W O 97/18449 PCT~US96/17652 TEMPEl~ATUl~E ~DICATING DEVICE
~ Field of the Invention s This invention relates to critical temperature indicating devices. Moreparticularly, it relates to a critical temperature in-liriqting device comprising an indicating composition that provides an irreversible visual signal to the user that a product has been exposed to a predetermined temperature.
lo Back~round of th~ Invention Blood, emulsions, pharmaceuticals, beverages, and other items are often chilled in order that they may be preserved for later use. If exposed to too low a temperature, however, the characteristics of these items may change so that they are undesirable for later use. In fact, many of these items may be rendered completely useless if exposed 1S to too low a temperature, such as the freezing point of water. It is, thel~fole, desirable to provide an indicating device that will accurately show whether or not the item is exposed to a temperature below a critical value. It is also typically desirable for the device to provide its indication relatively rapidly and that the indication be irreversible so that the user will be alerted to a previously ~tt~ined critical temperature, even if that condition is not m~int~ined.
Critical temperature indicating devices are known that utilize the expansion characteristic of water to break a frangible ampule. That is, once the indicating device is exposed to a temperature below the freezing point of water, the volume increases as the water in the ampule changes to ice, thereby causing the ampule to break. After the ice is formed and the surrounding temperature returned to a point about the melting point of the ice, the resultant water is absorbed by a pad, thus providing an indication that the device had gone through a freeze stage and back through a thaw stage. Such indicating devices are not always accurate due to the super-cooling effect of water.
Under some conditions, water may be cooled to as low as -16~C without freezing.
This problem has been partially overcome by the addition of nu~ ting agents to the water to enhance ice formation.
W O 97/18449 PCT~US96/17652 Water-based indicating devices are also known that utilize a microporous layer, water, and a second liquid that can wet out the microporous layer upon soli~lific~tion ofthe water. See, U.S. Patent No. 4,846,095 (F.m.~l~n~1er) The micropores ofthe microporous layer cause scattering of 1,i.,.~ ed light, causing the microporous layer 5 to appear opaque. When the voids are filled with a liquid having substantially the same index of refraction as the material of the m-icroporous layer, the filled voids do not significantly scatter ~ n~ ed light, thus rendering the microporous layer tr~n~miesive to visible light. The opacity of the microporous layer masks a visible indicator, which can be seen after the indicator is activated (i.e., after the second liquid lo enters the voids of the microporous layer). F.m.cl~n~er also discloses that a seeding agent or a salt can be added to the aqueous mixture to slightly modify the indicating temperature. F.m~l~n~ r further discloses that two nonaqueous compounds (ethanolamine and n-butanol), one of which solidifies and one of which wets out the microporous layer, can be used in the indicating devices cont~ining a microporous 1S layer.
Other temperature indicating devices are known that include organic compounds in a capillary tube or bulb attached to a capillary tube. See, for example, U.S. Patent Nos. 4,457,252 and 4,4571253. These indicating devices utilize the volume reduction characteristics of organic compounds as they undergo a change from 20 the liquid state to the solid state. Two organic liquids are separated by a porous plug and/or a separating liquid that is immi.cc.ible with the two organic liquids. One of the organic liquids is colored and has a freezing point that is higher than that of the other ~colorless) organic liquid. At the critical temperature, the colorless organic liquid solidifies and the colored liquid is drawn into that portion of the capillary tube or bulb 2~ cont~inin.E~ the colorless, solidified organic liquid, thereby providing a visual indication that the first compound solidified.
Even with these nonaqueous in(~ ting devices, there is a need for additional inrli~ting devices, particularly those that are responsive relatively rapidly and reproducibly within a relatively narrow tt;lllpel ~lure range. Furthermore, there is a 30 need for additional indicating devices that are capable of being readily modified to a wide range of critical temperatures.
W O 97/18449 PCT~US96/17652 S. ~ry of the Invention The present invention provides a device for in-lic~ting if an object is exposed to a critical te~l~pel~LLIre; the indicating device comprising:
(a) amicroporous membrane;
(b) an indicating composition co~ g less than about 10 wt-% water; the composltlon comprlsmg:
(i) a major amount of a plilnaly organic component cornprising at least one compound that has a freezing point above the critical temperature and does not lo spontaneously wet out the microporous membrane at a temperature at least about 30~C above the critical temperature;
~ii) a modifying component comprising at least one compound that has a freezing point be}ow the critical temperature; and (iii) a wetting component comprising at least one compound that has a S freezing point below the critical temperature and is capable of spontaneously wetting out the microporous membrane at about the critical temperature; and (c) means for cont~ining the microporous membrane and the indicating composition;
wherein the primary organic component, modifying component, and wetting 20 component are miscible liquids above the critical temperature, and are present in a ratio such that the composition does not spontaneously wet out the microporous membrane at a temperature at least about 30~C above the critical temperature, but does wet it out at about the critical temperature upon solidification of a portion of the composition.
2s The present invention also provides a device for indicating if an object is exposed to a critical temperature; the indicating device comprising:
(a) a microporous membrane;
(b) an indicating composition cont~ining less than about ~ wt-% water; the composition comprising:
(i) at least about 50 wt-% of a primary organic component comprising at least one compound that has a freezing point above the critical temperature and does W O 97/18449 PCT~US96/17652 not spontaneously wet out the microporous l.,el~lbr~ne at a temperature at least about 30~C above the critical temperature;
(ii) no greater than about 40 wt-% of a modifying component comprising at least one compound that has a freezing point below the critical temperature; and(iii) no greater than about 20 wt-% of a wetting component co"~l~, ising at least one compound that has a freezing point below the critical temperature and is capable of spontaneously wetting out the microporous membrane at about the critical temperature; and (c) means for co~ it,;~.g the microporous membrane and the indicating composition;
wherein the primary organic component~ modifying component, and wetting component are miscible liquids above the critical temperature, and are present in a ratio such that the composition does not spontaneously wet out the microporous blane at a temperature at least about 30~C above the critical temperature, but does spontaneously wet it out at about the critical temperature upon solidification of a portion of the composition.
