CN102853946B - Monitor thermo-responsive article and add up the method for received heat and the indicator of use thereof - Google Patents
Monitor thermo-responsive article and add up the method for received heat and the indicator of use thereof Download PDFInfo
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- CN102853946B CN102853946B CN201110178976.4A CN201110178976A CN102853946B CN 102853946 B CN102853946 B CN 102853946B CN 201110178976 A CN201110178976 A CN 201110178976A CN 102853946 B CN102853946 B CN 102853946B
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Abstract
The present invention relates to monitor thermo-responsive article and add up the method for received heat and the indicator of use thereof.The present invention monitors the method for thermo-responsive article received heat and comprises the following steps: (a) provides thermo-responsive article；(b) certain area one layer of volatile dye of attachment on these thermo-responsive article；C () adheres to one layer of adsorbing material in this volatile dye；D () adheres to diaphragm seal at above-mentioned certain area and periphery thereof, this diaphragm seal makes described sorbing material layer and the sealing of volatile dye layer be attached on described thermo-responsive article；Wherein, described volatile dye can be volatilized under heating condition, described adsorbing material irreversibly adsorbs volatilized dyestuff, and the color of volatile dye layer takes off the being proportionate property of volatile quantity of variable and dyestuff, the being proportionate property of heat that the latter is absorbed with thermo-responsive article again.The inventive method and the time temperature indicator provided according to these methods can indicate situation of being heated and the quality state of thermo-responsive article effectively.
Description
Technical Field
The invention belongs to the technical field of materials, and relates to a method for monitoring accumulated heating capacity of a heat-sensitive article by using a heat-sensitive material. In particular, the invention relates to a time-temperature indicator which is made by utilizing the volatilization property of materials, realizes the color change of functional parts of the indicator through the heat-volatilization-adsorption material transfer process, and shows whether an article using the time-temperature indicator, in particular a heat-sensitive article, is deteriorated or failed due to excessive heat.
Background
Some articles or products with very temperature-sensitive stability need to be stored or transported at low temperature, such as most vaccines, biological products, bioactive samples and parts of pharmaceuticals, and fresh foods such as fresh milk, dairy products, fresh meat, fresh fish, etc. For a long time, the labeling of expiration or freshness date has been the main method for ensuring the safe use of these articles/products, especially medicines or foods, but these methods often fail to reflect whether those medicines or foods that need to be stored and transported under low temperature conditions are exposed to temperatures exceeding safe storage and transportation temperatures for too long a period of time. The simple and cheap method is adopted to accurately indicate whether various heat-sensitive articles such as fresh food needing low-temperature storage, vaccine (mostly between 2 ℃ and 8 ℃), bioactive samples and the like are deteriorated, invalid or inactivated due to exceeding the safe storage and transportation temperature in the storage or transportation process, so that the use safety and the effect of the articles can be better ensured.
In the nineties of the last century, the World Health Organization (WHO) started to focus on the problem of over-heating of vaccines during cold chain storage and transportation, as this would lead to a reduction in the immune efficacy of the vaccine, thereby reducing the protective effect of the vaccine. Subsequently, WHO called to develop a convenient-to-use, low-cost label to accurately reflect the history of cumulative exposure of the vaccine to heat during its shipment and storage to the end user. The basic requirements for this tag are as follows: 1. whether the vaccine is overheated or not can be accurately indicated, so that the vaccine which is overheated is limited to be used; 2. the volume is small, and the adhesive can be pasted on a vaccine bottle, an ampoule bottle and an injector; 3. the whole process from production to actual use is stable and reliable; 4. is suitable for mass production, has low cost and can meet the requirement of the Union Children Foundation (UNICEF) on the global vaccine.
In 1996, a company named TempTime in the United states (formerly Lifelines) first developed a label that meets the WHO requirements and applied to poliomyelitis vaccines produced by three vaccine manufacturers, GlaxoSmithKline, Sanofi-Pasteur and Novartis. The labels supplied by Temptime corporation are mainly classified into three types according to the function of use. The first type is a Critical Temperature Indicator (CTI), which changes color as soon as the Temperature exceeds a set value. The second type is a so-called Critical Temperature-Time Indicator (CTTI), which is a label that changes color at a delayed rate and changes color after exposure to a Temperature higher than a set Temperature for several minutes or several tens of minutes. The response Time of the third type of label needs to be longer, called a Time-temperature indicator (TTI), which is a label that changes color after the temperature-sensitive material receives a certain amount of heat, and is suitable for indicating the heat history of the vaccine.
Currently, there are hundreds of international patents on such time-temperature indicators. These patented technologies can be classified into mechanical type, chemical type, enzyme reaction type, microbial type, polymer type, electronic chemical type, diffusion type, etc. according to the operation principle of the product. These technologies are mainly based on mechanical properties, electrical properties, diffusion properties, bio-enzymatic reactions, polymerization reactions, etc. of materials, and there are three main types of relatively mature and commercialized TTI labels: polymer type, enzyme reaction type, and diffusion type.
The polymer type was developed by TempTime corporation, usa and is mainly based on solid-state 1, 4-addition polymerization of substituted diacetylene derivatives to produce colored polymers. The rate of the polymerization reaction increases with increasing temperature, and the resulting polymer is continuously darker in color, which, by contrast with the surrounding color, indicates whether the vaccine is overheated. Such labels require screening for the synthesis of suitable polymeric monomers and storage at temperatures of-18 c or even lower after label preparation.
Early enzyme-responsive indicators were essentially pH indicators that caused a change in pH of the medium by measuring the proton H + released by enzyme-catalyzed hydrolysis of a lipid substrate, thereby causing a color change that indicated temperature or heat history. The enzymatic hydrolysis reaction is accelerated with increasing temperature and the rate of release of protons is thus increased. Typically, the Vitsab ring indicator is developed by a company in sweden.
A representative product of the earlier diffusion type time-temperature indicators is the 3M MonitorMark brand indicator manufactured by 3M company in the united states, which is based on the diffusion of a dye on a string, the temperature indication range and the response period depending on the type of dye. Another form of diffusion-type indicator is a porous substrate coated with a material of a specific melting point, the optical indices of refraction of which are close. When the coated material is melted above a certain temperature and diffused into the porous substrate, the light transmittance of the substrate is increased after the air in the pores of the substrate is exhausted, and thus a color change can also be achieved, indicating a thermal process.
Currently, the WHO classifies nearly twenty vaccines into 4 classes according to their heat stability properties: most unstable vaccines, stable vaccines and high stable vaccines, and accordingly puts product specifications on the corresponding time-temperature indicators. The technical standard established in this way takes into account the performance of the existing indicator products and is not entirely based on the heat-stable performance of the vaccine itself. In fact, in nearly twenty vaccines that require cold chain storage and transportation and monitoring throughout, the thermal stability of each vaccine is not the same, and the ideal time-temperature indicator should be a personalized time-temperature indicator that adequately reflects the thermal stability performance of the indicated product, i.e. the speed of color change and its temperature effect are as consistent as possible with the indicated product failure process.
Therefore, the present invention is expected to provide a method for monitoring the cumulative heat of heat-sensitive articles, which can know whether the cumulative heat is beyond the expected control range when monitoring the storage and transportation of heat-sensitive articles.
Disclosure of Invention
The invention aims to provide a simple and effective method for monitoring the accumulated heat of a heat-sensitive article, which can indicate whether the accumulated heat exceeds the expected control range of people when the method is used for monitoring the storage and transportation process of the heat-sensitive article. The inventor attaches a substance (which can be called volatile dye in the text) with certain color and volatility to a heat-sensitive article, a layer of adsorbent capable of adsorbing the dye is attached outside the volatile dye, and a sealing layer is used for sealing the volatile dye layer and the adsorbent layer on the heat-sensitive article; thus, during the storage and transportation of the heat-sensitive article, the volatile dye absorbs heat to volatilize and be adsorbed by the adsorbing material layer, and the volatilization amount of the dye has positive correlation with the accumulative absorbed heat (which is related to the degradation speed or degree of the heat-sensitive article); selecting the type and the amount of the dye according to specific heat-sensitive articles, and regulating the volatilization speed of the dye by combining other methods; the dye layer according to an embodiment of the present invention is lightened in color by endothermic volatilization, and the color change response of the dye layer can be almost completely consistent with the change in activity of the heat-sensitive article, whereby whether the heat-sensitive article is in the expiration date or shelf life can be easily determined simply by the color change of the dye layer. The present invention has been completed based on the above findings.
To this end, a first aspect of the present invention provides a method for monitoring cumulative heat exposure of a heat-sensitive article, the method comprising the steps of: (a) providing a heat sensitive article; (b) attaching a layer of volatile dye to an area of the heat sensitive article; (c) attaching a layer of adsorbing material on the volatile dye; (d) attaching a sealing film to the certain region and the periphery thereof, wherein the sealing film enables the adsorption material layer and the volatile dye layer to be attached to the heat-sensitive article in a sealing manner; the volatile dye can volatilize under the heated condition, the adsorbing material can irreversibly adsorb the volatilized dye, the color fading quantity of the volatile dye layer is in positive correlation with the volatilization quantity of the dye, and the color fading quantity of the volatile dye layer is in positive correlation with the heat quantity absorbed by the heat-sensitive article.
According to a second aspect of the present invention, there is provided a method of monitoring the quality status of a heat-sensitive article.
According to a third aspect of the present invention there is provided a method of monitoring for failure of a heat sensitive article.
According to a fourth aspect of the present invention there is provided a time temperature indicator comprising two parts, an indicating functional layer and an adsorbing functional layer, which are separate from each other prior to use.
According to a fifth aspect of the present invention there is provided a heat-sensitive article monitored using the method of the first, second or third aspects of the present invention.
In accordance with a sixth aspect of the present invention, there is provided a heat-sensitive article for monitoring heat exposure, monitoring quality status or monitoring for failure using the time-temperature indicator of the fourth aspect of the present invention.
According to a seventh aspect of the present invention, there is provided a heat-sensitive article comprising a heat-sensitive article body, and a time-temperature indicator adhered thereto, the time-temperature indicator comprising two parts, an indicating functional layer and an adsorbing functional layer.
According to a eighth aspect of the present invention there is provided a compound of formula I, for use as a volatile dye in the present invention:
according to a ninth aspect of the present invention there is provided the use of a compound of formula I according to the eighth aspect of the present invention for monitoring cumulative exposure to heat, monitoring quality status and/or failure of a heat-sensitive article; or a volatile dye for use in the method of the first, second or third aspect of the invention; or a volatile dye layer for use in the time-temperature indicator according to the fourth aspect of the invention; or a volatile dye layer for use in the heat-sensitive article of the seventh aspect of the present invention.
Drawings
Fig. 1 is a schematic structural diagram of a time-temperature indicator made in accordance with an embodiment of the present invention.
FIG. 2A is a schematic diagram of the use and color change process of a time-temperature indicator made in accordance with an embodiment of the present invention. FIG. 2B is a schematic view of the time-temperature indicator made by an embodiment of the present invention viewed from another angle and showing the color change.
FIG. 3 is a graph showing the effect of the time-temperature indicator using and color-changing process of example 1 of the present invention made by using dye A as the heat-sensitive functional material.
Fig. 4a and 4b are graphs showing the color change speed of the time-temperature indicator manufactured by using the dye a as the thermosensitive functional material in example 2 of the present invention at different temperatures.
FIG. 5 is a time-temperature indicator made of dye A as a heat-sensitive functional material according to example 2 of the present invention, with a color difference Δ E* abActivation energy of discoloration process determined as end point of discoloration 10.
FIG. 6 is a time-temperature indicator designed and made for hepatitis B vaccine (Hep-B) in example 2 of the present invention using dye A as the heat sensitive functional material, wherein the color change response of the time-temperature indicator is almost completely consistent with the activity change of the vaccine.
Fig. 7 shows the initial colorimetric values of indicators fabricated by using different ink (i.e., dye) concentrations and the same ink loading and the color change process at the same temperature, according to example 3 of the present invention, using dye a as the heat-sensitive functional material.
FIG. 8 is a graph showing that in example 3 of the present invention in which dye A is used as a thermosensitive functional material, indicators were produced using different ink concentrations and the same ink loading, and the time until the end of the indicator was reached was linear with the amount of thermosensitive functional material printed per unit area.
FIG. 9 shows the color difference at 50 ℃ as a function of time for a temperature-sensitive material of example 4 of the present invention using three compounds of formula I (each dye A, B, C) as time-temperature indicators.
FIG. 10 shows the color difference of the indicator with time at the same temperature in example 5 of the present invention, which uses cyclohexane, dichloromethane, methyl acetate, ethanol, ethyl acetate as solvent to print dye A as the heat-sensitive functional material.
FIG. 11 shows the color difference change at 80 ℃ as a function of time of an indicator prepared by adding an appropriate amount of a binder EC (ethyl cellulose) to an organic solution of dye A in example 6 of the present invention.
FIG. 12 shows the time-temperature indicator made of dye B as the heat-sensitive functional material and three different adsorbing materials in example 7, wherein the color difference of the indicating functional layer of the indicator changes with time under the same temperature environment.
Some of the terms and their reference numbers used in the present invention are summarized below:
an indication function layer 1, a second release film layer 11, a volatile dye layer 15, an adsorption material layer 21,
an absorption function layer 2, a self-adhesive layer 12, a reference color layer 16, a self-adhesive layer 22,
a heat-sensitive article 3, a sealing film layer 13, a first release film layer 17, a release film layer 23,
a substrate material layer 10, a sealant layer 14, a substrate material layer 20, and a spacer layer 24.
Detailed Description
In a first aspect, the present invention provides a method for monitoring cumulative heat exposure of a heat-sensitive article, the method comprising the steps of:
(a) providing a heat sensitive article;
(b) attaching a layer of volatile dye to an area of the heat sensitive article;
(c) attaching a layer of adsorbing material on the volatile dye;
(d) attaching a sealing film to the certain region and the periphery thereof, wherein the sealing film enables the adsorption material layer and the volatile dye layer to be attached to the heat-sensitive article in a sealing manner;
wherein the volatile dye is volatile under heat (e.g. in the case of the temperature at which handling is desired, e.g. in the case of the desired storage and/or transport temperature, e.g. in the case of an unexpected increase in the handling temperature, e.g. in the case of the accelerated test desired handling temperature, e.g. in the case of an accelerated test desired handling temperature of 25 ℃ and/or 37 ℃), the adsorption material irreversibly adsorbs the volatile dye, and the Color Fading (CF) of the volatile dye layer is positively correlated with the amount of volatilization of the dye, which in turn is positively correlated with the amount of heat absorbed by the heat-sensitive article.
The method according to the first aspect of the present invention, wherein the monitoring of the cumulative exposure of the heat-sensitive article is characterized by a color fading amount and/or a color fading rate of the volatile dye layer. In one embodiment, the color fading may be further measured by the color difference Δ E of the volatile dye layer* abIs characterized by a change in (c); in one embodiment, the rate of color fading of the volatile dye layer may be characterized by a set color difference range divided by the time required to reach the color difference range; in one embodiment, the change in color fading rate with temperature is subject to the Arrhenius equation, which can be used to derive the activation energy EaAnd (5) characterizing.
