 of the volatile paint layer, where if the actual color difference C2 of the volatile paint layer is greater than the final color difference C1, it is indicated that the thermally sensitive article remains in an effective state of quality, if the actual color difference C2 of the volatile paint layer is less than the difference of the final color C1, it is indicated that the thermally sensitive article has already failed or deteriorated.
[00193] Preferably, before attaching the layer of absorbent material, a layer of substrate material is attached to the thermally sensitive article.
[00194] Preferably, an insulation layer is fixed between the layer of volatile paint and the layer of adsorption material.
[00195] According to the fourth aspect of the present invention, preferably, after the thermally sensitive article in which all the layers are fixed is previously subjected to the process of deterioration and failure, the color difference of the thermally sensitive article when it fails or deterioration is measured with a colorimeter, and recorded as the final color difference. Before the thermally sensitive article is used, the actual color difference of the volatile paint layer is measured with a colorimeter, and the actual color difference is compared to the final color difference. If the actual color difference is greater than the final color difference, the thermally sensitive article that has not failed or deteriorated, and is in a state of usable quality. If the actual color difference is less than the final color difference, the thermally sensitive article has failed or deteriorated, and is in a state of useless quality.
[00196] Preferably, a reference color marking having the final color difference is prepared with a non-volatile dye or a non-volatile pigment. Before the thermally sensitive article is used, the actual color of the volatile paint layer is observed visually, and the actual color is compared to the reference color marking. If the actual color is darker than the reference color marking, the thermally sensitive article has not failed or deteriorated, and is in a state of usable quality. If the actual color is lighter than or equal to that of the reference color marking, the thermally sensitive article has failed or deteriorated, and is in a state of useless quality.
[00197] The reference color marking can be independent of the indication function layer and the adsorption function layer. Preferably, the reference color marking is included in the indication function layer. Preferably, after coating the volatile ink layer, a non-volatile dye or non-volatile pigment has the final color differences coated around the volatile ink layer in order to form the reference color marking. The reference color marking can be arranged in the vicinity of the volatile ink layer in any possible way, for example, the reference color marking is arranged side by side with the volatile ink layer, or arranged around the ink layer volatile, or similar
[00198] For example, if a thermally sensitive article will deteriorate or not, after time t1 at temperature T1, then the thermally sensitive article in which all layers are fixed is subjected to a treatment for moment t1 at T1 temperature, and the color difference of the volatile paint layer after treatment is recorded as the value of the final color difference.
[00199] The thermally sensitive article is selected from vaccines, biological articles, bioactive samples, medicines, food or drinks. Preferably, the thermally sensitive article is an article that needs to be stored and / or transported at a temperature in the range of -40 ° C to 50 ° C, preferably from -30 ° C to 40 ° C, preferably from - 30 ° C to 30 ° C, preferably from -20 ° C to 20 ° C, preferably from -20 ° C to 10 ° C, preferably from -10 ° C to 10 ° C, preferably from 0 ° C at 10 ° C, as well as from 2 ° C to 8 ° C. For example, it can be any item that needs to be stored and / or transported at a temperature in the range of 2 ° C to 8 ° C recorded in volumes of one, two and three of the "Chinese pharmacopoeia", 2005 or 2010 edition The thermally sensitive article that includes, but is not limited to: vaccines, such as thermally unstable vaccines, such as polio vaccine, typhoid vaccine, hepatitis B vaccine and the like; biological articles, such as human immunoglobulin, porcine human anti-immunoglobulin T lymphocytes, and the like; bioactive samples, such as plasma, blood, serum and the like; medications, such as the injection of posterior pituitary, etifenin and stannous chloride for injection and the like; foods, such as fresh meat, fresh fish and the like; beverages, such as fresh milk, milk product, yogurt, pasteurized milk and the like.
[00200] In the present invention, the difference between the activation energy of the volatilization process of the volatile paint layer and the activation energy of the quality variations or failure process of the thermally sensitive article is in a predetermined range, and preferably, the difference is in the range of ± 10 kJ / mol, more preferably ± 5 kJ / mol. Preferably, the energy for activating the volatilization process of the volatile paint layer is 60-140 kJ / mol. The activation energy of the volatilization process of the volatile ink layer described in the present invention refers to the apparent activation energy of the time-temperature indicator of the present invention in use during the volatilization process of the volatile ink layer.
[00201] Preferably, the volatile ink layer is in a solid or liquid state, at a temperature in the range 0 to 80 ° C, more preferably, in the solid state at a temperature in the range 0 to 50 ° C.
[00202] In the present invention, the volatile dye is not particularly limited, and any volatile dye that can achieve the purpose of the present invention can be used. Preferably, the volatile dye is at least one selected from azo dyes, anthraquinone dyes, compounds of formula I and derivatives thereof, or a combination thereof, wherein the compounds of formula I have the following formula :

[00203] where,
[00204] R1 is selected from the group consisting of hydrogen, halogen, C1-6 straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n pentyl, isopentyl, neopentyl, n-hexyl and the like; C1-6 linear or branched alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like; -COR2, -COOR2;
[00205] R2 is selected from the group consisting of hydrogen, C1-6 straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl , isopentyl, neopentyl, n-hexyl and the like; C1-6 linear or branched alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, hexylamino and the like.
[00206] More preferably, the volatile dye is selected from the compound of formula I.
[00207] Preferably, the volatile paint layer also contains one or more volatilization additives. In the present invention, the volatilization additive is not particularly limited, and any volatilization additive, which can achieve the objective of the present invention, can be used. The volatilization additive in the present invention can accelerate or delay the volatilization of the volatile dye. Preferably, the volatilization additive is one or more selected from the following volatile compounds:
[00208] linear alkanes, branched alkanes, cycloalkanes, aromatic hydrocarbons, such as hexane, heptane, octane or the isomer thereof, cyclohexane, heptane, cyclopentane, naphthalene, anthracene and the like;
[00209] linear or branched or aromatic or cyclic, such as butantetraol, lauryl alcohol, tridecanol, tetradecanol, pentadecanol, hexadecanol, stearyl alcohol and the like;
[00210] linear or branched or cyclic carboxylic acids, or aromatics, such as maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid and the like;
[00211] amino acids, such as aminobenzoic acid, leucine, phenylalanine and the like;
[00212] esters;
[00213] sulfones, such as diphenyl sulfone, diphenyl disulfone, di benzyl sulfone, dibutyl sulfone and the like;
[00214] and various volatile natural materials, including naphthalene, camphor and the like;
[00215] Preferably, the volatile paint layer also contains one or more solvents. In the present invention, the solvent is not particularly limited, and any solvent that can achieve the purpose of the present invention can be used. Preferably, the solvent is one or more selected from the group consisting of water, hexane, cyclohexane, tetrahydrofuran, benzene, dimethyl-benzene, methanol, ethanol, isopropyl alcohol, 2-butanol, acetone, diethyl ether , methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane and dichloroethane.
[00216] Preferably, the volatile ink layer is formed on the first layer of substrate material, after mixing the volatile dye, volatilization additive and the solvent. The coating method is not particularly limited, and any coating method can be used as long as the layer of volatile paint is formed. For example, any method known for the purpose of forming the coating, such as spraying, printing, smearing and the like, can be used.
[00217] Preferably, the adsorption material of the present invention irreversibly adsorbs the volatilized dye from the volatile paint layer, and more preferably, the adsorption rate at which the adsorption material adsorbs the volatilized volatile dye from the layer Volatile ink is much higher than volatile dye volatilization rate. When the rate of adsorption at which the adsorption material adsorbs the volatile volatile dye from the volatile dye layer is much higher than the volatilization rate of the volatile dye, the absorption rate of the volatile dye is substantially only related to the volatilization rate. Therefore, the volatilization rate of the dye is only influenced by the temperature, but not, for example, by the factor that is blocked by the saturated steam and / or quasi-saturated steam produced through its volatilization, and the like. As the amount of volatilization of the dye is only influenced by temperature and time, the thermal history of the thermally sensitive article can be monitored more precisely. Certainly, if this is necessary in order to reduce the volatilization rate of the volatile paint layer, the adsorption material with relatively low adsorption rate, such as the adsorption material, where the absorption rate is lower than the absorption rate volatilization of the dye, can be selected. In the present invention, the type of the adsorption material is not particularly limited, and any adsorption material that can achieve the purpose of the present invention can be used. In one embodiment, the adsorption material includes, but is not limited to, oily or aqueous glue, commercial adhesive paper, adhesive tape and the like.
[00218] In the present invention, the materials of the first layer of substrate material and the second layer of substrate material are not particularly limited, and any substrate material, which can achieve the purpose of the present invention can be used. The same material or different materials can be used for the first layer of substrate material and the second layer of substrate material.
[00219] The fifth aspect of the present invention provides a compound, which has a structure of formula I:
[00220] where,
[00221] R1 is selected from the group consisting of hydrogen; halogen; C1-6 straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like; C1-6 linear or branched alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like; -COR2, -COOR2 and the like;
[00222] R2 is selected from the group consisting of hydrogen; C1-6 straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl; C1-6 linear or branched alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino and hexylamino, and the like.
[00223] In the compound according to the fifth aspect of the present invention,
[00224] R1 is selected from hydrogen, -COR2 and -COOR2;
[00225] R2 is selected from the group consisting of hydrogen; C1-4 straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl; C1-4 linear or branched alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino and hexylamino, and the like.
[00226] In the compound according to the fifth aspect of the present invention, R1 is selected from hydrogen, -COOH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH (CH3) 2 and the like.
[00227] Throughout the present invention, the compound in which R1 is -COOH, -COOCH2CH3 and -COOCH (CH3) 2 respectively can be called dye A, dye B and abbreviated C respectively.
[00228] The total content of the documents cited in the present patent application is incorporated into the present invention by reference. Unless otherwise described in the present invention, the various terms and phrases in the present patent application have general meanings, which are known to a person skilled in the art.
[00229] As described in the present invention, the term "deterioration" refers to the fact that the thermally sensitive article loses its original quality state or cannot meet the quality requirement after a certain time of storage and transportation. In storage and transportation, food and medicine always deteriorate due to heat or other factors. In the general case, the higher the temperature for storage and transportation is the higher the deterioration rate. The thermally sensitive article generally has a specified storage and transport temperature, and therefore has a certain quality guarantee period or service life. If the storage and transport of the thermally sensitive article exceeds the specified storage and transport, the rate of deterioration is accelerated and the quality guarantee period is reduced. In the prior art, many foods and medicines only indicate the specified storage and transport and quality guarantee period for them, but that cannot be found if the actual storage and transport temperature during storage and transport is always kept below specified transport and storage temperature. In the present invention, it was surprisingly found that the rate of volatilization of the dye in the volatile ink layer can be made close to or consistent with the rate of change in the quality of the thermally sensitive article, that is, the rate of color fading of the volatile dye is close to or consistent with the rate of change in the quality of the thermally sensitive article, by adjusting the activation energy of the volatilization process of the volatile ink layer, so that the change of the quality thermally sensitive article can be accurately monitored. When the storage and transport temperature increases, the volatilization rate of the volatile ink layer increases, and the color fading rate increases, so that the time to reach the final color difference or the final color is reduced, the which indicates that the quality guarantee period of the thermally sensitive article is correspondingly reduced. When the color difference of the time-temperature indicator of the present invention reaches or is less than the final color difference, that is, the color of it is equal to the final color or is lighter than the final color, it is indicated that the thermally sensitive article has deteriorated, although the storage and transport time of this thermally sensitive article has not reached the marked quality guarantee period. Therefore, with the time-temperature indicator of the present invention or the method of monitoring the quality status of a thermally sensitive article of the present invention, the quality status of a thermally sensitive article can be controlled with greater precision and safety use of the thermally sensitive article can be ensured.
[00230] As described in the present invention, the term "failure" refers to that the thermally sensitive article that loses its original effectiveness or cannot satisfy the quality requirement after a certain time of storage and transportation. For example, before using vaccines, their activity must meet the specified standard, and after storage and transport, if the activity of the vaccine cannot meet the specified standard, such vaccines can be thought to fail and cannot be used . For example, if vaccine activity after storage and transport is specified to be 90% or more, the failure is considered to be below 90%. There are different failure patterns for different heat-sensitive articles. When using the time-temperature indicator of the present invention, the final color difference must be measured according to the failure patterns of various heat-sensitive articles. The failure process of the thermally sensitive article is closely related to the temperature of the process of storage and transportation of the same. When the temperature increases, the failure process of the thermally sensitive article is accelerated, that is, the failure rate increases, and the quality assurance of the same period is shortened. Currently, there are many heat-sensitive items, only storage and transport and the quality guarantee period for them are specified, but the thermal history of the item is not detected. The user cannot find out whether storage and transport during storage and transport exceed the specified storage and transport. In the present invention, it has surprisingly been found that the rate of volatilization of the dye in the volatile paint layer can be made close to or consistent with the failure rate of the thermally sensitive article, that is, the color rate of the volatile dye layer is fading close to or consistent with the failure rate of the thermally sensitive article, by adjusting the activation energy of the volatilization process of the volatile paint layer, so that the failure of the thermally sensitive article can be precisely controlled. When the storage and transport temperature increases, the volatilization rate of the volatile ink layer increases, and the color fading rate increases, so that the time to reach the final color difference or the final color is reduced, the which indicates that the quality guarantee period of the thermally sensitive article is correspondingly reduced. When the color difference of the time-temperature indicator of the present invention reaches or is less than the final color difference, that is, the color of it is equal to the final color or is lighter than the final color, it is indicated that the thermally sensitive article has failed, although the storage and transport time for this thermally sensitive article has not reached the scheduled quality assurance period. Therefore, with the time-temperature indicator of the present invention or the method for the purpose of monitoring the failure of a thermally sensitive article of the present invention, the failure of a thermally sensitive article can be more accurately controlled, if the thermally sensitive article cannot be determined more precisely, and the safety of using the thermally sensitive article can be guaranteed. This plays an important role in the field of vaccines, medicines, food and the like.