The method according to the first aspect of the invention, wherein the heat-sensitive article is an article which needs to be stored and/or transported at-40 ℃ to 50 ℃, preferably an article which needs to be stored and/or transported at-30 ℃ to 40 ℃, preferably an article which needs to be stored and/or transported at-30 ℃ to 30 ℃, preferably an article which needs to be stored and/or transported at-20 ℃ to 20 ℃, preferably an article which needs to be stored and/or transported at-20 ℃ to 10 ℃, for example an article which needs to be stored and/or transported at-10 ℃ to 10 ℃, for example an article which needs to be stored and/or transported at 0 ℃ to 10 ℃, for example an article which needs to be stored and/or transported at 2 ℃ to 8 ℃. In one embodiment, the heat-sensitive articles include, but are not limited to: vaccines (e.g., vaccines that are not heat stable, such as poliomyelitis vaccine, typhoid vaccine, hepatitis b vaccine, etc.), biological products (e.g., human immunoglobulin, anti-human T cell porcine immunoglobulin, etc.), biologically active samples (e.g., plasma, whole blood, serum, etc.), drugs (e.g., posterior pituitary injection, stannous etifiline for injection, etc.), foods (e.g., fresh meat, fresh fish, etc.), drinks (e.g., fresh milk, milk products, yogurt, pasteurized milk), etc.
The method according to the first aspect of the present invention, wherein the volatile dye is a colored substance or a combination of colored substances having volatility at a certain temperature, including but not limited to volatile inorganic dyes or organic dyes and combinations thereof. Volatile dyes may also be referred to as heat sensitive materials in the present invention. In one embodiment, the volatile dye includes, but is not limited to, azo-based dyes, anthraquinone-based dyes, compounds of formula I or derivatives thereof, or combinations thereof.
The method according to the first aspect of the present invention, wherein the volatile dye is a compound of formula I:
wherein,
r1 is selected from hydrogen, halogen, C1-6Straight or branched alkyl, C1-6Linear or branched alcohols, -COR2, -COOR 2;
r2 is selected from hydrogen and C1-6Straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.), C1-6Straight or branched alkylamines (e.g., methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, n-pentylamine, isopentylamine, neopentylamine, n-hexylamine, etc.).
In one embodiment, R1 is selected from hydrogen, halogen, -COR2, -COOR2, R2 is selected from hydrogen, C1-4Straight or branched chain alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl), C1-4Straight or branched alkylamines (e.g., methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, and the like). In one embodiment, the R1 is selected from the group consisting of hydrogen, -COOH, -COOCH3、-COOCH2CH3、-COOCH2CH2CH3、-COOCH(CH3)2。
The method according to the first aspect of the present invention, wherein the volatile dye layer may further include one or more volatile additives, and the volatile additives may be various volatile substances capable of regulating the volatilization speed of the pigment or dye and the temperature effect thereof. In one embodiment, the volatilization aid can be a variety of volatile compounds including, but not limited to, linear or branched chain or cycloalkanes or aromatics (including, but not limited to, naphthalene, anthracene), various linear or branched chain or aromatic or cyclic alcohols (including, but not limited to, erythritol, lauryl alcohol, tridecanol, tetradecanol, pentadecanol, palmityl alcohol, heptadecyl alcohol, stearyl alcohol, etc.), various linear or branched chain or aromatic or cyclic carboxylic acids (including, but not limited to, maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid, etc.), various amino acids (including, but not limited to, aminobenzoic acid, leucine, phenylalanine, etc.), various ester compounds, various sulfones (including, but not limited to, diphenylsulfone, diphenyldisulfone, dibenzylsulfone, dibutylsulfone, etc.), or volatile natural materials, including but not limited to naphthalene, camphor, and the like.
The method according to the first aspect of the present invention, wherein the volatile dye layer is coated on the substrate material. In one embodiment, the volatile dye layer is coated on a backing material and the backing material is adhered to the heat sensitive article. In one embodiment, the backing material includes, but is not limited to, paper, such as plain copy paper, printing paper, sticker label paper; polymeric films such as polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene terephthalate, and the like. In one embodiment, the volatile dye is dissolved in a solvent and then coated onto the substrate material. In one embodiment, the solvent includes, but is not limited to, water, and organic solvents such as hexane, cyclohexane, tetrahydrofuran, benzene, xylene, methanol, ethanol, isopropanol, 2-butanol, acetone, diethyl ether, methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, methylene chloride, dichloroethane, and the like, and combinations thereof.
The method according to the first aspect of the invention, wherein the adsorbent material is any material capable of irreversibly adsorbing the volatile dye. In one embodiment, the absorbent material adsorbs the volatile dye at a rate greater than the rate of volatilization of the volatile dye. In one embodiment, the adsorbent material adsorbs the volatile dye at a rate substantially greater than the rate of volatilization of the volatile dye. In one embodiment, the adsorbent material adsorbs the volatile dye at a rate substantially greater than the volatile dye so that the rate at which the dye is adsorbed is substantially related only to the volatile dye rate. In one embodiment, the absorbent material adsorbs the volatile dye at a rate much greater than the volatile dye so that the apparent rate of volatilization of the dye is affected only by temperature (or heat absorbed) and not by factors such as the blockage of saturated/near saturated vapors produced by the material after volatilization. In one embodiment, the adsorbent material includes, but is not limited to, oil or water-based stickers, commercial self-adhesive papers, stickers, and the like.
The method according to the first aspect of the present invention, wherein the sealing film may be such that the absorbent material layer and the volatile dye layer are sealingly attached to the heat-sensitive article. Thus, in the case of monitoring the extent to which the heat-sensitive article is subjected to heat or temperature, for example during storage and/or transportation, the volatile dye and the absorbent material are in a closed system formed by the sealing film and the heat-sensitive article and do not escape, so that the dye which has volatilized by exposure to heat/temperature changes is substantially completely absorbed into the absorbent material. The method according to the first aspect of the present invention, wherein in the case of ending the monitoring of the degree of heat or temperature influence of the heat-sensitive article, for example after passing through a required storage and/or transportation process, the sealing film may be peeled off from the heat-sensitive article, optionally separating both the volatile dye layer and the adsorbing material layer, when the heat-sensitive article is subjected to further processing (for example, using the article, judging whether the quality of the article is deteriorated, etc.), so that the remaining amount of dye in the volatile dye layer can be observed or measured. The amount of dye remaining is in a positive correlation with the color of the volatile dye layer, and thus, in one embodiment, the amount of dye remaining can be characterized by the color of the volatile dye layer.
In a second aspect, the present invention provides a method of monitoring the condition of the quality of a heat sensitive article, the method comprising the steps of:
(i) providing a heat-sensitive article, determining the time (which in the present invention may refer to the maximum time that can be sustained, which may also be referred to as the useful life, which may be represented by T1) for which the heat-sensitive article can maintain an effective quality state at the temperature (which may be represented by T1 in the present invention) at which it is desired to handle (e.g., store and/or transport, or stability acceleration test), and optionally determining therefrom the amount of heat (which in the present invention may be represented by ca (tolerance)) that the heat-sensitive article is allowed to absorb while maintaining an effective quality state; wherein the expiration date may also be determined at a plurality of different desired treatment temperatures;
(ii) attaching a layer of volatile dye to a certain area of the heat-sensitive article (in this case, there is no volatile amount, and in this case, the initial color amount of the dye layer can be expressed as C0);
determining the theoretical residual quantity of the color of the dye layer after the volatile dye layer with the amount of C0 is treated under the treatment conditions of T1 and T1 according to the temperature (T1) at which the heat-sensitive article is expected to be treated and the time (T1) for which the heat-sensitive article can maintain the effective quality state under the treatment condition of T1 (the theoretical residual quantity of the color of the dye layer can be expressed as C1 at this time);
(iii) attaching a layer of adsorbing material on the volatile dye;
(iv) attaching a sealing film to the certain region and the periphery thereof, wherein the sealing film enables the adsorption material layer and the volatile dye layer to be attached to the heat-sensitive article in a sealing manner;
wherein the volatile dye is volatile under heat (e.g. at the temperature at which handling is desired, e.g. at the temperature at which storage and/or transport is desired, e.g. at the temperature at which handling is desired to be accidentally increased, e.g. at the temperature at which handling is desired to be accelerated, e.g. at 25 ℃ and/or 37 ℃), the adsorbent material irreversibly adsorbing the volatile dye, and the colour fading quantity of the volatile dye layer (i.e. the amount of volatilization of the dye, which in the present invention may be denoted as CF, wherein CF ═ C0-C1) is positively correlated with the amount of heat absorbed by the heat-sensitive article;
(v) after the heat-sensitive article adhered with the volatile dye layer, the absorbent material layer and the sealing film in step (iv) is disposed (for example, the article is actually stored and/or transported), the volatile dye layer is separated from the absorbent material layer, and the actual residual amount of the color in the volatile dye layer is observed or measured (in this case, the dye layer is subjected to the actual storage and/or transportation of the heat-sensitive article, and the actual residual amount of the color can be expressed as C2):
if the actual residual amount of the color (C2) of the dye layer is greater than or equal to the theoretical residual amount of the color (C1) in the step (ii), indicating that the heat-sensitive article is kept in an effective quality state;
if the actual residual amount of the color (C2) of the dye layer is smaller than the theoretical residual amount of the color (C1) in the step (ii), the heat-sensitive article is beyond the effective quality state.
The method according to the second aspect of the present invention, wherein the temperature at which handling of the heat-sensitive article is desired is the temperature at which handling (e.g. storage and/or transport, or stability acceleration test) of the article is required, e.g. the storage and/or transport temperature, e.g. the handling temperature desired for the stability acceleration test. The method according to the second aspect of the present invention, wherein the heat-sensitive article maintains an effective quality state means that the article still meets its corresponding quality standard after being disposed. The method according to the second aspect of the present invention, wherein the time (T1) for which the heat-sensitive article maintains an effective quality state at T1 means that the article has an expiration date at T1 at a temperature of T1.
According to the method of the second aspect of the invention, the heat-sensitive article is subjected to the temperature T1 and the time T1, wherein the quantity of the heat-sensitive article in the effective quality state left is positively correlated with the theoretical residual quantity of color (C1) of the dye layer. Thus, for a particular heat-sensitive article, it maintains an effective quality state (e.g., maintaining the active ingredient at 90% or more) at a temperature T1 for a time T1 as described above, which time T1 substantially corresponds to the time at which the dye layer changes from a C0 amount to a C1 amount at a temperature T1.
The method according to the second aspect of the invention, wherein the actual residual amount of color in the volatile dye layer is observed or determined by comparing the shades of the color exhibited by both the actual residual amount of color (C2) and the theoretical residual amount of color (C1). In one embodiment, the theoretical residual amount of color (C1) is provided in a reference color label. In one embodiment, the actual residual amount of color in the volatile dye layer is observed or determined by comparing the shade of color of the dye layer to the shade of color of the reference color label. In one embodiment, if the dye layer is darker in color shade than the reference color label, it indicates that the heat-sensitive article remains in an effective quality state; if the dye layer is lighter than the reference color label, it indicates that the heat-sensitive article is out of effective quality, i.e., has exceeded its useful life or has failed. In one embodiment, the shade of the color of the reference color label is substantially determined from the theoretical residual amount of color (C1) of a volatile dye layer in an amount of C0 after the dye layer has been treated under conditions of both T1 and T1.
In a third aspect, the present invention provides a method of monitoring the failure of a heat sensitive article, the method comprising the steps of:
providing a heat-sensitive article, determining the useful life (in the present invention, T1) of the heat-sensitive article at a temperature (in the present invention, T1) at which it is desired to be handled (e.g., storage and/or transportation, or stability acceleration test); wherein the expiration date may also be determined at a plurality of different desired treatment temperatures;
secondly, attaching a layer of volatile dye to a certain area of the heat-sensitive article (no volatile amount exists at the moment, and the initial color depth (namely the initial color amount) of the dye layer can be expressed as C0 at the moment);
determining the theoretical depth of color of the dye layer after treatment of an amount of C0 at the treatment conditions of T1 and T1 (in which case the theoretical depth of color of the dye layer may be represented as C1) based on the temperature at which the heat-sensitive article is expected to be treated (T1) and the expiration date at T1 (T1), whereby the theoretical depth of color provides a reference color label (whose color and shade are substantially equivalent to the theoretical depth of color C1);
thirdly, attaching a layer of adsorbing material on the volatile dye;
adhering a sealing film to the certain area and the periphery of the certain area, wherein the sealing film enables the adsorption material layer and the volatile dye layer to be attached to the heat-sensitive article in a sealing mode;
wherein the volatile dye is volatile under heat (e.g. at the temperature at which handling is desired, e.g. at the temperature at which storage and/or transport is desired, e.g. at the temperature at which handling is desired to be accidentally increased, e.g. at the temperature at which handling is desired to be accelerated, e.g. at 25 ℃ and/or 37 ℃), the adsorbent material irreversibly adsorbing the volatile dye, and the colour fading quantity of the volatile dye layer (i.e. the amount of volatilization of the dye, which in the present invention may be denoted as CF, wherein CF ═ C0-C1) is positively correlated with the amount of heat absorbed by the heat-sensitive article;
fifthly, after the heat-sensitive article adhered with the volatile dye layer, the adsorption material layer and the sealing film is treated (for example, the article is actually stored and/or transported), the volatile dye layer is separated from the adsorption material layer, and the actual color depth of the volatile dye layer is observed or measured (at this time, the dye layer is actually stored and/or transported by the heat-sensitive article, and the actual color depth can be expressed as C2):
if the actual depth of color of the dye layer (C2) is greater than or equal to the theoretical depth of color (C1) at this time, or the actual depth of color of the dye layer (C2) is darker than or equal to the color of the reference color label at this time, indicating that the heat-sensitive article is still valid;
if the actual depth of color of the dye layer (C2) is less than the theoretical depth of color (C1) at this time, or the actual depth of color of the dye layer (C2) is lighter than the color of the reference color label at this time, it is indicated that the heat-sensitive article has failed.
The method according to the third aspect of the present invention, wherein the reference color label is attached to the heat-sensitive article together with the volatile dye layer. In one embodiment, the reference color label is located adjacent to the volatile dye layer (e.g., label is positioned side-by-side with the dye layer, label is positioned around the dye layer, etc.) and is coated together on a backing material layer, and the backing material layer is attached to the heat-sensitive article. In one embodiment, the volatile dye layer is coated on a backing material layer that is the same color and color depth as the reference color label, so that the backing material layer can now be used as a form of the reference color label.
The method according to the third aspect of the present invention, wherein the reference color label is attached to the heat-sensitive article together with the volatile dye layer, and both the reference color label and the volatile dye layer are covered with an absorbent material layer.
The method according to the third aspect of the present invention, wherein the reference color label is attached to the heat-sensitive article together with the volatile dye layer, and both the reference color label and the volatile dye layer are covered with an absorbent material layer, and the sealing film sealingly attaches the absorbent material layer and the volatile dye layer, the reference color label, to the heat-sensitive article. In one embodiment, the volatile dye layer is separated from the wicking material layer after the heat-sensitive article to which the dye layer, the reference color label, the wicking material layer, and the sealing film are affixed is disposed (e.g., actual storage and/or transportation of the article), with the reference color label and the volatile dye layer being located adjacent to each other (e.g., the label is positioned side-by-side with the dye layer, the label is positioned around the dye layer, etc., such adjacent location being particularly advantageous for visual comparison of the two colors and/or shades of color).
The method according to the third aspect of the present invention, wherein in the fifth step, comparing the color depth of the volatile dye layer and the color depth of the reference color label, if the color depth of the dye layer is greater than or equal to the color depth of the reference color label, it indicates that the heat-sensitive article is still effective; if the color depth of the dye layer is less than the color depth of the reference color label, it indicates that the heat-sensitive article has failed.