[00231] As described in the present invention, the term "activation energy from the failure or deterioration process of a thermally sensitive article" refers to the activation energy and a thermally sensitive article from the Arrhenius equation
during the failure or deterioration process, and this activation energy refers to the apparent activation energy of a thermally sensitive article during the actual failure or deterioration process. Without limiting itself to any theory, the present invention considers the process of failure or degradation of a thermally sensitive article that obeys the Arrhenius equation. In practice, the failure or rate of deterioration of the thermally sensitive article which is measured with the thermally sensitive article under at least two different temperatures, preferably 5 or more, more preferably, temperatures below 10 or more temperatures. Then, a logK curve as a function of temperature T is plotted on a rectangular co-ordinate system, and this curve is a straight line or almost a straight line. The apparent activation energy and the constant A of the process of failure or deterioration of the thermally sensitive article can be obtained from the slope and interception of this line.
[00232] Likewise, the term "activation energy of the volatilization process of the volatile paint layer" refers to the activation energy and the volatile paint layer in the Arrhenius equation
, during the volatilization process, and this activation energy refers to the apparent activation energy of the volatile dye layer of the time-temperature indicator of the present invention during the actual volatilization process. Without limiting itself to any theory, the present invention considers that the volatilization process of the volatile paint layer obeys the Arrhenius equation. In practice, the volatilization rate of the volatile paint layer is measured with the time-temperature indicator of the present invention, under at least two different temperatures, preferably less than 5 or more temperatures, more preferably 10 or more temperatures. Then, a logK curve as a function of temperature T, is plotted on a rectangular coordinate system, and this curve is a straight line or almost a straight line. The apparent activation energy and the constant of the volatilization process of the volatile paint layer of the time-temperature indicator of the present invention can be obtained from the slope and ordered at the origin of this straight line.
[00233] In the present invention, the apparent activation energy and constant A of the volatilization process of the volatile paint layer can be controlled by choosing the volatile dye and / or the volatilization additive and / or the solvent and the value thereof, and can be done close to or even consistent with the apparent activation energy and constant A of the process of failure or deterioration of the thermally sensitive article, so that the volatilization rate of the dye in the volatile paint layer is made close or even consistent with the degradation rate or failure rate of the thermally sensitive article, and the thermal history of the thermally sensitive article is accurately monitored according to the color change of the volatile dye layer.
[00234] In the present invention, the activation energy defined in the present invention is represented with E or Ea.
[00235] As described in the present invention, the term "color difference" refers to the color that is measured with a colorimeter and represented by means of a number. The color space L * a * b * (also known as CIELAB) is used. In this color space, L * represents the brightness, and a * b * are chromatic coordinates, a * b * represents the color directions, + a * represents the direction of red, -a * represents the direction of green, + b * represents the yellow direction and -b * represents the blue direction. The center is colorless, and when the values of a * b * increase and move out of the center, the color saturation increases. The colorimeter is widely used to accurately measure color difference. In the system, the color space L * a * b *, the color difference can be represented as a single numerical value with AE * ab, and that represents the magnitude of the color difference, but does not indicate that the aspect in which colors are different. AE * ab is defined as follows: AE * ab = [(AL *) 2 + (Aa *) 2 + (Δb *) 2] 0.5).
[00236] Although the color difference may decrease with the volatilization of the dye, for the white standard, when AE * ab measured is 10 or less, such a change can hardly be observed by the human eye. Therefore, AE * ab that is 10 or more can be defined as the difference of the final color, so that the user can compare the color intensity, in a direct way, through visual observation. For example, AE * ab that is equal to 10, 15, 20, 25 or similar can be defined as the final color difference. When preparing the time-temperature indicator of the present invention, the initial color difference CO can be easily determined according to the predetermined final color difference, the volatilization rate of the actually measured volatile ink layer and the corresponding color unloading. In other words, if the initial color difference CO is defined as above and the color difference of the volatile dye layer is made to be CO, then after the time-temperature indicator has been subjected to a treatment process even if the process fails or deteriorates from the thermally sensitive article, the color difference at its ends is just the predetermined color difference, for example AE * ab is equal to 10, 15, 20, 25 or the like. After C0 is determined, the volatile ink layer with C0 can be obtained by means of factors such as the type and content of the volatile dye in the volatile ink layer, and the type and content of the solvent volatilization additive and the like. In addition, it can be understood that when the actual color difference is compared to the final color difference through visual observation, the difference in the initial color of the volatile C0 paint layer must be large enough to ensure that the color of the marking reference color, with the final color difference being in the range that can be distinguished by the human eye, that is, the final color difference value must be 10 or more, such as 10, 15, 20, 25 or more .
[00237] As the user only needs to compare the color depth during the visual comparison of the color intensity, AE * ab can be directly compared without determining the particular values of L *, a * and b * . Therefore, volatile dye of any color can be used in which the time-temperature indicator of the present invention.
[00238] In the present invention, "the time-temperature indicator of the present invention is subjected to the same process as the process of failure or deterioration of the thermally sensitive article" or similar description has the following meaning: if the thermally sensitive article fails or if it deteriorates after time t1 at temperature T1, and does not fail or deteriorates before time t1, then the time-temperature indicator is maintained at temperature T1 of time t1. For example, the quality assurance period for some of the -8 ° C vaccines is two years, so the time-temperature indicator of the present invention can be maintained at -8 ° C for two years to determine the difference final color or their final color. However, in practice, if the quality assurance period for a thermally sensitive article is too long, then the time period for determining the time-temperature indicator of the present invention is too long, and this is not realistic. Therefore, the final color difference or the final color can be determined according to the accelerated test that is known to those skilled in the art, or specified by a specific thermally sensitive article, or commonly used. For example, the method indicated in related textbooks, such as the content of the sections related to the stability of materials, such as medicines, please refer to Physical Chemistry, People's Education Press, 1979, edited by Tianjin University ; Su, Desen et al, Pharmaceutical Physics, Chemical Industry Press, Beijing, 2004; Nianzhu Xi, Pharmaceuticals, the third edition, Popular Medical Publishing House, Beijing, 1994, et al ,. For example, the conventional test method indicated in the book (Nianzhu Xi, Pharmacist, third edition, Popular Medical Publishing House, Beijing, 1994, P141) is referenced. For example, if after the above vaccine, with a shelf life of two years at 2 to 8 ° C, is maintained at 25 ° C for 8 weeks, its activity decreases to the specified low limit standard of 90%, then the time-temperature indicator of the present invention can be maintained at 25 ° C for 8 weeks, and the color difference of their volatile dye layer is determined as the final color difference. Compared to what is being maintained at 2 to 8 ° C for two years, the final color difference or the final color of the time-temperature indicator of the present invention can be determined more quickly in such a method. In addition, the final color difference or final color can also be determined by reference to the classic method of constant temperature indicated in the book (Nianzhu Xi, Pharmacist, third edition, Popular Medical Publishing House, Beijing, 1994, P141). Such a method is generally based on the Arrhenius equation
, in which parameters such as activation energy and speed constant k, absolute temperature T and the like are included.
[00239] It should be understood by means of those persons who are versed in the technique that "in the thermally sensitive article" or "in one or more areas of the thermally sensitive article" mentioned in the present invention, includes "in the packaging of the thermally sensitive article" or " in one or more areas of the thermally sensitive article packaging ", such as on the outer surface of the primary packaging (or the minimal package, such as a vaccine vial) of vaccines, drugs and the like, such as the outer surface of a bottle of vaccine or medicine glass that is provided with a glass bottle, or on the outer surface of a flexible plasma or milk bag, which is provided with a soft pouch. There is no limitation on the position of the area, but it must be relatively uniform. There is no limitation on the size of the area either, but for the present invention, it is preferably from 0.2 to 20 cm2, more preferably from 0.5 to 5 cm2, more preferably from 0.5 to 4 cm2, more preferably from 0.5 to 2.5 cm2, more preferably from 0.5 to 1 cm2.
[00240] In the present invention, the color marker or reference color reference layer is prepared with a non-volatile dye or pigment. The type of non-volatile dye or pigment is not particularly limited in the present invention, and any commercially available non-volatile dye can be used, as long as it can achieve the specified color or color difference.
[00241] As described in the present invention, "if the thermally sensitive article fails" refers to the fact that that article is in the range of a quality requirement specified by the validity period thereof. For example, having the active ingredient content as an example, some drugs specify that the amount of the active ingredient in it must be 90% or more of the indicated amount, so "if it fails" it can be determined if the same value of the ingredient active drug is 90% or more after it has been stored and / or transported. For example, if the amount of the active ingredient is greater than 90%, the drug has not failed; if the amount of the active ingredient is less than 90%, it is indicated that the drug has failed.
[00242] Many types of time-temperature indicators (TTI) are well known by a person who is well versed in the technique. For example, CN101652645A describes a time-temperature indicator, comprising the following time-temperature indicator: the time-temperature indicator that comprises at least one metallic layer or one layer containing a metal, and at least one doped polymer layer that is in direct contact with the metal layer or a metal-containing layer, where the dopant is acid, base or salt, or photolactant acid or photolacting base, and is added to the polymer, and / or, at least one polymer layer, in which the polymer is functionalized with a latent acid group or basic latent group, or comprising the sequence of the time-temperature indicator: the time-temperature indicator comprising at least one polymer layer which contains metal particles and photolacting acid or photolacting base, or at least one polymer layer containing metal particles, in which the polymer is functionalized with a latent acid or latent base group. For another example, CN1914509A describes a time-temperature indicator that comprises at least one indicating compound in the form of the first isomer, and in the case that the chemical atoms or groups attached to the indicating compound do not transfer in the isomerization reaction, the indicating compound is converted into a indicating compound in the form of the second isomer in a manner that depends on time and temperature, in which the formation of the indicating compound in the form of the second isomer can be detected by monitoring the physical characteristics of the indication compound. However, according to the detailed description of the present invention, the time-temperature indicator of the present invention is distinct from the time-temperature indicator in the state of the art, in theory, the structure and composition, and the time-temperature of the present invention is very advantageous in production, costs, simplicity of use and the like. Certainly, the entire content of the above patent documents is incorporated into the present invention by reference for a better understanding of the present invention.
[00243] The "sealing adhesive layer" in the indication function layer or the absorption material layer can prevent the dye from permeating through the substrate material layer and then transfer or even volatilize. Although it is desirable to use the layer of substrate material, which it can avoid from permeation and transferring as much as possible in the present invention, it is preferred to coat the sealing adhesive layer on the side of the layer of substrate material opposite the paint layer for the purpose of the present invention. The sealing material or adhesive of the sealing adhesive layer can be widely selected, and non-limiting examples of these include normal, commercially available glue.
[00244] Similar to the "sealing adhesive layer", the "sealing film layer" in the indication function layer can prevent the dye from permeating through the layer of substrate material and then transferring or even volatilizing . The sealing film material or sealing film layer can be widely selected, and non-limiting examples include polymeric film, such as polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene glycol terephthalate and the like.
[00245] The "adhesive layer" in the indication function layer or the adsorption function layer can provide adhesion effect and sealing effect for the corresponding material layer. The two-layer "adhesive layers" of the indication function layer and the adsorption function layer can be the same or different, but the "adhesive layer" depending on the adsorption layer is expected to have good sealing properties, and an enclosed space that can prevent the leakage dye from being formed by combining the layer of substrate material with the thermally sensitive article strongly in the use of the indicator of the present invention. The material that the adhesive or adhesive layer can be widely selected from, and non-limiting examples include oily or aqueous adhesive, commercial adhesive paper, adhesive tape and the like.
[00246] In the present invention, the "quality", "quality status", "shelf life", "failure" and the like of the thermally sensitive article of the present invention are mentioned, and these conditions of the thermally sensitive article can be represented by through titration, for example, for some biological products, or they can be represented through activity, or they can also be represented through content, such as the content of the active ingredient. The methods that represent them are not particularly limited in the present invention.