A fourth aspect of the invention provides a time-temperature indicator comprising two laminated portions, an indicating functional layer and an adsorbing functional layer, which are independent of each other before use, wherein:
the indication function layer includes:
a layer of substrate material;
the volatile dye layer is coated on one side of the substrate material layer;
an optional reference color layer coated on the same side of the backing material layer as the volatile dye layer and located adjacent to the volatile dye layer (e.g., the reference color layer is disposed alongside the volatile dye layer, the reference color layer is disposed around the volatile dye layer, etc., such adjacent location being particularly advantageous for visual comparison of the color and/or shade of the color); and
a first release film layer covering the volatile dye layer and the reference color layer; and optionally:
the sealing glue layer is coated on one side, opposite to the volatile dye layer, of the substrate material layer;
a sealing film layer covering the sealing adhesive layer;
the non-drying glue layer is coated on the sealing film layer; and/or
A second release film layer covering the non-drying adhesive layer;
the adsorption function layer includes:
a layer of substrate material;
an absorbent material layer coated on one side of the substrate material layer, and optionally a separation layer covered on the absorbent material layer, wherein the size of the absorbent material layer and the optional separation layer is larger than or equal to the size of the volatile dye layer (preferably larger than or equal to the size of both the reference color layer and the volatile dye layer);
a non-drying glue layer coated on the substrate material layer and surrounding the periphery of the adsorption material layer and the optional isolation layer; and
a release film layer overlying the tack coat layer and the layer of adsorbent material and optional barrier layer.
In the present invention, in the adsorption function layer, the substrate material layer and the optional separation layer are respectively located on both sides of the adsorption material layer.
According to a fourth aspect of the invention, the time-temperature indicator, wherein the two laminated portions of the indicating functional layer and the adsorbing functional layer are in the form of two laminated sheets physically independent from each other before use.
A time-temperature indicator according to a fourth aspect of the invention is used in the method of the first, second or third aspect of the invention to monitor the amount of heat applied to the heat sensitive article, or to monitor the quality status of the heat sensitive article, or to monitor whether the heat sensitive article has failed.
In the time-temperature indicator according to the fourth aspect of the present invention, when the two laminated portions of the indicating functional layer and the absorbent functional layer are used, the optional second release film layer is peeled off to attach the indicating functional layer to the heat-sensitive article, and then the first release film layer is peeled off; and stripping the release film layer on the adsorption function layer to enable the adsorption material layer part to be aligned to the volatile dye layer on the indication function layer part, and covering the whole indication function layer with the adsorption function layer and tightly attaching the adsorption function layer to the heat-sensitive article.
According to a fourth aspect of the invention, a time temperature indicator is provided, wherein the dye in the volatile dye layer is enclosed between the first release film layer and the backing material layer before use of the indicator functional layer. In this closed state, the volatile dye does not volatilize out due to a change in temperature (e.g., in the range of-50 ℃ to 50 ℃). In one embodiment, prior to use of the indicator functional layer, the dye in the volatile dye layer is enclosed on one side within a first release film layer and on the other side within a laminate structure comprising a backing material layer and at least one of the following layers: the adhesive tape comprises a sealing adhesive layer, a sealing film layer, a non-drying adhesive layer and a second release film layer. The combination of the first release film layer and the laminate structure seals the volatile dye layer to better prevent the volatile dye from escaping, and the laminate structure provides benefits for the indicator function layer to more conveniently and/or closely adhere to the heat-sensitive article. For example, in the case where a sealant layer, a non-drying adhesive layer, and a second release film layer are sequentially disposed on one side of the substrate material layer, the second release film layer provides a relatively closed environment for the entire indicating function layer before use, and after peeling the second release film layer, the exposed non-drying adhesive layer can be very conveniently and/or tightly attached to the heat-sensitive article. Also for example, a sealant layer and a sealing film layer may be used as a supplement to the backing material layer to prevent escape of volatile dyes.
The time-temperature indicator according to the fourth aspect of the present invention, wherein the reference color layer is coated on the same side of the substrate material layer as the volatile dye layer in a manner of surrounding the volatile dye layer. In an alternative embodiment of the invention, the color and color depth of the reference color layer are the same as the color and color depth of the substrate material layer, in which embodiment the reference color layer may be merged with the substrate material layer into the same layer, i.e. no separate reference color layer may be provided at this point, and the color and/or color depth of the substrate material layer may serve the function and effect of the reference color layer.
The time-temperature indicator according to the fourth aspect of the invention, wherein the colour and/or colour depth of the reference colour layer is substantially the same as the colour and/or colour depth of the dye in the volatile dye layer after being subjected to the treatment conditions. The disposal condition is that the volatile dye layer experiences the temperature (at least two different temperatures) of the heat-sensitive article at its intended disposal (e.g. storage and/or transport, or stability acceleration test) when the volatile dye layer is contacted with the absorbent material layer under conditions that are effective for carrying out the volatilisation-sorption process of the invention (i.e. the volatile dye is volatilised under heat exposure (e.g. at the temperature at which disposal is desired, e.g. at the temperature at which storage and/or transport is desired, e.g. at the temperature at which disposal is accidentally increased, e.g. at the temperature at which accelerated test is desired, e.g. at 25 ℃ and/or 37 ℃), the volatilised dye is irreversibly adsorbed by the adsorbing material, and the colour fading of the volatile dye layer is positively correlated with the amount of heat absorbed by the heat-sensitive article, which in the present invention may be represented by T1) for a period of time (which in the present invention may be referred to as the longest period of time during which the effective quality state can be maintained, which may also be referred to as the effective period of time, which may be represented by T1). It will be appreciated that after a heat-sensitive article (e.g. a vaccine which requires storage at 2-8 ℃) has been subjected to an effective period at its prescribed storage temperature, the amount of active ingredient of effective quality (e.g. potency, percentage of active ingredient) remaining corresponds to the colour and/or colour depth exhibited by the volatile dye layer after it has been subjected to T1 and T1 as described above, and this colour and/or colour depth is substantially the same as that of the reference colour layer. This is the primary basis for achieving the various objects of the present invention, and as further detailed in the context of the present invention, depending on the requirements of the use of different heat sensitive articles, the skilled artisan can readily determine the starting color of the volatile dye layer and its depth, and the color of the reference color layer and its depth, by adjusting one or more factors, including but not limited to: the type, composition and dosage of the volatile dye, the formula of the dye coating liquid (such as a solvent and/or an auxiliary agent used therein), the adsorption performance of the adsorption material and the like. In one embodiment of the present invention, the difference in color and/or color depth between the reference color layer and the volatile dye layer can be distinguished by the naked eye.
The time-temperature indicator according to the fourth aspect of the present invention, wherein the first release film layer is any release film satisfying the following conditions: which can seal the volatile dye in the interlayer with other layers (e.g., a backing material layer and optionally a sealant layer, a sealing film layer, a tack coat layer, and a second release film layer), the dye does not volatilize out due to elevated temperatures; the indicating functional layer can be peeled off from the indicating functional layer, so that the indicating functional layer and the adsorption functional layer are combined and attached to the heat-sensitive article conveniently in use.
According to the time-temperature indicator of the fourth aspect of the present invention, in the indicating functional layer, a sealant layer, a tack coat layer, and a second release coat layer are provided in this order from the inside to the outside on the side of the backing material layer opposite to the volatile dye layer. The benefits of this arrangement have been described above, for example, the second release film layer provides a relatively closed environment for the entire indicating functional layer prior to use, and the exposed non-drying adhesive layer can in turn facilitate and/or tightly apply the indicating functional layer to the heat-sensitive article after peeling the second release film layer. Also for example, a sealant layer and a sealing film layer may be used as a supplement to the backing material layer to prevent escape of volatile dyes.
According to a fourth aspect of the invention, a time-temperature indicator is provided which, in use, allows direct contact between the absorbent material layer and the volatile dye layer. In a preferred embodiment, however, it is desirable to provide a barrier film layer therebetween. The isolation film layer has the advantages that a physically relatively separated space can be provided between the volatile dye layer and the adsorption material layer, and the dyes are prevented from being adsorbed into the adsorption material layer in a 'transfer' mode due to direct contact of the volatile dye layer and the adsorption material layer; meanwhile, when the dye is volatilized due to the temperature rise, the dye can freely pass through the separation film layer and be rapidly and irreversibly adsorbed into the adsorption material layer.
According to the time-temperature indicator of the fourth aspect of the present invention, the size of the absorbent material layer and the optional separation layer is greater than or equal to the size of the volatile dye layer (preferably greater than or equal to the size of both the reference color layer and the volatile dye layer). The size design can provide more absorbing materials for the volatile dye on one hand, and provide uniform volatilization speed for the dye at different positions so that the volatile dye layer can have a uniform color after the heat-sensitive article is actually treated (for example, subjected to vaccine or drug storage and/or transportation process), and the comparison with the reference color layer is facilitated.
In accordance with the time-temperature indicator of the fourth aspect of the invention, in the adsorptive function layer, the backing material layer desirably has good mechanical stability to maintain the heat-sensitive article in good form and to maintain the function of the inner layers throughout actual handling. Further, it is desirable that the substrate material layer has a certain coatable or printable property so that the absorbent material layer and the pressure sensitive adhesive layer can be effectively coated thereon, or optionally some product information or use information is printed on one side thereof. It is also desirable to have a strong adhesion between the backing material layer and the sticker layer, on the one hand to firmly adhere the backing material layer to the heat-sensitive article, and on the other hand to allow the sticker layer and the backing material layer, along with the absorbent material layer and optional barrier layer, to be peeled off from the heat-sensitive article when peeling is required after use, without peeling off only the backing material layer and the absorbent material layer remaining stuck to the heat-sensitive article and covering the volatile dye layer.
According to the time-temperature indicator of the fourth aspect of the invention, the self-adhesive layer in the adsorption function layer surrounds the periphery of the adsorption material layer and the optional isolation layer and is coated on the substrate material layer. Regardless of the variation of the conditions under which the heat sensitive article is actually handled, it is contemplated that the layer of tack adhesive may form an enclosed space with the layer of backing material and the surface of the heat sensitive article, particularly the heat sensitive article, and the dye cannot escape outside the enclosed space regardless of whether it is volatilized or not. Further, for convenience in use, when it is intended to monitor whether or not the heat-sensitive article is failed, the pressure-sensitive adhesive layer and the backing material layer, together with the adsorbing material layer and the optional separating layer, can be easily peeled off from the heat-sensitive article, while the volatile dye layer and the reference color layer, and the optional sealant layer, the seal film layer, and the pressure-sensitive adhesive layer remain adhered to the heat-sensitive article, whereby it is possible to easily compare the shades of both the volatile dye layer and the reference color layer by naked eyes, thereby judging whether or not the heat-sensitive article is failed.
A fifth aspect of the invention provides a heat-sensitive article monitored using the method of the first, second or third aspects of the invention.
A sixth aspect of the present invention provides a heat-sensitive article for monitoring heat exposure, monitoring quality status, or monitoring for failure using the time-temperature indicator of the fourth aspect of the present invention.
The seventh aspect of the present invention provides a heat-sensitive article comprising a heat-sensitive article body, and a time-temperature indicator adhered thereto, the time-temperature indicator comprising two laminated portions of an indicating functional layer and an adsorbing functional layer, wherein:
the indication function layer includes:
a layer of substrate material;
the volatile dye layer is coated on one side of the substrate material layer;
an optional reference color layer coated on the same side of the backing material layer as the volatile dye layer and located adjacent to the volatile dye layer (e.g., the reference color layer is disposed alongside the volatile dye layer, the reference color layer is disposed around the volatile dye layer, etc., such adjacent location being particularly advantageous for visual comparison of the color and/or shade of the color);
wherein the side of the backing material layer not coated with the volatile dye layer is adhered to the heat-sensitive article and optionally comprises between the backing material layer and the heat-sensitive article:
the sealing glue layer is coated on one side, opposite to the volatile dye layer, of the substrate material layer;
a sealing film layer covering the sealing adhesive layer; and/or
The non-drying glue layer is coated on the sealing film layer;
the adsorption function layer includes:
a layer of substrate material;
an absorbent material layer coated on one side of the substrate material layer, and optionally a separation layer covered on the absorbent material layer, wherein the size of the absorbent material layer and the optional separation layer is larger than or equal to the size of the volatile dye layer (preferably larger than or equal to the size of both the reference color layer and the volatile dye layer); and
a non-drying glue layer coated on the substrate material layer and surrounding the periphery of the adsorption material layer and the optional isolation layer;
wherein the absorbent material layer and optional barrier layer cover the indicator function layer adhered to the heat-sensitive article; the self-adhesive layer is adhered to the heat-sensitive article and forms a space for enclosing the indicating functional layer together with the backing material layer and the surface of the heat-sensitive article, especially the heat-sensitive article.
The heat-sensitive article according to the seventh aspect of the present invention, wherein the two laminated portions of the indicator functional layer and the absorbent functional layer are combined for monitoring heat exposure, quality status, and/or failure of the heat-sensitive article.
The heat-sensitive article according to the seventh aspect of the present invention, wherein the two laminated portions of the indicator functional layer and the absorbent functional layer are in the form of two laminated sheets physically independent from each other before use (i.e., adhesion to the heat-sensitive article), each of which optionally further comprises a release film to facilitate their production, transportation and use. For example, for the indicating functional layer portion, each of two sides thereof optionally further comprises a release film, such as the first release film layer and/or the second release film layer according to the fourth aspect of the present invention; for another example, for the part of the adsorption function layer, the self-adhesive layer is optionally sealed by a release film layer, such as the release film layer described in the fourth aspect of the present invention. When the two laminated layers of the indicating functional layer and the absorption functional layer are used on the heat-sensitive article, peeling off the release films, such as peeling off the optional second release film layer, so that the indicating functional layer is attached to the heat-sensitive article, and peeling off the first release film layer; and stripping the release film layer on the adsorption function layer to enable the adsorption material layer part to be aligned to the volatile dye layer on the indication function layer part, and covering the whole indication function layer with the adsorption function layer and tightly attaching the adsorption function layer to the heat-sensitive article.
The heat-sensitive article of the seventh aspect, wherein the reference color layer is coated on the same side of the backing material layer as the volatile dye layer in a manner surrounding the volatile dye layer. In an alternative embodiment of the invention, the color and color depth of the reference color layer are the same as the color and color depth of the substrate material layer, in which embodiment the reference color layer may be merged with the substrate material layer into the same layer, i.e. no separate reference color layer may be provided at this point, and the color and/or color depth of the substrate material layer may serve the function and effect of the reference color layer.
The heat-sensitive article of the seventh aspect of the present invention, wherein the color and/or color depth of the reference color layer is substantially the same as the color and/or color depth of the dye in the volatile dye layer after being subjected to the treatment condition. The disposal condition is that the volatile dye layer experiences the temperature (at least two different temperatures) of the heat-sensitive article at its intended disposal (e.g. storage and/or transport, or stability acceleration test) when the volatile dye layer is contacted with the absorbent material layer under conditions that are effective for carrying out the volatilisation-sorption process of the invention (i.e. the volatile dye is volatilised under heat exposure (e.g. at the temperature at which disposal is desired, e.g. at the temperature at which storage and/or transport is desired, e.g. at the temperature at which disposal is accidentally increased, e.g. at the temperature at which accelerated test is desired, e.g. at 25 ℃ and/or 37 ℃), the volatilised dye is irreversibly adsorbed by the adsorbing material, and the colour fading of the volatile dye layer is positively correlated with the amount of heat absorbed by the heat-sensitive article, which in the present invention may be represented by T1) for a period of time (which in the present invention may be referred to as the longest period of time during which the effective quality state can be maintained, which may also be referred to as the effective period of time, which may be represented by T1). It will be appreciated that after a heat-sensitive article (e.g. a vaccine which requires storage at 2-8 ℃) has been subjected to an effective period at its prescribed storage temperature, the amount of active ingredient of effective quality (e.g. potency, percentage of active ingredient) remaining corresponds to the colour and/or colour depth exhibited by the volatile dye layer after it has been subjected to T1 and T1 as described above, and this colour and/or colour depth is substantially the same as that of the reference colour layer. This is the primary basis for achieving the various objects of the present invention, and as further detailed in the context of the present invention, depending on the requirements of the use of different heat sensitive articles, the skilled artisan can readily determine the starting color of the volatile dye layer and its depth, and the color of the reference color layer and its depth, by adjusting one or more factors, including but not limited to: the type, composition and dosage of the volatile dye, the formula of the dye coating liquid (such as a solvent and/or an auxiliary agent used therein), the adsorption performance of the adsorption material and the like. In one embodiment of the present invention, the difference in color and/or color depth between the reference color layer and the volatile dye layer can be distinguished by the naked eye.
In the heat-sensitive article according to the seventh aspect of the present invention, in the indicating functional layer, a sealant layer, a sealing film layer, and a pressure-sensitive adhesive layer are provided in this order from inside to outside on the side of the backing material layer opposite to the volatile dye layer, and the indicating functional layer optionally further includes a second release film layer before being adhered to the heat-sensitive article. The benefits of this arrangement have been described above, for example, the second release film layer provides a relatively closed environment for the entire indicating functional layer prior to use, and the exposed non-drying adhesive layer can in turn facilitate and/or tightly apply the indicating functional layer to the heat-sensitive article after peeling the second release film layer. Also for example, a sealant layer and a sealing film layer may be used as a supplement to the backing material layer to prevent escape of volatile dyes.
The heat-sensitive article according to the seventh aspect of the invention, which allows the absorbent material layer to be in direct contact with the volatile dye layer in use. In a preferred embodiment, however, it is desirable to provide a barrier film layer therebetween. The isolation film layer has the advantages that a physically relatively separated space can be provided between the volatile dye layer and the adsorption material layer, and the dyes are prevented from being adsorbed into the adsorption material layer in a 'transfer' mode due to direct contact of the volatile dye layer and the adsorption material layer; meanwhile, when the dye is volatilized due to the temperature rise, the dye can freely pass through the separation film layer and be rapidly and irreversibly adsorbed into the adsorption material layer.
According to the heat-sensitive article of the seventh aspect of the present invention, the size of the adsorbing material layer and the optional spacer layer is greater than or equal to the size of the volatile dye layer (preferably greater than or equal to the size of both the reference color layer and the volatile dye layer). The size design can provide more absorbing materials for the volatile dye on one hand, and provide uniform volatilization speed for the dye at different positions so that the volatile dye layer can have a uniform color after the heat-sensitive article is actually treated (for example, subjected to vaccine or drug storage and/or transportation process), and the comparison with the reference color layer is facilitated.
According to the heat-sensitive article of the seventh aspect of the present invention, in the adsorption functional layer, the substrate material layer desirably has good mechanical stability so that the heat-sensitive article maintains good form and maintains the functions of the inner layers throughout the actual handling. Further, it is desirable that the substrate material layer has a certain coatable or printable property so that the absorbent material layer and the pressure sensitive adhesive layer can be effectively coated thereon, or optionally some product information or use information is printed on one side thereof. It is also desirable to have a strong adhesion between the backing material layer and the sticker layer, on the one hand to firmly adhere the backing material layer to the heat-sensitive article, and on the other hand to allow the sticker layer and the backing material layer, along with the absorbent material layer and optional barrier layer, to be peeled off from the heat-sensitive article when peeling is required after use, without peeling off only the backing material layer and the absorbent material layer remaining stuck to the heat-sensitive article and covering the volatile dye layer.
According to the heat-sensitive article of the seventh aspect of the invention, the self-adhesive layer in the adsorption function layer surrounds the periphery of the adsorption material layer and the optional isolation layer and is coated on the substrate material layer. Regardless of the variation of the conditions under which the heat sensitive article is actually handled, it is contemplated that the layer of tack adhesive may form an enclosed space with the layer of backing material and the surface of the heat sensitive article, particularly the heat sensitive article, and the dye cannot escape outside the enclosed space regardless of whether it is volatilized or not. Further, for convenience in use, when it is intended to monitor whether or not the heat-sensitive article is failed, the pressure-sensitive adhesive layer and the backing material layer, together with the adsorbing material layer and the optional separating layer, can be easily peeled off from the heat-sensitive article, while the volatile dye layer and the reference color layer, and the optional sealant layer, the seal film layer, and the pressure-sensitive adhesive layer remain adhered to the heat-sensitive article, whereby it is possible to easily compare the shades of both the volatile dye layer and the reference color layer by naked eyes, thereby judging whether or not the heat-sensitive article is failed.
In an eighth aspect, the present invention provides a compound of formula I:
wherein,
r1 is selected from hydrogen, halogen, C1-6Straight or branched alkyl, C1-6Straight or branched chain alcohols, -COR2, -COOR2, and the like;
r2 is selected from hydrogen and C1-6Straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.), C1-6Straight or branched alkylamines (e.g., methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, n-pentylamine, isopentylamine, neopentylamine, n-hexylamine, etc.), and the like.
The compound according to the eighth aspect of the present invention, wherein,
r1 is selected from hydrogen, -COR2, -COOR 2;
r2 is selected from hydrogen and C1-4Straight or branched alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl), C1-4Straight or branched alkylamines (e.g., methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, and the like), and the like.
A compound according to an eighth aspect of the invention wherein R1 is selected from hydrogen, -COOH, -COOCH3、-COOCH2CH3、-COOCH2CH2CH3、-COOCH(CH3)2And the like.
In a ninth aspect, the present invention provides the use of a compound of formula I according to the eighth aspect of the invention in the preparation of a reagent for monitoring heat exposure, quality status and/or failure of a heat sensitive article.
The ninth aspect of the present invention also provides the use of a compound of formula I as described in the eighth aspect of the present invention in the preparation of a volatile dye for use in the process of the first, second or third aspect of the present invention.
The ninth aspect of the present invention also provides the use of a compound of formula I according to the eighth aspect of the present invention for the preparation of a volatile dye layer for use in a time-temperature indicator according to the fourth aspect of the present invention.
The ninth aspect of the present invention also provides the use of a compound of formula I according to the eighth aspect of the present invention in the preparation of a volatile dye layer for use in a heat-sensitive article according to the seventh aspect of the present invention.
According to a ninth aspect of the invention, the use is described, wherein the compound of formula I is optionally used in combination with one or more volatilization aids, which can be various volatile substances that can regulate the speed of volatilization of the pigment or dye and the temperature effect thereof. In one embodiment, the volatilization aid can be a variety of volatile compounds including, but not limited to, linear or branched chain or cycloalkanes or aromatics (including, but not limited to, naphthalene, anthracene), various linear or branched chain or aromatic or cyclic alcohols (including, but not limited to, erythritol, lauryl alcohol, tridecanol, tetradecanol, pentadecanol, palmityl alcohol, heptadecyl alcohol, stearyl alcohol, etc.), various linear or branched chain or aromatic or cyclic carboxylic acids (including, but not limited to, maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid, etc.), various amino acids (including, but not limited to, aminobenzoic acid, leucine, phenylalanine, etc.), various ester compounds, various sulfones (including, but not limited to, diphenylsulfone, diphenyldisulfone, dibenzylsulfone, dibutylsulfone, etc.), or volatile natural materials, including but not limited to naphthalene, camphor, and the like.
The use according to a ninth aspect of the invention, wherein the compound of formula I is dissolved in a solvent and then used in the reagent for monitoring the heat exposure, the quality status and/or whether it is spent, or in the method of the various aspects of the invention, or in the time-temperature indicator or the heat sensitive article of the invention, for example by coating the substrate material with the compound of formula I dissolved in a solvent. In one embodiment, the solvent includes, but is not limited to, water, and organic solvents such as hexane, cyclohexane, tetrahydrofuran, benzene, xylene, methanol, ethanol, isopropanol, 2-butanol, acetone, diethyl ether, methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, methylene chloride, dichloroethane, and the like, and combinations thereof.
Features of any aspect of the invention or any embodiment of any aspect are equally applicable to any other aspect or any embodiment of any other aspect, provided they are not mutually inconsistent, although appropriate modifications to the respective features may be made as appropriate when applicable to each other.
Various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
As used herein, the term "heat-sensitive article" may refer to any article that is unstable to heat, in particular any article which for example needs to be stored and/or transported at-40 ℃ to 50 ℃ (the storage time in this temperature range may be in the range between 1 hour and 10 years), preferably an article which needs to be stored and/or transported at-30 ℃ to 40 ℃, preferably an article which needs to be stored and/or transported at-30 ℃ to 30 ℃, preferably an article which needs to be stored and/or transported at-20 ℃ to 20 ℃, preferably an article which needs to be stored and/or transported at-20 ℃ to 10 ℃, for example, an article that needs to be stored and/or transported at-10 ℃ to 10 ℃, for example, an article that needs to be stored and/or transported at 0 ℃ to 10 ℃, for example, an article that needs to be stored and/or transported at 2 ℃ to 8 ℃. It can be, for example, any item that is currently in need of storage and/or transport at 2 ℃ to 8 ℃, in particular vaccines, biologicals, bioactive samples, pharmaceuticals, foods, drinks, etc. In particular any vaccine, biological product, bioactive sample, pharmaceutical product currently on the market, such as any item requiring storage and/or transport at 2 ℃ to 8 ℃ carried in the first, second or third pharmacopoeia of the people's republic of china, 2005 edition or 2010 edition. Although some articles, such as some pharmaceuticals, which are indicated to have a shelf life of 2 years when stored at 2 ℃ to 8 ℃ will decay by endotherms when placed at temperatures above 8 ℃ as heat sensitive articles of the present invention, it will be appreciated by those skilled in the art that such pharmaceuticals stored strictly at 2 ℃ to 8 ℃ will also decay to some extent by endotherms, although the extent of low temperature decay will be less than the decay temperature at higher temperatures. The inventor expects to monitor the heat effect of accumulated contact of the heat-sensitive article during storage and/or transportation by the method, for example, for the medicine with the expiration date of 2 years stored at 2-8 ℃, the heat effect exposed during storage at 2-8 ℃ is accumulated with the heat effect exposed at higher temperature, the accumulated heat effect is represented by the volatilization amount of the dye, and then whether the heat-sensitive article exceeds the preset expiration date standard during actual storage and/or transportation is judged.
As described herein, the term "heat affected" may also be referred to as "heat absorbed," or the cumulative amount of heat absorbed by a heat sensitive article in contact with ambient temperature. As described above, it may be characterized by the color fading amount and/or the color fading rate of the volatile dye layer. In one embodiment, the color fading quantity may be further defined by a color difference Δ E* abIs characterized by a change in (c); in one embodiment, the rate of color fading of the volatile dye layer may be characterized by a set color difference range divided by the time required to reach the color difference range; in one embodiment, the change in color fading rate with temperature is subject to the Arrhenius equation, which can be used to derive the activation energy EaAnd (5) characterizing. Furthermore, the heat exposure according to the invention can also be characterized by the amount of active ingredient lost from the article under the relevant storage conditions. Alternatively, the amount of heat applied according to the invention can also be determined by the effect of the product of the temperature of the article and the storage time, for example, for some articles, the amount of heat absorbed during storage at 5 ℃ for 2 years corresponds to storage at 25 ℃The amount of heat absorbed in 4 weeks was comparable for both conditions. Thus, in the present invention, the term "heat exposure" may reflect whether the activity/potency of the heat-sensitive article after being subjected to specific storage and transportation conditions is in an effective state as specified by product standards (e.g. the active ingredient content is still above 90%).
As used herein, the term "on the heat-sensitive article" may refer to an outer or inner surface of the heat-sensitive article, preferably to an outer surface of the heat-sensitive article, such as an outer surface of a primary package (or a minimal package, such as an ampoule of vaccine) of a vaccine, a pharmaceutical, etc., such as an outer surface of a glass bottle of a glass-bottled vaccine or pharmaceutical, or an outer surface of a soft bag of plasma, milk of a soft bag package.
As used herein, the term "region" refers to an area on the heat-sensitive article that is not particularly limited in location, but for purposes of the present invention is desirably relatively uniform to avoid non-uniform attachment of the functional layers of materials of the present invention to the heat-sensitive article, which may result in escape of volatile dyes. For example, for heat sensitive articles packaged in glass bottles, the certain area is desirably at a uniform portion of the body of the bottle and not at a bend, for example where people are commonly labeled, and not at the neck, mouth, etc. In addition, the size of the certain area is not particularly limited, but for the purpose of the present invention, 0.2 to 20cm2It is usually preferred, and more preferably 0.5 to 5cm2More preferably 0.5 to 4cm2More preferably 0.5 to 2.5cm2More preferably 0.5 to 1cm2。
As used herein, the term "attached" when referring to "attaching a layer of volatile dye to an area on the heat sensitive article," for example, can be coated; can also be pasted on; or printed; it can also be manually placed on the surface and then fixed by another functional layer. Similarly, the term "coating" can be applied in a variety of ways, such as but not limited to knife coating, spin coating, spray coating, printing, and the like. Similarly, the term "adhered" can be applied in a variety of ways, such as but not limited to adhesive attachment, or film covering.
As used herein, the term "volatile dye" is one of the main functional materials used for the purpose of the present invention, and can be any one or more of colored substances having volatility, including organic substances and inorganic substances, in theory. For the purposes of the present invention, particularly preferred "volatile dyes" according to the invention are colored substances having a melting point of from 0 ℃ to 80 ℃, preferably a melting point of from 10 ℃ to 80 ℃, preferably a melting point of from 20 ℃ to 80 ℃, preferably a melting point of from 30 ℃ to 60 ℃, preferably a melting point of from 40 ℃ to 80 ℃, preferably a melting point of from 40 ℃ to 60 ℃, preferably a melting point of from 50 ℃ to 80 ℃. For example, some dyes used in the present invention have a melting point of 30 ℃ to 60 ℃, particularly 40 ℃ to 60 ℃. In the present invention, volatile dyes are, in particular, dyes having a melting point of from 0 ℃ to 80 ℃ which have a certain volatility both at temperatures below the melting point and at temperatures above the melting point, however, it is understood by those skilled in the art that the volatility is relatively low at temperatures below the melting point, that the volatility increases greatly above the melting point, and that the rate of volatilization follows the Arrhenius equation.