[00247] In the present invention, the compound of formula I can be prepared using the known method by a person skilled in the art. For example, the compound of formula I in which R1 is hydrogen (this is referred to as dye H in the present invention) can be used as a raw material, and the substituent R1 can be converted to halogen, C1-6 straight or branched alkyl, C1-6 linear or branched alkoxy, -COR2, -COOR2 or the like through halogenation, alkylation or acylation and then hydrolysis or alcohol, or the like, wherein R2 is as described in the present invention. Examples
[00248] The present invention can be further described by means of the following different examples, but the scope of the present invention is not limited to the following examples. They can be understood by those skilled in the art that various variations and modifications of the present invention can be made without departing from the spirit and scope of the present invention. The materials and test methods used for the tests are generally and / or specifically described in the present invention. Although many materials and methods of operation used to achieve the objective of the present invention are known in the art, they are still described in detail as possible in the present invention. A. Examples of the time-temperature indicator
[00249] The present invention makes use of the volatilization property of the material and prepares a time-temperature indicator, and achieves the desired effect of color change through a volatilization-adsorption process. The structure of the time-temperature indicator according to an example of the present invention and the theory of its operation are shown schematically in Figure 1, Figure 2A and Figure 2B.
[00250] Figure 1 shows a time and temperature indicator according to an example of the present invention, which consists of two portions, wherein the portion of a is a layer of an indication function 1, and the portion b is an adsorption function layer 2, the two parts are respectively prepared, stored and transported, and in use are combined together and glued to the surface of the container or packaging of the thermally sensitive article to be monitored.
[00251] In the indication function layer, an adhesive sealing layer is printed under the substrate material layer 10, and a sealing film layer 13 is additionally printed under the sealing adhesive layer to prevent the sealing layer. volatile dye 15 diffuses to a lower portion. An adhesive layer 12 is further printed under the sealing film 13, and is protected by the release layer of the film 11. If the sealing effect of the sealing adhesive is sufficient, the sealing film 13 is not necessary. If the layer 10 substrate material alone has a sufficient sealing effect, the sealing adhesive layer 14 and the sealing film 13 are not necessary. Adhesive layer 12 is understood to be optional.
[00252] A layer of functional color material (i.e., volatile dye) is printed in the functional position on the substrate material layer 10 such as a volatile dye layer, in order to form the volatile ink layer 15 on the present invention, and the color of the volatile dye layer 15 (dark blue in the figure) appears very different from that of the substrate dye layer 10 or the reference color layer 16 printed around the volatile dye layer 15 (light blue in the figure ). The volatilization rate of the volatile dye used and the effect of its temperature must be in accordance with the rate of degradation or failure of the thermally sensitive article and indicating the effect of their temperature as much as possible. After the indication function layer has been printed and dried, it is sealed with a film 17 release layer. This layer 17 release film is used for sealing, and has no adsorption effect on the volatile dye used. . The sealing property ensures that the indicating function layer will be stored and transported at room temperature.
[00253] In an adsorption function layer 2, information about the appropriate product (such as the type of the thermally sensitive article for which it is applicable TTI) or information on the use of the indicator (such as information on how the indicator works when it is required to use the indicator to determine if the article is thermally sensitive, it cannot be printed on the substrate material layer 20. In a position corresponding to the position of the indication function layer under the substrate material layer 20 , a layer of adsorption material that can effectively adsorb the volatile thermally sensitive volatile dye is printed or coated in order to form a layer of adsorption material 21, an adhesive layer 22 is printed around the layer of adsorption material 21, and then the absorption function of layer 2, which is formed by lamination is sealed and preserved with a film release layer 23. If it is necessary to prevent and the adsorption material will be directly contacted with the volatile material (ie volatile dye), an insulation layer 24, which is optional, can be additionally produced on the underside (ie, far away) of the substrate material layer 20) of the adsorption material of layer 21. In reality, the insulating layer can also be located between the dye layer 15 and the film release layer 17.
[00254] In addition, Figure 2 illustrates the use and the process of using the time-temperature indicator shown in Figure 1. In part A of figure 2A, two portions of laminate, that is, the indication function layer 1 and the adsorption function layer 2, which are respectively produced, stored and transported are combined: the release film 11 at the bottom of the indication function layer is removed first, and the indication function layer 1 is glued to the surface of the container or packaging of the thermally sensitive article 3 to be monitored, the release film 17 of the indicating function layer 1 and the release film 23 of the adsorption function layer 2 are removed, and the portion of the layer adsorption function 2 is aligned with the indicating function layer 1 and glued to the surface of the container or packaging of the thermally sensitive article 3 to be monitored. In a preferred embodiment, the shape and size of the adsorption material layer 21 are the same or slightly larger than both the volatile paint layer 15 and the reference color layer 16. In this way, as shown in the figure, the adsorption material layer 21 and optional insulation layer 24 completely cover both the volatile paint layer 15 and the color of the reference layer 16, and the adhesive layer 22 on the periphery of the adsorption material layer 21, together with the layer of substrate material adhering thereto can be firmly adhered to the container of the packaging of the thermally sensitive article 3, so that the material of the substrate layer 20, the adhesive layer 22 and the packaging container of the thermally sensitive article 3 together form a space that can seal both function layers. The selection of substrate materials with two function layers and the material to which the adhesive that ensures the indication layer function will be firmly adhered to the surface of the product container or packaging, and the adsorption function layer has adequate firmness when being adhered, it can effectively seal the volatile dye printed on the indication function layer, and can be removed, in which the removal process does not negatively influence the indication function layer.
[00255] In the process of using this indicator, in the case where the volatile dye in the volatile paint layer 15 has not been completely volatilized (part B in Figure 2A), after the adsorption function layer 2 has been removed, the dye (blue ) to the left, in the volatile paint layer 15 there is still a color obviously different from the color of the reference layer 16 (light blue) on its periphery (part C in Figure 2A), that is, the color of the volatile dye layer 15 it is darker than the reference color layer 16, which reflects that the indicated product is still valid and usable. In the event that the thermally sensitive material in the volatile paint layer has been completely volatilized (part d in Figure 2A), after the adsorption function layer 2 has been removed, the dye (light blue or colorless) in the volatile paint layer 15 is close to or lighter than the color of the reference color layer 16 (light blue) on its periphery (part and in Figure 2A), that is, the color of the volatile dye layer 15 is comparable to or lighter than of the reference color layer 16, indicating that the monitored product may deteriorate or fail due to overheating.