For example, if vaccines are to be monitored that require storage at 2-8℃ for periods of validity (greater than 90% activity retention) of up to 2 years as required, volatile dyes will evaporate more slowly at temperatures of 2-8℃ if they are used with a melting point of about 40℃. Based on this principle, an initial amount of dye used (that is, referred to as color depth, C0) can be set, the initial amount is sealed in a closed system including an adsorbing material, and then they are placed at a temperature of 2 to 8 ℃ for 2 years, and the amount of residual dye (that may also be referred to as color theory residual amount or color depth, C1) of the volatile dye layer is used as the reference color depth of the present invention, and a reference color card, such as the reference color layer described in the fourth aspect of the present invention, can be produced based on the reference color depth; if the volatile dye layer is subjected to the actual storage/transport process together with the vaccine,if the actual color depth of the dye layer is darker or equivalent compared with the reference color depth, the vaccine still has the valid period after the actual storage and transportation, and if the actual color depth of the dye layer is lighter compared with the reference color depth, the vaccine is possibly heated and the activity is reduced to be less than 90 percent after the actual storage and transportation, and the vaccine is failed. The method of the invention allows vaccine quality to be identified in a very simple and inexpensive manner, avoiding the introduction into the use of products which have in fact failed but are still in the effective period from the production time point of view. In the above-described process for preparing a reference color card, a volatile dye is used to experience a thermal effect at 2-8 ℃ for 2 years, and the skilled person can also determine the color depth of the reference color card according to the prior knowledge by raising the temperature appropriately to shorten the time, for example, by using accelerated test methods well known to those skilled in the pharmaceutical field, for example, these methods are described in relevant textbooks (see, for example, the contents of the chapters related to the stability of substances such as drugs in the institute of Physichemistry, Ministry of education, 1979; Sudyson, et al, Physicologies, chemical industry, publishers, Beijing, 2004; Mitsui Zhu, pharmacy, third edition, Ministry of health, Beijing, 1994, etc.). For example, with reference to the conventional test method described in textbook (xi ju zhu, pharmacy, third edition, public health press, beijing, 1994, p141), if the activity of the above-mentioned vaccine with a lifetime of 2 years at 2-8 ℃ falls to the lower limit of the standard specification of 90% when left at 25 ℃ for 8 weeks, an initial amount of dye used (C0) can be set, this initial amount is sealed in a closed system comprising an adsorbing material, and then they are left at 25 ℃ for 8 weeks, and the residual dye amount (C1) of the volatile dye layer is used as the reference color depth of the present invention, and a reference color chart can be produced based on this reference color depth, which determines that the color depth of the reference color chart is faster than the mode of 2-8 ℃ plus 2 years. In addition, the reference color card can be determined by referring to the passage of a thermostatic method described in textbooks (xi monilia, pharmacy, third edition, people's health press, Beijing, 1994, p 141). The method is generally based on the Arrhenius equationThe method comprises key parameters such as activation energy E, rate constant k, thermodynamic temperature T and the like. For a heat-sensitive article with a certain specific property, the principle of the Arrhenius equation can be used to comprehensively determine the design requirements of the volatile dye layer and the reference color layer of the present invention suitable for the article, such as the composition and coating concentration of the dye layer, the color depth of the reference color layer, and the like. The Arrhenius equation is described in further detail below.
As used herein, the term "adsorbent material" or "adsorbent material layer" formed therefrom may include, but is not limited to, oily or aqueous stickers, commercial self-adhesive papers, stickers, and the like.
As used herein, the term "sealing film" in the method of the first, second or third aspects of the invention, or the term "backing material" in the absorbent functional layer of the time-temperature indicator of the fourth aspect of the invention, are any film layer that allows the absorbent material layer and volatile dye layer to be sealingly attached to the heat-sensitive article. Thus, in the case of monitoring the extent to which the heat-sensitive article is subjected to heat or temperature, for example during storage and/or transportation, the volatile dye and the absorbent material are in a closed system formed by the sealing film and the heat-sensitive article and do not escape, so that the dye which has volatilized by exposure to heat/temperature changes is substantially completely absorbed into the absorbent material. In the present invention, the term "sealing film" or the term "backing material layer" used in the absorbent functional layer of the present invention, and the material constituting these sealing film or backing material layer may include, but is not limited to, paper (e.g., ordinary copy paper, printing paper, sticker label paper), polymer film (e.g., polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene terephthalate, etc.), and the like.
As used herein, the phrase "volatile dye volatilizes under heat conditions" means that the dye volatilizes in contact with heat at a rate related to the intensity of the heat of contact, even at storage temperatures specified by standards for heat sensitive articles. The higher the temperature is, the faster the volatilization speed is, and the higher the temperature is, the faster the activity/titer of the heat-sensitive article is reduced, so that the volatilization speed of the dye is positively correlated with the reduction speed of the activity or the titer of the heat-sensitive article.
As used herein, the term "remaining in an effective quality state" means that the article is still in an effective life or is still in an effective active or potency state as specified by the standard, e.g., the limit of the amount of an active ingredient specified for a pharmaceutical product should be greater than 90% of the indicated amount, and "remaining in an effective quality state" means that the amount of the active ingredient in the article is greater than 90% of the indicated amount. Similarly, as used herein, the term "out of effective quality state" means that the quality state of the article has not been met, e.g., the limit for the amount of active ingredient in a pharmaceutical product is greater than 90% of the indicated amount, and "out of effective quality state" means that the amount of active ingredient in the article has been less than 90% of the indicated amount.
As used herein, the term "reference color label" is used to denote a color chart showing the color type and/or depth of the dye layer described herein at the theoretical residual amount of color, which reference color label may specifically be, for example, a reference color layer in an indicator functional layer of the present invention.
As used herein, reference to whether a heat-sensitive article "fails" refers to whether the article is within the quality requirements specified for its useful life. For example, where a pharmaceutical standard specifies that the amount of active ingredient is greater than 90% of the indicated amount, for example, in terms of the amount of active ingredient, then "failure" may be determined by whether the pharmaceutical product is greater than 90% of the indicated amount, for example, if the active ingredient is greater than 90% and not greater than 90%, or if the active ingredient is less than 90%.
As used herein, the term "desirable handling" refers to the handling processes that the heat-sensitive item needs or is expected to undergo, such as storage and/or transportation at the standard specified storage and transportation temperatures, as well as handling processes at higher temperatures for accelerated testing for certain purposes.
As used herein, reference to "the reference color label being located adjacent to the volatile dye layer" preferably means that both the label and the dye layer are located on the same plane. Further, reference to "the label being disposed side-by-side with the dye layer" may mean that both the label and the dye layer are disposed in a left-right, left-middle-right, up-down, up-middle-down manner, such as a dye layer coated in a square, with labels disposed on the left, right, or left and right sides thereof. Further, reference to a label disposed around a dye layer may refer to a label further coated with a dye layer around the coated dye layer, such as a square coated with the dye layer, and a label disposed around the square, which may be square or other shapes such as a circle.
There are various types of time-temperature indicators (TTI) known to those skilled in the art. For example, CN101652645A discloses a time-temperature indicator, which comprises the following time-temperature indicators: comprising at least 1 metal layer or metal-containing layer, and at least 1 doped polymer layer in direct contact with said metal layer or said metal-containing layer, wherein a dopant is an acid, base or salt or a photolatent acid or a photolatent base, which dopant is added to said polymer, and/or at least 1 polymer layer, wherein the polymer is functionalized with acidic or latent acidic or basic or latent basic groups; or a time temperature indicator comprising at least 1 polymer layer comprising metal particles and a photolatent acid or a photolatent base, or at least 1 polymer layer comprising metal particles, wherein the polymer is functionalized with latent acidic or latent basic groups. As another example, CN1914509A discloses a time temperature indicator comprising at least one indicator compound in a first isomeric form, which indicator compound is converted in a valence isomerization reaction in a time and temperature dependent manner into a second isomeric form of said indicator compound without migration of an atom or chemical group attached to said indicator compound, wherein the formation of said second isomeric form is detectable by monitoring a physical characteristic of the indicator compound. However, according to the detailed description of the present invention, the time-temperature indicator of the present invention is completely different from the existing time-temperature indicators in principle, structure and composition, and is very beneficial in terms of production, cost, convenience of use, etc. Of course, the entire contents of the above-mentioned patent documents are incorporated herein by reference in order to facilitate understanding of the present invention.
As used herein, the term "laminate" refers to a combination of multiple layers formed by laminating a plurality of layers together. In the case of the time-temperature indicator according to the fourth aspect of the present invention, the indicating functional layer and the absorbent functional layer are two laminated portions which are physically separated from each other before use. However, in the case of the heat-sensitive article according to the seventh aspect of the present invention, the two layered portions of the indicator functional layer and the absorbent functional layer adhered thereto are not spaced apart significantly, for example, in which the volatile dye layer in the indicator functional layer is in direct contact with the absorbent material layer (or the separator, if present) in the absorbent functional layer, and therefore, in the case of the heat-sensitive article according to the seventh aspect of the present invention, the division of the indicator functional layer and the absorbent functional layer into the two layered portions is merely for descriptive convenience with reference to the structure of the time temperature indicator according to the fourth aspect of the present invention.
As used herein, the term "substrate material layer" in the context of the time-temperature indicator of the fourth aspect of the invention includes such a substrate material layer stack in both the indicator functional layer and the absorbent functional layer portions, the substrate material layers of the two stack portions may be the same or different, but should meet their respective requirements for the purposes of the present invention. For example, in the case of a backing material layer in the absorbent functional layer, which is adhered to the heat-sensitive article by a non-drying adhesive layer, a sealed environment should be provided for the dye layer and the absorbent material layer inside the absorbent functional layer to prevent the dye from volatilizing outside the time-temperature indicator. For the backing material layer of the indicating functional layer, however, it should firstly meet the requirements of being able to print or coat dyes thereon. In one embodiment of the present invention, the backing material or backing material layer in the indicator functional layer includes, but is not limited to, paper (e.g., plain copy paper, printing paper, sticker label paper), porous or fibrous polymer film (e.g., polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene terephthalate, etc.), and the like. In one embodiment of the present invention, the backing material or backing material layer in the absorbent functional layer includes, but is not limited to, paper (e.g., plain copy paper, printing paper, sticker label paper), polymer film (e.g., polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene terephthalate, etc.), and the like.
As used herein, the term "reference color layer" refers to a reference color that is set for evaluating the degree of dye volatilization of a volatile dye layer, such as a color chart that is often used by people. In the present invention, the color kind of the reference color layer may be the same as or different from that of the volatile dye layer. In one embodiment, the color of the reference color layer is the same as the color of the volatile dye layer, and the same color is obviously beneficial, for example, the difficulty in judging or misjudging the real quality state of the heat-sensitive article due to the difference in the color types can be avoided. In the present invention, if the color of the volatile dye layer after the heat-sensitive article is disposed is darker than the reference color, the heat-sensitive article is considered to be still in an effective quality state, and if the color of the volatile dye layer is lighter than the reference color, the heat-sensitive article is considered to have failed.
As used herein, the term "release film" is a film material, which is used in both functional laminates of the time-temperature indicator of the fourth aspect of the present invention, and is designed for the production and use of the time-temperature indicator, so that other material layers are not contaminated with foreign materials, and can be easily peeled off during use. The present invention indicates that the first and second release film layers used in the functional layer and the release film layer used in the absorbent functional layer, which may be the same or different, are capable of achieving their intended purpose. In one embodiment, it is desirable that the first release film layer be capable of avoiding volatilization of the dye covered therein. In the present invention, the material used for the release film is widely selectable, and non-limiting examples include: paper, wax paper, polymeric films (e.g., polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene terephthalate, etc.), and the like.
The "sealant layer" in the indicator functional layer may prevent the dye from migrating or even volatilizing after penetrating through the backing material layer. Although the present invention contemplates the use of a backing material layer that is resistant to bleeding and migration, for the purposes of the present invention, it is preferred to coat the backing material layer with a layer of sealant on the side opposite the dye layer. The materials of the sealant or sealant layer are widely selected, non-limiting examples of which include: common glue is sold in the market.
Similar to the function of the sealant layer, the sealant layer in the indicator functional layer can prevent the dye from penetrating through the substrate material layer and then migrating or even volatilizing. The material of the sealing film or the sealing film layer is widely selected, and non-limiting examples include polymer films (e.g., polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene terephthalate, etc.), and the like.
The "tack coat" in the indicator or absorbent functional layer may provide an adhesive and sealing function for the respective material layer. The "tack adhesive layer" in the indicating functional layer and the adsorbing functional layer may be the same or different, however, it is expected that the "tack adhesive layer" in the adsorbing functional layer has good sealing performance, so that the substrate material layer and the heat-sensitive article can be tightly combined to form a closed space capable of avoiding dye leakage when the indicator of the present invention is used. The material of the sticker or sticker layer is widely selectable, non-limiting examples of which include oily or aqueous stickers, commercial stickers, sticker tapes, and the like.
The "wicking layer" in the wicking functional layer is intended to irreversibly wick dye that is volatilized from the dye layer, and is expected to have a wicking rate that is sufficiently high that it is not a dye volatilization rate limiting process, and that is substantially affected only by temperature/heat.
The 'isolating layer' in the adsorption function layer can provide a buffering space between the adsorption material and the dye layer so as to facilitate the completion of the volatilization-adsorption process of the dye. The materials of the barrier layer are widely selectable, non-limiting examples of which include: non-woven fabrics, nylon P6 mesh, nylon P66 mesh.
In the present invention, as the substrate material layer of the indicating functional layer, a sealant layer, a tack coat layer, and a second release coat layer may be appropriately selectively used depending on the specific material used for the substrate material layer. For example, if the substrate material layer in the indicating functional layer is coated with a volatile dye on one side and has sufficient properties to prevent the dye from diffusing to the other side of the substrate, the sealant layer, the tack coat layer, and the second release coat layer may all be omitted; of course, in order to facilitate the incorporation of the indicating functional layer with the heat-sensitive article, a tack coat layer and a second release film layer may preferably be included. Of course, in one embodiment, on one side of the substrate material layer, the sealant film layer, the non-drying adhesive layer, and the second release film layer described above are included in this order.
In the invention, the non-drying glue layer in the adsorption function layer, the substrate material layer in the adsorption function layer and the heat-sensitive article form a closed space together. The term "enclosed space" is not intended to be a void state, but rather various layers of material filled therein to form a substantially solid lamellar enclosed space.
The methods of the various aspects thereof, and the time-temperature indicators provided according to the invention, the time and temperature ranges over which they monitor, can be very broad, and the length of time indicated at a certain temperature or within a certain temperature range can be easily varied by, for example, setting the color depth of a reference color layer, such as an article intended to be stored at about 5 ℃, for example, with the indicated time being set to 1 day, 30 days, 6 months, 1 year, 2 years, 3 years, etc. These temperature and time settings are for example but not limited to: the temperature ranges from-20 ℃ to 50 ℃ and the time is 1 hour to 10 years; the temperature ranges from-10 ℃ to 50 ℃ and the time ranges from 1 hour to 8 years; the temperature ranges from 0 ℃ to 50 ℃ and the time ranges from 1 hour to 8 years; 1 hour to 50 days at 37 ℃; at 25 ℃, 5 hours to 1 year; 5 ℃ for 1 day to 6 years.
In the present invention, when referring to a "layer", it may refer to either a specific material layer or a specific material as long as the context does not contradict. For example, reference to a "sealing film layer" may also be referred to as a "sealing film" where applicable.
In the present invention, the reference to the "first release film layer" and the "second release film layer" does not indicate any relationship in tandem or order or otherwise, but is merely for convenience of description. They may both be referred to as "release film layers" or "release films".
As used herein, the term "on the heat sensitive article," or "on the heat sensitive article" or "on the packaging container of the heat sensitive article" and the like, referred to in similar contexts, may refer to either the heat sensitive article itself or the packaging container in which the heat sensitive article is packaged. For example, when referring to "attaching a layer of volatile dye to an area of the heat-sensitive article," it is meant that a layer of volatile dye is attached to an area of the heat-sensitive article or the packaging container in which the heat-sensitive article is packaged. In addition, reference to "on a heat-sensitive article" or "on a packaging container for a heat-sensitive article" in a similar context may refer to the inner or outer face of said "heat-sensitive article", in particular the inner or outer face of the "packaging container in which the heat-sensitive article is packaged". For example on the outer surface of the container; alternatively, the indicator of the present invention is attached to the container and then a covering layer (which may be an anti-counterfeiting layer or an anti-counterfeiting cue layer) is attached to the indicator.
In the present invention, reference is made to "quality", "quality status", "effective", "ineffective" and the like of the heat-sensitive article of the present invention, and these conditions of the heat-sensitive article can be expressed both in terms of potency, such as certain biological products; or may be expressed in terms of activity; it may also be expressed in terms of content, such as the content of active ingredient. The present invention is not limited to the method of representing them.