[00256] In Figure 2B, the process of changing the volatile ink layer 15 of a time and temperature indicator according to an example of the present invention, during the process of use are observed in a direction perpendicular to the indicator. It is indicated that the present invention makes use of the volatilization property of the material to prepare a time-temperature indicator, achieves the color change of the indicator's function position through a volatilization-adsorption process, and indicates whether the product using this time the temperature indicator deteriorates or fails due to overheating or a very long time. In this example, the volatile dye layer has a square shape (seen in part in figure 2B, that is, the state at the beginning, is a dark blue square), and the color of this volatile dye layer appears much different than that of the reference color layer (seen from part (a) in Figure 2B, the reference color layer is light blue, and corresponds to the reference color layer 16 in Figure 1), where the reference color layer 16 can be the substrate or a printed reference color layer.
[00257] In the use process after the time-temperature indicator has been combined with the thermally sensitive article, the color intensity of the reference color layer 16 does not change, but the color of the volatile dye layer 15 becomes lighter, due to the dye volatilization. The rate that becomes lighter is influenced by the temperature. Even if it is under a storage and transport temperature, which is specified for the thermally sensitive article, the volatile dye layer volatilizes at a certain rate. For example, for a drug with a 2-year shelf life, stored at 2 to 8 ° C, after this drug has been stored strictly at 2 to 8 ° C for 2 years, the volatile dye layer 15 will become lighter gradually due to the slow volatilization of the dye. At this time, the color of the volatile dye layer will be darker or slightly darker than that of the reference color layer 16, indicating that the drug is still valid after being stored at 2 to 8 ° C for two years. If the storage time is extended, the volatile ink layer 15 will continue to become lighter due to the continuous volatilization of the dye, and then the color of the volatile dye layer will be close to or lighter than that of the layer reference color 16, indicating that the medicine has expired. In the process of using the indicator, when the non-volatile dye layer has been completely volatilized, after the adsorption film has been removed, the left volatile dye may still appear a color obviously different from the reference color layer on the periphery (seen in part (b) in Figure 2B, that is, the state at the intermediate point), and the blue square is darker than the color of the light reference color rounds, reflecting that the indicated product is still valid. When the dye layer remains volatile to volatilize or is completely volatilized, after the adsorption film has been removed, the color of the volatile dye layer 15 is close to (part (c) in Figure 2B, the state, at the end) or lighter than (part (d) in Figure 2B, the state of the dot after the end) than the reference color layer on the periphery, to indicate that the monitored product may deteriorate or fail due to overheating. B. The preparation of the time-temperature indicator and the determination of the position color in the reference color layer
[00258] After the time-temperature indicator has been produced according to the structure shown in Figure 1, under different temperatures (such as 5 ° C, 10 ° C, 25 ° C and / or 37 ° C), the change of color difference in the functional position of the indicator over time is measured with a colorimeter, and the rate of color change of the indicator and the effect of its temperature can be obtained.
[00259] The color change can be digitized with a colorimeter. When the color change is measured with a colorimeter, a color space, such as the L * a * b * color space (also known as the CIELAB color space) is defined first. In this color space, L * represents luminosity, a * and b * are the chromatic coordinates, and represent the color directions; + a * represents the direction of red, -a * represents the direction of green, + b * represents the direction of yellow, -b * represents the direction of blue, and the center is colorless. When the values of a * b * increase and move out of the center, the color saturation increases. In this color space, the color difference can be represented as a single numerical value;

[00260] in which, ΔL * is the change in brightness, Δa * is the change in the red-green color axis, and Δb * is the change along the yellow-blue color axis. Color is quantified with a colorimeter such as Chroma Meter Minolta CR-310 or similar, so that the color difference can be quantified, and the color change function of the produced time-temperature indicator can be evaluated. A substrate, such as white A4 paper, is used as a reference when measuring color difference. When the color difference ΔE * ab <10, the color is more or less close to the color of the substrate. An even greater reduction in the color difference is not noticeable for human eyes, so the color difference ΔE * ab = 10 acts as the end of the color change during the evaluation. In practical application, the final color difference can be defined according to the actual conditions, for example, depending on the type of thermally sensitive article, ΔE * ab can be defined as other values, such as ΔE * ab = 15, ΔE * ab = 20, ΔE * ab = 25, and / or ΔE * ab = 30.
C. Description of the design and application of the method or an indicator of the present invention, with particular examples Example 1:
[00261] A dye is used as the volatile dye in the time-temperature indicator, and 2% dye A is quantitatively printed on plain A4 paper (the solvent is ethyl acetate, the amount of dye A coating is about 200 mg per square centimeter) in order to form an indication function layer; commercially available adhesive paper that can effectively adsorb dye a is placed on top of dye a and faces the adhesive to the dye layer in order to form an adsorption function layer, the indication layer function and the adsorption function layer they are more sealed with a film that is not permeable to sealing, and the sealed sample is kept at a constant temperature of 25 ° C. After standing for a certain period of time, the color of the indicator is observed and recorded. Figure 3 is the color register of an indicator, which was maintained at a constant temperature of 25 ° C from 0 to 105 days. After dye A has been completely volatilized, there is no trace of dye remaining under naked eyes, and the functional position of the indication almost returns to the original color of the white paper. Example 2:
[00262] Figures 4A and 4B show the change in color difference AE * ab of a time-temperature indicator produced with dyes A as the volatile dye according to the method described in example 1 over time t, at different temperatures. The time and rate of this color change indicator can be calculated with the color difference AE * ab = 10, such as the end of which the color change, and the activation energy of the color change process can be deduced as plus 97.4 kJ / mol (Figure 5) from the Arrhenius equation, in order to obtain the parameter for characterizing the temperature effect of the color change process of the indicator. This activation energy can very well cover the activation energy range of 73.6 to 109 kJ / mol, where the literature reports that polio vaccines are inactivated, and can also cover the activation energy range in which some other vaccines are inactivated.
[00263] Figure 6 shows a label designed for a hepatitis B vaccine, with a dye, and the color change response of the TTI of the present invention is almost consistent with the change in vaccine activity. Example 3:
[00264] The total time of the color change of the indicator can be adjusted by adjusting the amount of the volatile dye printed by means of the area unit in the functional indicator position of the indicator, which can be adjusted, adjusting the amount of dye or the concentration of the dye during printing.
[00265] Figure 7 shows the difference in the initial color of the indicator and the process of color change, at the same temperature, in which the indicator is obtained with a dye such as the volatile dye through the use of different concentrations of the dye and the same amount of dye according to the method described in example 1. The time that the indicator passes to reach the end is in linear relation to the amount of volatile dye printed per unit area (figure 8). Example 4:
[00266] The time for changing the indicator and the effect of its temperature can be adjusted by changing the composition and structure of the dye. Figure 9 shows the color difference of a time-temperature change indicator over time at 50 ° C, where the time-temperature indicator is produced with the three compounds of formula I (dye A, dye B and dye C, respectively), as their volatile dye according to the method described in example 1. The color change time and rate of this indicator at different temperatures can be calculated with the color difference AE * ab = 10 as the end of the color change, and the activation energies of the indicator change process in which dye B and dye C, respectively, are used as dyes in volatiles can still be deducted as 122 and 75 kJ / mol, respectively, from the Arrhenius equation, in order to obtain the parameter of characterization of the temperature effect of the color change process of the indicator. It can be seen from the result that the activation energies of the indicators with dye B and dye C are different from those of the indicator with dye A. Dye B and dye C can be used to design a TTI suitable for other heat-sensitive articles, or used for combining different dyes. Example 5:
[00267] During the printing of the volatile dye layer, the rate of color change of the indicator and the effect of its temperature can be adjusted appropriately by means of different solvents. Figure 10 shows the change in color difference of an indicator over time, at the same temperature, in which dye A is printed as the volatile dye layer, and cyclohexane, dichloromethane, methyl acetate, ethanol and ethyl acetate are used respectively as a solvent according to the method in example 1. It is indicated in the result that, when ethanol is used as solvent, the rate of color change of the indicator is higher, when cyclohexane and acetate of methyl are used as the solvent, the rate of color change of the indicator is moderate, and less than that of the indicator with ethanol as the solvent, when ethyl acetate is used as the solvent, the rate of color change of the indicator is lower, the color difference increases significantly when the same amount of volatile dye is printed with dichloromethane as solvent, and the rate of color change of the indicator becomes much lower than that of the indicator with other solvents, the which is the lowest of all the solvents tested. Example 6:
[00268] During the printing of the volatile dye, the rate of color change of the indicator and the effect of the temperature of the same can be adjusted appropriately by adding suitable additives. Figure 11 shows the relationship between the change in color difference of an indicator and the time of 80 ° C, in which the indicator is produced by the addition of a suitable binder CE (ie cellulose acetate) in the organic solution of a dye according to the method described in example 1. It is indicated in the result that after adding the binder (as shown in the CE curve in the figure), the time that the indicator passes to reach the end is 3.5 times the time that the indicator without ligand passes (the curve shown as none in the figures). The color change time and rate of the indicator at different temperatures can be calculated with the color difference with AE * ab = 10, as the end of the color change, and then the addition of the binder to the activation energy of the change process the indicator can still be deduced as 67 kJ / mol from the Arrhenius equation, which changes a lot compared to the indicator without the ligand. Example 7:
[00269] The rate of color change of the time-temperature indicator and the effect of its temperature can be adjusted through the selection and use of different adsorption materials. Figure 12 shows that the change in color difference in the indication function layer of a time-temperature indicator over time, at the same room temperature looks significantly different, in which the time-temperature indicator is produced with the dye B, such as the volatile dye through the selection and use of three different adsorption materials (in the figure, materials 1, 2 and 3 are commercially available adhesive paper, commercially available A4 adhesive coating and A4 paper oily adhesive coating commercially available, respectively) according to the method described in example 1.
[00270] From the examples above, the present invention surprisingly finds that the color change is achieved using the material's volatilization property through a volatilization-adsorption process, and is very simple and effective to indicate whether the product may deteriorate or fail due to overheating. A personalized time-temperature indicator which adequately reflects the thermal stability of the indicated product can be produced by tracking volatile dyes or other volatile materials or, if necessary, material formulations to contain additives produced at an appropriate rate volatilization and activation energy. By producing an adsorption function layer layer that can effectively adsorb the volatile dyes over the sealing indicator and the indication function layer and the adsorption function layer effectively, product contamination and packaging through volatilized material it can be avoided while the functional position of the indicator can be prevented from external contamination. Furthermore, through the use of an adsorption layer of the diffusion process of the thermally sensitive material after volatilization has been artificially defined as an adsorption process of the adsorption layer, in order to effectively reduce the influence of the non-temperature factors that influence the volatilization rate of the apparent thermally sensitive material during storage and transportation of the product and increase the accuracy of the product. In addition, the indicator is designed in such a way that the two function portions are produced, sealed and stored, respectively, and they are combined when the indicator is glued to the surface of the product container or packaging, so that the indicator can be stored and transported at room temperature.
[00271] The examples in the description above and the exemplary examples do not limit the scope of protection of the present invention. All technical solutions formed by identical alternation or equivalent substitution, or any time-temperature indicator prepared with different processes, or formulation according to the technical solution or concept of the present invention are within the scope of protection of the present invention.

权利要求:
Claims (13)
[0001]
1. Combination of: a time-temperature indicator to monitor the quality status of a thermally sensitive article (3), comprising two laminated portions: an indication function layer (1) and an adsorption function layer (2) ; the thermally sensitive article (3) characterized by the fact that the indication function layer (1) and adsorption function layer (2) are physically independent of each other before use, in which: the indication function layer ( 1) comprises: a first layer of substrate material (10); a layer of volatile paint (15), which is coated on one side of the first layer of substrate material (10), in which the difference between the activation energy of the volatilization process of the volatile paint layer (15) and the process altering the quality of the thermally sensitive article (3) is in a predetermined range of ± 10 kJ / mol, and the activation energy of the volatilization process of the volatile paint layer (15) is from 60 to 140 kJ / mol; and a first release film layer (17), which covers the volatile paint layer (15), wherein the first layer of substrate material (10) and the first layer of the release film (17) are larger than the layer of volatile paint (15) in dimension, and the layer of volatile paint (15) is sealed between the first layer of substrate material (10) and the first layer of the release film (17); the adsorption function layer (2) comprises: a second layer of substrate material (20); a layer of adsorption material (21), which is coated on one side of the second layer of substrate material (20), where the layer of adsorption material (21) is larger than the layer of volatile paint (15) in size, preferably the adsorption material can irreversibly adsorb the volatilized paint from the volatile paint layer (15), and more preferably the adsorption rate at which the adsorption material adsorbs the volatile paint is much higher than the rate volatilization of volatile paint; an adhesive layer (22), which is coated over the second layer of substrate material (20), and surrounds the periphery of the adsorption material layer (21); and a second layer of release film (23), covering the adhesive layer (22) and the layer of adsorption material (21): and the thermally sensitive article (3) is an article that needs to be stored and / or transported at a temperature in the range of -40 ° C to 50 ° C, and is selected from vaccines, biological articles, bioactive samples, medicines, food or drinks.
[0002]
2. Combination according to claim 1, characterized in that the first layer of substrate material (10) has one or more transparent areas or the first layer of substrate material (10) is transparent in itself.