In the present invention, reference is made to the temperature at which the heat-sensitive article is desired to be handled, which may be a temperature range (e.g. storage temperature 2-8 ℃) or a specific temperature (e.g. the average of the above storage temperatures, about 5 ℃); in one embodiment, the temperatures at which the heat-sensitive article is desired to be handled are at least two different temperatures, for example one is a storage average temperature of 5 ℃ and one is an accelerated test temperature such as 25 ℃ or 37 ℃. In one embodiment, the temperatures at which the heat sensitive article is expected to be handled are at least two different temperatures, which may both be accelerated test temperatures such as 25 ℃ and 37 ℃. Since certain heat-sensitive articles, while having the same shelf life (e.g., a time to 90% titer, e.g., 2 years each) at their desired and/or specified storage temperature (e.g., 5 ℃), may differ in the time required for their titer to decrease to the same extent at the accelerated test temperature, e.g., 25 ℃. Thus, in the present invention, it is beneficial to determine C1 at the temperature (T1) at which at least two heat-sensitive items are expected to be handled and at T1 thereof.
In the present invention, the compounds of formula I have the following structure:
in one embodiment, R1 in the compounds of formula I are each-COOCH3、-COOCH2CH3and-COOCH (CH)3)2. In the present invention, R1 are each-COOCH3、-COOCH2CH3and-COOCH (CH)3)2The compounds of (a) may be referred to simply as dye a, dye B and dye C, respectively.
In the present invention, the compounds of formula I may be prepared using methods known to those skilled in the art. For example, R1 substituent can be obtained by halogenation, alkylation, acylation, hydrolysis, alcoholysis, etc. of a compound of formula I (which may be referred to as dye H in this invention) wherein R1 is hydrogenConversion to halogen, C1-6Straight or branched alkyl, C1-6Straight or branched chain alcohols, -COR2, -COOR2, and the like, wherein R2 is as defined herein.
The existing time-temperature indicator product has high manufacturing cost, so that the popularization and application of the existing time-temperature indicator product in the whole monitoring field of vaccine cold chain storage and transportation in China and other developing countries are limited, meanwhile, the existing product does not reach the level of a personalized time-temperature indicator with color change speed and temperature effect which fully reflect the thermal stability performance of the indicated product, and the indicator product needs to be stored at the temperature of 18 ℃ below zero or even lower after being manufactured. The invention aims to overcome the defects, and utilizes the volatilization property of a substance to manufacture a time-temperature indicator with low comprehensive cost through a heating-volatilization-adsorption process.
It is an object of one embodiment of the present invention to reduce the cost of making and using an indicator by employing a novel indicator color change principle. Unlike polymeric, enzyme-reactive, and diffusive indicators, the present invention utilizes the volatile nature of the substance to effect a color change through a heat-volatile-adsorptive dye transfer process. After the novel principle is adopted, the material with low price can be selected, the selection range of the material is greatly widened, and the comprehensive cost for manufacturing the indicator is reduced.
It is an object of one embodiment of the present invention to make a personalized time-temperature indicator whose color change rate and its temperature effect are such as to adequately reflect the thermal stability performance of the indicated product, which personalized indicator can be designed for the specific storage requirements and characteristics of a certain kind of heat-sensitive articles. In one embodiment this may be accomplished by screening volatile dyes or other volatile opaque materials for their rate of volatilization and their activation energies that substantially reflect the thermal stability properties of the indicated product.
It is an object of one embodiment of the present invention to make dye or material formulations by adding adjuvants to selected volatile dyes or other volatile opaque materials to alter the rate of volatilization of the material and its temperature effect to substantially reflect the thermal stability of the indicated heat sensitive article.
An object of one embodiment of the present invention is that the time-temperature indicator is green and environmentally friendly in its manufacture and use, and may be achieved by selecting a green material that is non-toxic, harmless, and environmentally friendly; furthermore, the indicator effectively adsorbs the volatilized thermosensitive material through an adsorption functional layer, and the pollution to products and packages thereof after the material is volatilized is avoided through the effective sealing of the indication functional layer and the adsorption functional layer of the indicator, and meanwhile, the functional part of the indicator is protected from being polluted by the outside.
An object of an embodiment of the present invention is to make a time-temperature indicator that can be preserved at normal temperature, which can be achieved by: the indicating functional layer and the absorption functional layer of the indicator are respectively manufactured and stored, and are combined into one when in use. After the heat-sensitive material of the indicating functional layer is coated or printed, the heat-sensitive material is sealed and stored by a release film which has no adsorption effect on the heat-sensitive material, and when the indicator is adhered to the surface of a product container or a package, the sealing film is peeled off and replaced by the adsorbable functional layer. The indication functional layer and the adsorption functional layer are respectively manufactured and stored, and normal-temperature storage of the two functional parts is realized.
In one embodiment of the present invention, a method for monitoring cumulative heat exposure of a low-temperature stored and transported product (e.g., a heat-sensitive article according to the present invention) during storage and transportation is provided, for determining whether the product is deteriorated/failed/inactivated due to excessive heat exposure during cold chain storage and transportation, wherein: firstly, based on the volatilization property of the material, the heat absorption quantity of the product is quantified by utilizing the heat absorption quantity in the volatilization process of the material; the volatile material adopted by the second method is a colored material; and the three functions are that the colored volatile material is used for manufacturing a function indication area, and based on the fact that the material is transferred after the material is heated and volatilized, the color of the function indication area is obviously changed, and whether the commodity is still effective or is degenerated/invalid/inactivated is judged.
In one embodiment of the present invention, there is provided a time-temperature indicator manufactured based on the above method, characterized in that: the volatile property of the material is utilized, a double-layer structure of an indicating functional layer and an absorption functional layer is adopted, and the two functional parts are respectively manufactured and stored, are combined into a whole when in use, and are adhered to the surface of a container or a package of a sample to be monitored (such as the heat-sensitive article). After the time-temperature indicator is used for the commodity or the package thereof which needs to be stored and transported under low temperature conditions, if the commodity is exposed to the set storage and transportation temperature for a specific time in the cold chain storage and transportation process, the indicator shows obvious color change, thereby judging whether the commodity is still effective or is degenerated/invalid/inactivated.
In one embodiment of the present invention, there is provided a thermosensitive functional material for use in an indicating functional layer of the above time-temperature indicator, characterized in that: the material is volatilized after absorbing heat, the speed of volatilization and the temperature effect thereof fully reflect the speed of deterioration or failure of the indicated product and the temperature effect thereof, and therefore, the selection and the regulation of the thermosensitive functional material are based on the thermal stability of the indicated product.
In one embodiment of the present invention, there is provided a thermosensitive functional material for use in an indicating functional layer of the above time-temperature indicator, characterized in that: the heat-sensitive functional material can be a single material or a mixture of several materials.
In one embodiment of the present invention, there is provided a thermosensitive functional material for use in an indicating functional layer of the above time-temperature indicator, characterized in that: the range of choices for the thermally sensitive functional material includes, but is not limited to, various volatile dyes that meet the requirements set forth in any of the embodiments of the present invention, such as azo-based dyes, anthraquinone-based dyes, compounds of formula I and their derivatives, or opaque volatile materials, such as naphthalene, camphor, and the like. In one embodiment, the mixture of heat-sensitive functional materials of the indicating functional layer of the time-temperature indicator, in particular, one or several components of the mixture, can regulate the volatilization speed of the heat-sensitive functional material and the temperature effect thereof.
In one embodiment of the present invention, there is provided a substrate material for use in the fabrication of an indicating functional layer of the above time-temperature indicator, characterized in that: the interaction between the substrate and the thermosensitive functional material of the covering layer can be regulated and controlled through the selection or modification of the substrate material, so that the volatilization speed and the temperature effect of the thermosensitive functional material can be regulated and controlled.
In one embodiment of the present invention, there is provided an adsorbent material for use in the production of the adsorption functional layer of the above time-temperature indicator, characterized in that: the adsorbing material has strong irreversible adsorption effect on the thermosensitive material, the adsorption speed is far higher than the volatilization speed of the thermosensitive functional material, and the apparent volatilization speed of the thermosensitive functional material is only influenced by temperature.
In one embodiment of the present invention, there is provided an adsorbent material for use in the production of the adsorption functional layer of the above time-temperature indicator, characterized in that: the adsorbing materials have irreversible adsorption effect on the thermosensitive materials, and the color change speed and the temperature effect of the time-temperature indicator are regulated and controlled by selecting different adsorbing materials.
In one embodiment of the present invention, there is provided a manufacturing method for manufacturing the above time-temperature indicator, characterized in that: the substrate of the indication function layer is colorless or white or other light colors, the thermosensitive function material is coated on the substrate of the indication function layer, and the color of the thermosensitive function material is in greater color contrast with that of the substrate.
In one embodiment of the present invention, there is provided a method of making the time-temperature indicator, characterized by: the heat sensitive functional material is dissolved or dispersed in a suitable solvent prior to coating or printing. Further, the volatilization speed and the temperature effect of the thermosensitive functional material are regulated and controlled through the selection of the solvent type.
In one embodiment of the present invention, there is provided a method for manufacturing and storing the time-temperature indicator, characterized in that: after the heat-sensitive material of the indicating functional layer is coated or printed, the heat-sensitive material is sealed and stored by a peelable sealing film having no adsorption effect on the heat-sensitive material, and when the indicator is adhered to the surface of the product container or package, the sealing film is peeled off and replaced by the adsorbable functional layer. The indication functional layer and the adsorption functional layer are respectively manufactured and stored, and the two functional parts are stored at normal temperature.
In one embodiment of the present invention, there is provided a method of making the time-temperature indicator, characterized by: the functional sites of the indicating functional layer and the adsorbing functional layer may or may not be in close contact.
In one embodiment of the present invention, there is provided a method of making the time-temperature indicator, characterized by: the indicating functional layer and the adsorption functional layer are effectively sealed after being combined into a whole, the functional part of the indicator is protected from being polluted by the outside, and meanwhile, the product or the package thereof is prevented from being polluted after materials are volatilized.
In one embodiment of the present invention, there is provided a method of making the time-temperature indicator, characterized by: the adsorption functional layer is used for adsorbing the thermosensitive material volatilized by heating, and the diffusion process of the thermosensitive material after volatilization is artificially set, namely the diffusion process is changed into the adsorption process of the adsorption functional layer, so that the influence of non-temperature factors in the storage and transportation environment of the product on the apparent volatilization speed of the thermosensitive material is effectively reduced, and the use accuracy of the product is improved.
In one embodiment of the present invention, there is provided a range of applications of the time-temperature indicator, characterized in that: the indicated temperature ranges are between 0 and 50 degrees celsius and the indicated time ranges vary with temperature, typical time ranges are between 1 hour and 50 days at 37 degrees celsius, between 6 hours and 1 year at 25 degrees celsius and between 1 day and 6 years at 5 degrees celsius.
In one embodiment of the present invention, the time-temperature indicator is provided for applications including, but not limited to, vaccines, biologicals, and other pharmaceuticals requiring low temperature storage and transportation.
In the invention, the indicating functional layer and the absorption functional layer of the indicator are respectively manufactured and stored and are combined into a whole when in use, thereby realizing the storage and/or transportation of the two functional parts at normal temperature. The adsorption functional layer has three functions: 1. the functional part of the label is protected from external pollution; 2. the product and the package thereof are prevented from being polluted after the material is volatilized; 3. the diffusion process after the heat-sensitive material volatilizes is set artificially, namely the diffusion process is changed into the adsorption process of the adsorption layer, so that the influence of the non-temperature factors in the storage and transportation environment of the product on the apparent volatilization speed of the heat-sensitive functional material is effectively reduced, and the use accuracy of the product is improved. Compared with other products needing cold chain storage and transportation, such as low-temperature food and the like, the time-temperature indicator provided by the invention fully reflects the characteristics of sealed package of vaccines or other heat-sensitive articles and the stability is only influenced by temperature.
The key to the practice of the invention is the selection of an appropriate volatile dye or combination of dyes and another adsorbent material or combination that effectively adsorbs the dye or combination thereof.
Examples
The present invention will be further described by way of various types of examples below, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.
A. Examples of time-temperature indicators
The invention utilizes the volatilization property of the substance to manufacture the time-temperature indicator, and realizes the required color change effect through a heating-volatilization-adsorption process. The structure of an exemplary time-temperature indicator designed by the present inventors and the operating principle thereof are depicted in fig. 1, 2A, 2B.
Referring to the cross-sectional view of fig. 1, there is depicted a time-temperature indicator of the present invention comprised of two parts, part a being an indicator functional layer 1 and part b being an absorbent functional layer 2, both parts being separately manufactured for storage and in use being combined into one and adhered to the surface of a container or package of a heat sensitive item to be monitored.
In the indicating function layer 1, a layer of sealant 14 is printed under the backing material layer 10, and a layer of sealing film 13 is added under the backing material layer to prevent the functional material dye layer from diffusing downward. The sealing film 13 may be an unnecessary layer if the sealing effect of the sealant is sufficiently good. A layer of adhesive sticker 12 is printed on the underside of the sealing film 13 and protected by a release film layer 11 (which may be referred to as the first release film layer in the present invention). The volatile dye layer 15 in the present invention is formed by printing a layer of colored functional material (dye) with specific volatility as a thermosensitive functional material on the functional part on the backing material layer 10, and the color (dark blue in the figure) of the dye layer 15 shows a large contrast with the backing material layer 10 or the reference color layer 16 (light blue in the figure) printed on the periphery. The speed of volatilization of the volatile dye and its temperature effect are as much as possible consistent with the indicated speed of deterioration or failure of the product and its temperature effect. After the indicating function layer is printed and dried, the indicating function layer is sealed and stored by a release film layer 17. This release film layer 17 plays sealed effect and does not have the adsorption to the volatile dyestuff that uses, and sealing performance guarantees that the instruction function layer can be stored and transported at room temperature.
In the adsorbent functional layer 2, the upper side of the substrate material layer 20 may be printed with appropriate product information (e.g., the type of heat sensitive article for which the TTI is applicable) or indicator usage information (e.g., information on how to operate when it is desired to use an indicator to determine whether a heat sensitive article has failed). The lower surface of the substrate material layer 20 is printed or coated with a layer of adsorbing material capable of effectively adsorbing volatile thermosensitive volatile dye at the position corresponding to the indication function layer to form an adsorbing material layer 21, a non-drying adhesive layer 22 is printed on the periphery of the adsorbing material layer 21, and then the laminated adsorbing function layer 2 is sealed and stored by a release film layer 23. If it is desired to prevent direct contact between the adsorbent material and the heat sensitive functional material (i.e., volatile dye), a further separation layer 24 (which is optional) may be formed on the side of the adsorbent material layer 21 that is below (i.e., away from the backing material layer 20).
Referring again to FIG. 2A, a cross-sectional view is shown depicting the use and course of use of one of the time-temperature indicators shown in FIG. 1. In fig. 2A, two functional laminated portions, namely, an indication functional layer 1 and an adsorption functional layer 2 of the indicator, which are respectively manufactured and stored, are combined into one: peeling off the release film 11 at the bottom of the indication functional layer 1, and sticking the indication functional layer 1 to the surface of the container or package 3 of the heat-sensitive article to be monitored; and peeling the release film 17 of the indication functional layer 1 and the release film 23 of the adsorption functional layer 2, and aligning and sticking the adsorption functional layer 2 part and the indication functional layer 1 to the surface of the heat-sensitive article container or package 3 to be monitored. The preferred embodiment is that the shape and size of the absorbent material layer 21 is the same as or slightly larger than the shape and size of both the volatile dye layer 15 and the reference color layer 16, so that the absorbent material layer 21 and the optional separation layer 24 just completely cover both the volatile dye layer 15 and the reference color layer 16 as shown in the figure, and the adhesive layer 22 at the periphery of the absorbent material layer 21 together with the backing material layer 20 adhered thereto can be closely adhered to the packaging container 3 of the heat-sensitive article, so that the backing material layer 20, the adhesive layer 22, and the packaging container 3 of the heat-sensitive article form a space which can seal the remaining functional layers. The selection of the two functional layer substrate materials and the self-adhesive material ensures that the indication functional layer is firmly bonded to the surface of a product container or a package, and the adsorption functional layer has proper firmness when being bonded, so that the thermosensitive material printed on the indication functional layer can be effectively sealed and can be peeled off, and the peeling process does not cause adverse effect on the indication functional layer.
In the use process of the indicator, in the case that the thermosensitive material of the volatile dye layer 15 is not completely volatilized (b in fig. 2A), after the adsorptive functional layer 2 is peeled off, the residual dye (blue) in the volatile dye layer 15 and the reference color layer 16 (light blue) around the residual dye can still show a significant color difference (c in fig. 2A), i.e. the color of the volatile dye layer 15 is darker than that of the reference color layer 16, which reflects that the indicated product is still effective and usable. In the case where the thermosensitive material of the volatile dye layer 15 is completely volatilized (d in fig. 2A), after the adsorptive function layer 2 is peeled off, the dye (pale blue or colorless) remaining in the volatile dye layer 15 is closer to or lighter than the color of its surrounding reference color layer 16 (pale blue) (e in fig. 2A), that is, the color of the volatile dye layer 15 is equivalent to or lighter than the color of the reference color layer 16, indicating that the monitored product may be deteriorated or deteriorated by excessive heat. In this time-temperature indicator, the rate of indicator color change depends on the rate of volatilization of the thermosensitive dye material, and the thermosensitive functional material and the adsorbing material may be screened from organic and/or polymeric materials, with appropriate modification if necessary.
Fig. 2B is a view from above of the time-temperature indicator according to the present invention showing the change of the volatile dye layer 15 and the reference color layer 16 during the use. The invention uses the volatilization property of the material to make the time-temperature indicator, realizes the color change of the functional part of the indicator through a heating-volatilization-adsorption process, and displays whether the product using the time-temperature indicator is deteriorated or invalid due to excessive heating. The indicating functional layer is made by coating or printing a layer of a colored functional material having a specific volatility (i.e., the volatile dye of the present invention) as a thermosensitive functional material (a in fig. 2B, starting point state, dark blue square, corresponding to the volatile dye layer 15 in fig. 1) on a substrate material, the color of the volatile dye (dark blue square in the figure) exhibiting a greater contrast with a reference color layer (a in fig. 2B, light blue circle, corresponding to the reference color layer 16 in fig. 1, which may be a substrate or a printed color layer).
In the process of using the time-temperature indicator and the heat-sensitive article in combination, the color depth of the reference color layer 16 is unchanged, the color depth of the volatile dye layer 15 is lightened due to heat absorption and volatilization, the lightening speed is influenced by the temperature, even under the temperature required by the heat-sensitive article, the volatile dye layer 15 is volatilized to a certain degree, for example, for a medicine with the storage period of 2 years at 2-8 ℃, the medicine is strictly stored at 2-8 ℃ for 2 years, the volatile dye layer 15 is lightened gradually due to slow volatilization of the dye, the color of the medicine is darker or slightly darker than that of the reference color layer 16, which indicates that the medicine is still qualified after being stored at 2-8 ℃ for 2 years; after the storage time continues to be extended, the volatile dye layer 15 will continue to lighten as the dye continues to volatilize, after which it will be substantially closer to or lighter than the reference color layer 16, indicating that the drug product has passed its expiration date; this process is also an embodiment of designing the material type and color depth of the volatile dye layer 15 and the color depth of the reference color layer 16, and an embodiment of the acceleration mode is also described herein. When the thermosensitive material is not completely volatilized during the use of the indicator, the thermosensitive material remaining after peeling off the adsorption film can still show a significant color difference from the peripheral reference color (B in fig. 2B, the middle point state, the blue square is darker in color than the reference light color circle), reflecting that the indicated product is still effectively usable. After the heat sensitive material is continuously or completely volatilized and the absorbent material layer is peeled off, the original volatile dye layer 15 portion shows a color close to or lighter than that of the reference color layer 16 portion around the original volatile dye layer (c in fig. 2B, end point state) or (d in fig. 2B, over-end point state, white square in the figure relative to the reference light color circle), thereby indicating that the monitored product may be deteriorated or failed due to excessive heating.
B. Production of a time-temperature indicator and color determination of a reference color layer region
In some embodiments, the substrate materials used to make the indicating functional layer and the absorbent functional layer of the time-temperature indicator of the present invention include, but are not limited to, plain paper (e.g., plain copy paper, printing paper, sticker label paper), polymeric films (e.g., polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyethylene terephthalate, etc.).
In some embodiments, the volatile heat-sensitive materials used to make the time-temperature indicators of the present invention include various volatile inorganic or organic pigments or dyes or combinations thereof, such as azo-based dyes, anthraquinone-based dyes, compounds of formula I and derivatives thereof, and also include various volatile materials that can modulate the rate of volatilization of the pigments or dyes and the temperature effects thereof, and can be various volatile compounds including, but not limited to, linear or branched chain or cyclic alkanes or aromatics (including, but not limited to, naphthalene, anthracene), various linear or branched chain or aromatic or cyclic alcohols (including, but not limited to, erythritol, lauryl alcohol, tridecanol, tetradecanol, pentadecanol, palmityl alcohol, heptadecyl alcohol, stearyl alcohol, and the like), various linear or branched chain or aromatic or cyclic chain carboxylic acids (including, but not limited to, maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, and the, Palmitic acid, adipic acid, sebacic acid, dodecanedioic acid, etc.), various amino acids (including but not limited to aminobenzoic acid, leucine, phenylalanine, etc.), various ester compounds, various sulfones (including but not limited to diphenyl sulfone, diphenyl disulfone, dibenzylsulfone, dibutyl sulfone, etc.), and various volatile natural substances, including but not limited to naphthalene, camphor, etc.
In some embodiments, the solvent used to dissolve the thermosensitive functional material used in the present invention includes, but is not limited to, water, hexane, cyclohexane, tetrahydrofuran, benzene, xylene, methanol, ethanol, isopropanol, 2-butanol, acetone, diethyl ether, methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane, dichloroethane, and like organic solvents.
In some embodiments, the material used for making the adsorption functional layer of the time-temperature indicator of the present invention can use various commercial adsorption materials or adsorption films, and the material is required to have strong irreversible adsorption effect on the thermosensitive material of the covering layer, and the adsorption speed is far greater than the volatilization speed of the thermosensitive functional material, so as to ensure that the apparent volatilization speed of the thermosensitive functional material is only influenced by temperature.
After a prototype time-temperature indicator is fabricated according to the structure shown in fig. 1, the color change speed and the temperature effect of the indicator can be obtained by measuring the change of the color difference of the indicator functional part with time under the corresponding constant temperature condition (for example, 5 ℃, 10 ℃, 25 ℃ and/or 37 ℃).
The change in color can be digitized using a colorimeter. When measuring color change using a colorimeter, a color space such as L is defined*a*b*Color space (also known as CIELAB color space). In this color space, L*Represents brightness; a is*And b*Is a chromaticity coordinate representing a color direction; + a*Indicating the red direction, -a*Indicates the green direction, + b*Represents the yellow direction, -b*Indicating a blue direction with a colorless center. When a is*And b*As the value increases and moves away from the center, the color saturation increases. In this color space, the color difference can be represented by a single numerical value:
ΔE* ab＝[(ΔL*)2+(Δa*)2+(Δb*)2]0.5
wherein, Δ L*For variations in brightness, Δ a*For variation along the red-green axis,. DELTA.b*As a function of the yellow-blue color axis. Color difference can be quantified by quantifying the color using a colorimetric instrument such as a Minolta CR-310 Chroma Meter, and the color change function of the manufactured time-temperature indicator can be evaluated. Color difference measurement is made with a white substrate such as A4 paper as a reference when the color difference Δ E is* abAt < 10, the color is more or less close to that of the substrate, and further reduction of the color difference is not noticeable to the human eye, so that the color difference Δ E will be evaluated* abEnd point of discoloration was 10. In practice, the color difference end point may be defined according to the actual situation, for example, according to the specific heat-sensitive article, Δ E* abCan be set to other values, e.g. Δ E* ab＝5、ΔE* ab＝15、ΔE* ab＝20、ΔE* ab25, and/or Δ E* ab30, etc.
C. The design and application of the method or indicator of the invention are illustrated by specific examples
Example 1:
using a dye A as a thermosensitive material of a time-temperature indicator, quantitatively printing 2% of the dye A (the solvent is ethyl acetate, and the amount of the dye A coated per square centimeter is about 200ug) on a common A4 paper as an indicating functional layer, placing a commercially available non-setting adhesive paper capable of effectively adsorbing the dye A above the dye A with the non-setting adhesive facing the dye layer, sealing the indicating functional layer with the non-setting adhesive as the adsorbing functional layer by using a dye-impermeable sealing film, and placing the sealed sample under a constant temperature condition of 25 ℃. After a certain time of standing, the color of the recording function indication layer was observed. FIG. 3 is a color record of the indicator after being left for 0-105 days at a constant temperature of 25 ℃. After the dye A is completely volatilized, almost no dye trace is left under the naked eye, and the functional part is indicated to be almost recovered to the original color of the white paper.
Example 2:
FIGS. 4a and 4b are color differences DeltaE at different temperatures of a time temperature indicator manufactured by the method of reference example 1 and using dye A as a thermosensitive functional material* abAs a function of time t. By a color difference Δ E* abAnd (5) calculating the color change time and speed of the indicator as the end point of the color change, and deducing the corresponding activation energy of the change process of the indicator to be about 97.4kJ/mol (figure 5) by using an Arrhenius equation, thereby obtaining the characterization parameter of the temperature effect of the color change process of the indicator. The activation energy can well cover the inactivation activation energy range of poliomyelitis vaccines reported in documents of 73.6-109 kJ/mol, and can also cover the inactivation activation energy range of other vaccines.
Figure 6 is a label designed for a hepatitis b vaccine using this dye, the color change response of the TTI of the present invention is almost completely consistent with the activity change of the vaccine.
Example 3:
by adjusting the amount of the heat-sensitive functional material printed per unit area of the indicator function indicating portion, the total time for the indicator to change color can be adjusted, which can be adjusted by adjusting the amount of ink applied or the concentration of ink during the printing process.
FIG. 7 shows the initial colorimetric values of indicators obtained using different ink concentrations and the same amount of ink, and the color change process at the same temperature, using dye A as a heat-sensitive functional material, in the method of reference example 1. The time to end of the indicator is linear with the amount of heat sensitive functional material printed per unit area (fig. 8).
Example 4:
by changing the composition and structure of the dye, the color change time and temperature effect of the indicator can be regulated and controlled. FIG. 9 shows the difference in color difference at 50 ℃ with time of a thermosensitive material using three compounds of formula I (each dye A, B, C) as a time-temperature indicator in the method of reference example 1. By a color difference Δ E* abAnd (3) obtaining the color changing time and speed of the indicator at different temperatures as the color changing end point 10, deducing dyes B and C as thermosensitive materials according to an Arrhenius equation, wherein the corresponding activation energies of the indicator in the color changing process are 122 kJ/mol and 75kJ/mol respectively, and thus obtaining the characterization parameters of the temperature effect of the indicator in the color changing process. As can be seen from the above results for dyes B and C with different activation energies than dye a, dyes B and C can be used to design TTIs suitable for other heat-sensitive articles, or for combinations of different dyes.
Example 5:
in the printing process of the thermosensitive functional material, different solvents are adopted to properly modulate the color changing speed and the temperature effect of the indicator. Fig. 10 is a change of color difference of indicator with time at the same temperature by printing dye a as a thermosensitive functional material using cyclohexane, dichloromethane, methyl acetate, ethanol, ethyl acetate as solvents, respectively, with reference to the method of example 1. The results show that the indicator changes color most rapidly by using ethanol as a solvent; cyclohexane and methyl acetate are used as solvents, and the color change speed of the indicator is equivalent to that of ethanol, and is slightly slower than that of ethanol; the indicator changes color more slowly using ethyl acetate as the solvent; printing equal amounts of the thermal sensitive material with methylene chloride as the solvent significantly increased the initial color difference value, the indicator color change speed was much slower than with the other solvents, the color change speed being the slowest of all solvents tried.
Example 6:
in the printing process of the thermosensitive functional material, the color changing speed and the temperature effect of the indicator can be properly modulated by adding proper auxiliary agents. FIG. 11 shows the color change at 80 ℃ as a function of time of an indicator produced by adding an appropriate amount of a binder EC (i.e., ethyl cellulose) to an organic solution of dye A, according to the method of example 1. The results show that the time required for the indicator to reach the end point after the addition of the binder (curve shown by EC in the figure) is about 3.5 times that of the indicator without the addition of the binder (curve shown by none in the figure). By a color difference Δ E* abThe time and speed of the indicator changing color at different temperatures can be obtained as 10 as the end point of the color change, and the Arrhenius equation can deduce that the activation energy corresponding to the change process of the indicator after the adhesive is added is 67kJ/mol respectively, and the change is also great compared with the indicator without the adhesive.
Example 7:
the color change speed and the temperature effect of the time-temperature indicator can be regulated and controlled by selecting different adsorbing materials. Fig. 12 shows the method of reference example 1, wherein the dye B is used as a thermosensitive functional material, three different adsorbing materials (in the figure, materials 1, 2, and 3 are respectively commercially available self-adhesive paper, commercially available water-based adhesive coated paper a4 paper, and commercially available oil-based adhesive coated paper a4 paper) are selected to manufacture the time-temperature indicator, and the color difference of the indicating functional layer of the indicator shows a significant difference with the change speed of time under the same temperature environment.
From the above examples, the inventors have surprisingly found that by using the volatile nature of the substance to effect a colour change by a heat-volatilisation-adsorption process, it is possible to indicate very simply and effectively whether the monitored product is likely to deteriorate or fail due to excessive heating. By screening volatile dyes or other volatile materials with suitable volatilization rates and activation energies, and making a material formulation containing an auxiliary agent as necessary, a personalized time-temperature indicator can be made that adequately reflects the thermal stability of the indicated product. The adsorption function layer capable of effectively adsorbing the thermosensitive material is manufactured above the indicator, and the indication function layer and the adsorption function layer of the indicator are effectively sealed, so that the phenomenon that the material volatilizes to pollute a product and a package of the product can be avoided, and meanwhile, the function part of the indicator is protected from external pollution. Furthermore, the diffusion process of the heat-sensitive material after volatilization is artificially set by the adsorption layer, namely the diffusion process is changed into the adsorption process of the adsorption layer, so that the influence of non-temperature factors in the storage and transportation environment of the product on the apparent volatilization speed of the heat-sensitive material is effectively reduced, and the use accuracy of the product is improved. Furthermore, the indicator is designed into two functional parts which are respectively manufactured and hermetically stored, and the two parts are combined into a whole when the indicator is pasted on a product container or a packaging surface, so that the indicator can be stored and transported at room temperature.
The above exemplary description does not set any limit to the scope of protection of the invention. The time-temperature indicator manufactured according to the technical scheme or idea of the invention by using the technical scheme or different processes or formulas and adopting the technical scheme or the equivalent replacement is within the protection scope of the right of the invention.