[0003]
3. Combination, according to claim 2, characterized by the fact that, in use, the first release film layer (17) and the second release film layer (23) are removed, the adsorption material layer (21) is aligned with the volatile paint layer (15) of the indication function layer (1), so that the adsorption function layer (2) covers the entire indication function layer (1), and the adsorption material layer (21) and volatile paint layer (15) are sealed between the first layer of substrate material (10) and the second layer of substrate material (20), the second layer of substrate material ( 20) or the first layer of substrate material (10) is glued to the thermally sensitive article (3).
[0004]
Combination according to any one of claims 1 to 3, characterized in that it additionally comprises a reference color marking which is independent of the indicating function layer (1) and the adsorption function layer (2) or is arranged adjacent to the volatile paint layer (15) in the first layer of substrate material (10) or is prepared by the first substrate material, where the color intensity of the reference color marking is the same as that of the layer of volatile ink (15) that was subjected to the same process as the failure treatment of the thermally sensitive article (3).
[0005]
Combination according to any one of claims 1 to 4, characterized in that the first layer of substrate material (10) of the indication function layer (1) alone acts as a reference color marking , the intensity of the color, which is the same as that of the volatile paint layer (15) that was subjected to the same process as the failure treatment of the thermally sensitive article (3).
[0006]
6. Combination according to any one of claims 1 to 5, characterized by the fact that the thermally sensitive article (3) is selected from vaccines, biological articles, bioactive samples, medicines, food or drinks.
[0007]
7. Combination according to any one of claims 1 to 6, characterized by the fact that the difference between the activation energy of the volatilization process of the volatile ink and the process of changing the quality of the thermally sensitive article (3) is in the ± 5 kJ / mol range.
[0008]
Combination according to any one of claims 1 to 7, characterized in that the volatile paint layer (15) is in solid or liquid state, at a temperature in the range of 0 to 80 ° C , preferably the volatile paint layer (15) is in the solid state at a temperature in the range of 0 to 50 ° C.
[0009]
Combination according to any one of claims 1 to 8, characterized in that the volatile ink in the volatile ink layer (15) is at least one selected from azo dyes, anthraquinone dyes, the compounds of formula I and derivatives thereof, or a combination thereof, in which the compounds of formula I have the following formula:
[0010]
Combination according to any one of claims 1 to 9, characterized in that the volatile paint layer (15) further comprises one or more additives and / or volatilizing solvents, wherein the volatilizing additives are one or more most selected from the following volatile compounds: linear alkanes, branched alkanes, cycloalkanes or aromatic hydrocarbons, including hexane, heptane, octane or the isomer thereof, cyclohexane, cycloheptane, cyclopentane, naphthalene, anthracene and the like ; linear or branched or aromatic or cyclic alcohols, including butantetraol, lauryl alcohol, tridecanol, tetradecanol, penta-decanol, hexadecanol, stearyl alcohol and the like; carboxylic acids, linear or branched or aromatic or cyclic, including maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid and the like; amino acids, including aminobenzoic acid, leucine, phenylalanine and the like; esters; sulfones, including diphenyl sulfone, diphenyl disulfone, dibenzyl sulfone, dibutyl sulfone and the like; and various volatile natural materials, including naphthalene, camphor and the like; the solvent is one or more selected from the group consisting of water, hexane, cyclohexane, tetrahydrofuran, benzene, dimethyl benzene, methanol, ethanol, isopropyl alcohol, 2-butanol, acetone, diethyl ether, methyl acetate , ethyl acetate, carbon tetrachloride, chloroform, dichloromethane and dichloroethane.
[0011]
Combination according to any one of claims 1 to 10, characterized in that, in use, an insulating layer (24) is further comprised between the volatile paint layer (15) and the adsorption material layer (21).
[0012]
12. Method including: a method of preparing a time-temperature indicator to monitor the quality status of a thermally sensitive article (3); providing the thermally sensitive article (3) to obtain a combination as defined in any one of claims 1 to 11; characterized by the fact that the thermally sensitive article (3) is an article that needs to be stored and / or transported at a temperature in the range of -40 ° C to 50 ° C, and is selected from vaccines, biological articles, bioactive samples, medicines, food or drinks, and the preparation method comprises the following steps: providing a first substrate material (10); coating a layer of volatile paint (15) on one side of the first layer of substrate material (10) to form a layer of volatile paint (15), in which the difference between the activation energy of the volatilization process of the paint layer volatile (15) and the process of changing the quality of the thermally sensitive article (3) is in a predetermined range of ± 10 kJ / mol, and the activation energy of the volatilization process of the volatile paint layer (15) is 60 at 140 kJ / mol; covering the volatile paint layer (15) with a first film release layer (17) to form an indication function layer (1); and providing a second layer of substrate material (20); coating an adsorption material on one side of the second layer of substrate material (20) to form a layer of adsorption material (21); wherein the layer of adsorption material (21) is larger than the layer of volatile paint (15) in dimension; coating an adhesive layer (22) around the layer of adsorption material (21) in the second layer of the substrate material (20); and covering the adhesive layer (22) and the adsorption material layer (21) with a second release film layer (23), and sealing the adsorption material layer (21) between the substrate material layer and the second release film to form an adsorption function layer (2).
[0013]
13. Method according to claim 12, characterized in that it further comprises: a step of coating a reference color layer in the vicinity of the volatile paint layer (15) after coating the volatile paint layer (15) , in which the reference color layer is made from non-volatile ink, and its color intensity is the same as that of the volatile ink layer (15), which was subjected to the same process as the treatment of failure of the thermally sensitive article (3), or a step of making a separate reference color marking from a non-volatile ink.

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CN111982336A|2020-08-26|2020-11-24|中国烟草总公司郑州烟草研究院|Tobacco hot processing strength detection method based on temperature-sensitive marker|

法律状态:
2017-08-29| B25D| Requested change of name of applicant approved|Owner name: SUZHOU QUALIMARK TECHNOLOGY CO., LTD. (CN) |

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2017-09-12| B25G| Requested change of headquarter approved|Owner name: SUZHOU QUALIMARK TECHNOLOGY CO., LTD. (CN) |

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2018-12-11| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2019-12-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-05-12| B09A| Decision: intention to grant|

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2020-10-06| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 26/06/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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CN201110178976.4A|CN102853946B|2011-06-29|Monitor thermo-responsive article and add up the method for received heat and the indicator of use thereof|

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CN201110178976.4|2011-06-29|

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PCT/CN2012/077568|WO2013000401A1|2011-06-29|2012-06-26|Time-temperature indicator and monitoring method for monitoring quality state of thermally sensitive article|

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