Claims (40)
1. A time-temperature indicator for monitoring the quality status of a heat-sensitive article, comprising two laminated portions of an indicating functional layer and an adsorbing functional layer which are physically independent of each other before use, wherein:
the indication function layer includes:
a first substrate material layer;
the volatile dye layer is coated on one side of the first substrate material layer, wherein the volatilization speed of the dye is in positive correlation with the reduction speed of the activity or the titer of the heat-sensitive article; and
a first release film layer overlying the volatile dye layer, wherein the backing material layer and the first release film layer are larger in size than the volatile dye layer and seal the volatile dye layer between the backing material layer and the first release film layer;
the adsorption function layer includes:
a second substrate material layer;
the adsorbing material layer is coated on one side of the second substrate material layer, wherein the size of the adsorbing material layer is larger than that of the volatile dye layer;
the non-drying glue layer is coated on the substrate material layer and surrounds the periphery of the adsorption material layer; and
and the second release film layer covers the non-drying adhesive layer and the adsorption material layer.
2. The time temperature indicator of claim 1, wherein the first substrate material layer is colorless by itself.
3. The time-temperature indicator of claim 2, wherein, in use, the first and second release film layers are peeled apart, the sorbent material layer is aligned with the volatile dye layer of the indicating functional layer, the sorbent functional layer covers the entire indicating functional layer, and the sorbent material layer and the volatile dye layer are enclosed between the first and second backing material layers; and attaching a second substrate material layer on the heat-sensitive article.
4. The time temperature indicator of claim 1, wherein, in use, the first and second release film layers are peeled apart, the sorbent material layer is aligned with the volatile dye layer of the indicator functional layer, the sorbent functional layer covers the entire indicator functional layer, and the sorbent material layer and the volatile material layer are enclosed between the first and second substrate materials; and attaching the first substrate material layer on the heat-sensitive article.
5. The time-temperature indicator of any one of claims 1-4, further comprising a reference color label separate from the indicator functional layer and the absorbent functional layer, the reference color label having a color depth that is the same as a color depth of the volatile dye layer after undergoing the same process as the heat-sensitive article failure treatment.
6. The time-temperature indicator of any one of claims 1-4, wherein the indicating functional layer further comprises a reference color label disposed on the backing material layer adjacent to the volatile dye layer, the reference color label having a color depth that is the same as a color depth of the volatile dye layer after undergoing the same process as the heat sensitive article failure handling.
7. The time-temperature indicator of any one of claims 1 to 4, wherein the backing material layer of the indicating functional layer itself serves as a reference color label having a color depth that is the same as a color depth of the volatile dye layer after undergoing the same process as the heat sensitive article failure treatment.
8. The time-temperature indicator of claim 1, wherein the heat sensitive article is selected from the group consisting of a vaccine, a biologic, a bioactive sample, a pharmaceutical, a food, or a beverage.
9. The time-temperature indicator of claim 1, wherein the volatile dye in the volatile dye layer is a colored substance having a melting point of from 0 ℃ to 80 ℃.
10. The time temperature indicator of claim 9, wherein the volatile dye has a melting point of from 50 ℃ to 80 ℃.
11. The time temperature indicator of claim 1, wherein the volatile dye in the volatile dye layer is selected from at least one of azo dyes, anthraquinone dyes, compounds of formula I and their derivatives, or combinations thereof, wherein the compounds of formula I have the following general formula:
wherein,
r1 is selected from hydrogen, halogen, C1-6Straight or branched alkyl, C1-6Linear or branched alkoxy, -COR2、-COOR2；
R2 is selected from hydrogen and C1-6Straight or branched alkyl, C1-6Straight or branched alkylamino groups.
12. The time-temperature indicator of claim 1, wherein the volatile dye layer further comprises one or more volatilization aids and/or solvents, the volatilization aids selected from one or more of the following volatile compounds:
straight-chain alkanes, branched-chain alkanes, cyclic alkanes or aromatic hydrocarbons, including naphthalene, anthracene;
linear or branched or aromatic or cyclic alcohols including butanetetraol, lauryl alcohol, tridecanol, tetradecanol, pentadecanol, palmitoyl alcohol, heptadecanol, stearyl alcohol;
linear or branched or aromatic or cyclic carboxylic acids including maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid;
amino acids, including aminobenzoic acid, leucine, phenylalanine;
an ester;
sulfones, including diphenyl sulfone, diphenyl disulfone, dibenzyl sulfone, dibutyl sulfone;
and various volatile natural substances including naphthalene and camphor;
the solvent is selected from one or more of water, hexane, cyclohexane, tetrahydrofuran, benzene, xylene, methanol, ethanol, isopropanol, 2-butanol, acetone, diethyl ether, methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane, and dichloroethane.
13. The time-temperature indicator of claim 1, wherein the adsorbent material is capable of irreversibly adsorbing dyes volatilized from the volatile dye layer.
14. A time temperature indicator according to claim 13, wherein the adsorbent material adsorbs the volatile dye at a rate substantially greater than the rate of volatilization of the volatile dye.
15. The time-temperature indicator of claim 1, wherein prior to use of the heat sensitive article, the absorbent material layer is peeled off, a color difference of the volatile dye layer is measured, and a determination is made as to whether the heat sensitive article has failed based on the color difference.
16. The time-temperature indicator of claim 5, wherein prior to use of the heat sensitive article, the absorbent material layer is peeled off, and the color of the volatile dye layer is visually observed, and if the color is darker than the color of the reference color label, the heat sensitive article has not failed; if the color is lighter than the color of the reference color label, it indicates that the heat-sensitive article has failed.
17. The time-temperature indicator of claim 6, wherein prior to use of the heat sensitive article, the absorbent material layer is peeled off, and the color of the volatile dye layer is visually observed, and if the color is darker than the color of the reference color label, the heat sensitive article has not failed; if the color is lighter than the color of the reference color label, it indicates that the heat-sensitive article has failed.
18. The time-temperature indicator of claim 7, wherein prior to use of the heat sensitive article, the absorbent material layer is peeled off, and the color of the volatile dye layer is visually observed, and if the color is darker than the color of the reference color label, the heat sensitive article has not failed; if the color is lighter than the color of the reference color label, it indicates that the heat-sensitive article has failed.
19. The time-temperature indicator of claim 1, further comprising a barrier layer between the volatile dye layer and the sorbent material layer, the barrier layer being positioned between the sorbent material layer and the second release film prior to assembly, in use.
20. A heat-sensitive article using the time-temperature indicator of any one of claims 1-19.
21. A method of making a time-temperature indicator for monitoring the quality status of a heat sensitive article, comprising the steps of:
providing a first substrate material;
coating a volatile dye on one side of a first substrate material to form a volatile dye layer, wherein the volatilization speed of the dye is in positive correlation with the reduction speed of the activity or titer of the heat-sensitive article;
covering a first release film on the volatile dye layer so as to form an indicating functional layer;
and
providing a second substrate material;
coating an adsorbing material on one side of a second substrate material to form an adsorbing material layer;
wherein the size of the absorbent material layer is larger than the size of the volatile dye layer;
coating a non-drying adhesive layer on the periphery of the adsorption material layer on the second substrate material layer; and
covering a second release film on the self-adhesive layer and the adsorption material layer, and sealing the adsorption material layer between the second substrate material and the second release film to form an adsorption function layer.
22. The method of claim 21, further comprising the step of applying a reference color layer adjacent to the volatile dye layer after applying the volatile dye and having a color depth that is the same as a color depth of the volatile dye layer after undergoing the same process as the thermally sensitive article failure treatment.
23. The method of any one of claims 21-22, wherein the heat sensitive article is selected from the group consisting of a vaccine, a biologic, a bioactive sample, a pharmaceutical, a food, or a beverage.
24. The method of any one of claims 21-22, wherein the volatile dye in the volatile dye layer is a colored substance having a melting point of from 0 ℃ to 80 ℃.
25. The method of claim 24, wherein the volatile dye has a melting point between 50 ℃ and 80 ℃.
26. The method of any one of claims 21-22, wherein the volatile dye in the volatile dye layer is selected from at least one of azo dyes, anthraquinone dyes, compounds of formula I and their derivatives, or combinations thereof, wherein the compounds of formula I have the following general formula:
wherein,
r1 is selected from hydrogen, halogen, C1-6Straight or branched alkyl, C1-6Linear or branched alkoxy, -COR2、-COOR2；
R2 is selected from hydrogen and C1-6Straight or branched alkyl, C1-6Straight or branched alkylamino groups.
27. The method according to any one of claims 21 to 22, wherein the volatile dye layer further comprises one or more volatile auxiliaries and/or solvents, the volatile auxiliaries being selected from one or more of the following volatile compounds:
straight-chain alkanes, branched-chain alkanes, cyclic alkanes or aromatic hydrocarbons, including naphthalene, anthracene;
linear or branched or aromatic or cyclic alcohols including butanetetraol, lauryl alcohol, tridecanol, tetradecanol, pentadecanol, palmitoyl alcohol, heptadecanol, stearyl alcohol;
linear or branched or aromatic or cyclic carboxylic acids including maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid;
amino acids, including aminobenzoic acid, leucine, phenylalanine;
an ester;
sulfones, including diphenyl sulfone, diphenyl disulfone, dibenzyl sulfone, dibutyl sulfone;
and various volatile natural substances including naphthalene and camphor;
the solvent is selected from one or more of water, hexane, cyclohexane, tetrahydrofuran, benzene, xylene, methanol, ethanol, isopropanol, 2-butanol, acetone, diethyl ether, methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane, and dichloroethane.
28. A method according to any one of claims 21 to 22, wherein the adsorbent material adsorbs the volatile dye at a rate substantially greater than the rate of volatilization of the volatile dye.
29. A method of monitoring the quality status of a heat sensitive article comprising the steps of:
(a) providing a heat-sensitive article that fails or deteriorates after a time T1 at a temperature T1 at which it is intended to be handled;
(b) attaching to one or more regions on the heat sensitive article:
a volatile dye layer, wherein the initial color difference of the volatile dye layer is C0, and the end point color difference after the time T1 at the temperature T1 is C1;
an absorbent material layer, wherein the absorbent material irreversibly absorbs the volatile dye from the volatile dye layer;
the size of the sealing film layer is larger than that of the adsorption material layer and that of the volatile dye layer, and the adsorption material layer and the volatile dye layer are hermetically attached to the heat-sensitive article;
the heat-sensitive article attached with the sealing film is actually treated;
observing or measuring the actual color difference C2 in the volatile dye layer after the volatile dye layer is actually treated;
comparing the actual color difference of volatile dye C2 with the terminal color difference C1, and if the actual C2 of the dye layer is greater than the terminal color difference C1, indicating that the heat-sensitive article is still valid or not deteriorated; if the actual color difference C2 of the volatile dye layer is less than or equal to the endpoint color difference C1, it indicates that the heat-sensitive article has failed or deteriorated.
30. The method of claim 29, wherein the adsorbent material layer is attached first, followed by the volatile dye layer.
31. The method of claim 29, wherein the volatile dye layer is attached first, then the wicking material layer is attached, and the wicking material layer is peeled away from the volatile dye layer prior to observing or determining the actual color difference.
32. The method of any one of claims 29-31, wherein the comparing the actual color difference of the volatile dye layer and the endpoint color difference is performed by visual observation or by determining the color difference Δ Ε ab of the volatile dye layer.
33. The method of any one of claims 29-31, wherein a reference color label having the end point color difference is prepared upon comparison by visual inspection, the reference color label being attached to the heat sensitive article.
34. The method of claim 33 wherein the reference color label is disposed adjacent to the volatile dye layer.
35. The method of any one of claims 29-31, wherein the heat sensitive article is selected from the group consisting of a vaccine, a biologic, a bioactive sample, a pharmaceutical, a food, and a beverage.
36. The method of any one of claims 29-31, wherein the volatile dye is selected from at least one of azo dyes, anthraquinone dyes, compounds of formula I and derivatives thereof, or combinations thereof, wherein the compound of formula I has the following general formula:
wherein,
r1 is selected from hydrogen, halogen, C1-6Straight or branched alkyl, C1-6Straight or branched chain alcohol, -COR2、-COOR2；
R2 is selected from hydrogen and C1-6Straight or branched alkyl, C1-6Straight or branched alkylamino groups.
37. The method according to any one of claims 29 to 31, wherein the volatile dye layer further comprises one or more volatile auxiliaries and/or solvents, the volatile auxiliaries being selected from at least one or a combination of the following volatile compounds:
straight-chain alkanes, branched-chain alkanes, cyclic alkanes or aromatic hydrocarbons, including naphthalene, anthracene;
linear or branched or aromatic or cyclic alcohols including butanetetraol, lauryl alcohol, tridecanol, tetradecanol, pentadecanol, palmitoyl alcohol, heptadecanol, stearyl alcohol;
linear or branched or aromatic or cyclic carboxylic acids including maleic acid, fumaric acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, adipic acid, sebacic acid, dodecanedioic acid;
amino acids, including aminobenzoic acid, leucine, phenylalanine;
an ester;
sulfones, including diphenyl sulfone, diphenyl disulfone, dibenzyl sulfone, dibutyl sulfone;
and various volatile natural substances including naphthalene and camphor;
the solvent is selected from one or more of water, hexane, cyclohexane, tetrahydrofuran, benzene, xylene, methanol, ethanol, isopropanol, 2-butanol, acetone, diethyl ether, methyl acetate, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane, and dichloroethane.
38. A method according to any one of claims 29 to 31, wherein the adsorbent material adsorbs the volatile dye at a rate substantially greater than the rate of volatilization of the volatile dye.
39. The method of any one of claims 29-31 further comprising the step of attaching a backing material layer over the heat sensitive article prior to attaching the volatile dye layer.
40. The method of claim 39 wherein the layer of backing material is itself a reference color label.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110178976.4A CN102853946B (en) | 2011-06-29 | Monitor thermo-responsive article and add up the method for received heat and the indicator of use thereof | |
| EP12803738.9A EP2728328B1 (en) | 2011-06-29 | 2012-06-26 | Time-temperature indicator and monitoring method for monitoring quality state of thermally sensitive article |
| PCT/CN2012/077568 WO2013000401A1 (en) | 2011-06-29 | 2012-06-26 | Time-temperature indicator and monitoring method for monitoring quality state of thermally sensitive article |
| JP2014517420A JP5779715B2 (en) | 2011-06-29 | 2012-06-26 | Time-temperature indicator and monitoring method for monitoring the quality state of a heat sensitive article |
| US14/127,410 US9618398B2 (en) | 2011-06-29 | 2012-06-26 | Time-temperature indicator and monitoring method for monitoring quality state of thermally sensitive article |
| BR112013033371-5A BR112013033371B1 (en) | 2011-06-29 | 2012-06-26 | COMBINATION AND MONITORING METHOD FOR MONITORING THE QUALITY STATUS OF A THERMALLY SENSITIVE ARTICLE |
| KR1020147002602A KR101568099B1 (en) | 2011-06-29 | 2012-06-26 | Time-temperature indicator and monitoring method for monitoring quality state of thermally sensitive article |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110178976.4A CN102853946B (en) | 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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| Publication Number | Publication Date |
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| CN102853946A CN102853946A (en) | 2013-01-02 |
| CN102853946B true CN102853946B (en) | 2016-12-14 |
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Address after: 215123 109, northwest 2 building, 99 Jinji Hu Avenue, Suzhou Industrial Park, Jiangsu. Patentee after: Suzhou Huashi heat sensitive technology Co., Ltd. Address before: 215152 Jianmin Road, East Bridge, Huang Dai Town, Xiangcheng District, Suzhou, Jiangsu 58 Patentee before: SUZHOU HUASHI MATERIAL TECHNOLOGY SERVICE CO., LTD. |