A further embodiment of the present invention is a device for indicating if an object is exposed to a critical temperature; the indicating device conl~ ing.
(a) a microporous membrane ~;olll~ ing a polyolefin;
(b) an in~lic.~ting composition Cont~ining less than about I wt-% water; the composition coln~l;sing:
(i) at least about 50 wt-% of a primary organic component comprising at least one polyfunctional alcohol that has a freezing point above the critical temperature and does not spontaneously wet out the microporous membrane at a temperature at 2s least about 30~C above the critical temperature;
(ii) no greater than about 40 wt-% of a modifying component comprising at least one polyfunctional alcohol that has a freezing point below the critical temperature; and (iii) no greater than about 20 wt-% of a wetting component comprising at least one compound selected from the group consisting of alcohols, ketones, ethers, alkanes, alkenes, amines, and combinations thereof; wherein the compound has a W O 97/18449 PCT~US96/17652 freezing point below the critical temperature and is capable of spontaneously wetting ~ out the microporous membrane at about the critical temperature; and (c) means for cont~ining the microporous membrane and the indicating composition and retarding tr~n~mi~sion of water vapor into the in~ic~tin~ composition;
s wherein the primary organic component, modifying component, and wetting component are miscible liquids above the critical temperature, and are present in a ratio such that the composition does not spontaneously wet out the microporous mt;,~ e at a temperature at least about 30~C above the critical temperature, butdoes spontaneously wet it out at about the critical temperature upon solit1ifiçS~tion of a lo portion of the composition.
In this application, "activated" refers to the condition of the intlic~ting device wherein the microporous membrane has been "wetted out" thereby providing an irreversible indication (e.g., a message or a colored composition) that the device has been exposed to the critical temperature for which it was designed;
"critical temperature" refers to the temperature at, or below which, the object being monitored is damaged such that it is undesirable for later use; at this temperature, a portion of the indicating composition solidifies sufficiently to change the surface tension of the indicating composition and cause wetting out of the pores of 2~ the microporous membrane;
"microporous membrane" refers to a polymeric material having a void volume (i.e., the total amount of space not occupied by polymer) ranging from about 20% to about 90% which is characterized by having open porosity (i.e., external pores or pores open to the surface of the membrane) with interconnected ~h~nnt?ls;
"rniscible liquids" refers to a combination of two or more liquids that form a clear solution upon viewing by the unaided eye;
"response time" refers to the time required for the intlic~ting device of the present invention to be activated at the critical temperature for which it is ~e~ignt?d;
"surface energy" refers to the critical wetting tension (~c) of a solid, which is equal to the surface tension of a liquid that would yield a zero contact angle W O 97/18449 PCT~US96/17652 when placed in contact with the solid (i.e.7 when the liquid completely wets out the solid);
"surface tension" refers to the force acting on the surface of a liquid tending to ."i~ e the area of the surface and is equal to the free energy per unit surface area; and "spontaneous wet out" refers to entry of a portion of the liquid indicating composition into the pores of the microporous membrane in the absence of a pressure gradient across the membrane; the portion of the li~uid in~ic~tin~ composition that enters the pores of the rnicroporous membrane includes at least the wettingo component, but it also may include the modifying component and/or nonsolidified primary component.
Brief Description of the Drawin~s Figure I is a sectional view of one embodiment of the indicating device of this invention.
~igure 2 is a sectional view of a second embodiment of the in-1ic~ting device ofthis invention.
Figure 3 is a sectional view of a third embodiment of the indicating device of this invention.
Figure 4 is a sectional view of the embodiment of Figure 3 adhered to an object being monitored.
Detailed DescriPtion The present invention provides a device for indicating whether an object has 2s been exposed to a critical temperature (i.e., a predeternnined temperature below which the object should not be exposed). The indicating device in~ln~ a microporous membrane; an indicating composition cont~ining less than about 10 percent by weight (wt-%) water, based on the total weight of the indicating composition; and means for co..l~ini,~g the microporous membrane and the indicating composition, and preferably, 30 retarding the tran.~mi~ion of water vapor into the indicating composition. Preferably, the indicating composition contains less than about 1 wt-% water.
-W O 97/18449 PCT~US96/17652 Typically, indicating devices cont~ining less than about 10 wt-% water are not subject to the problems associated with super-cooling. They tend to be relatively rapidly responsive. For example, p, e~l . ed indicating devices of the present invention have a response time of no greater than about 60 minutes (more preferably, no greater than about 45 minllte~, and most preferably, no greater than about 30 minutes). They also tend to be more precise and reproducible within a relatively narrow temperature range. For example, indicating devices of the present invention are preferably capable of being activated within ~2~C of the critical temperature of the object being monitored using the test method described herein, which generally involves a cooling lo rate of about 1~C per 30 minutes.
The indicating composition can be a solution, a dispersion, a gel (i.e., a high viscosity solution or dispersion), or the like. It in~llld~c at least three components: a first organic component (i.e., the primary organic component) that incl~ldes at least one compound that has a freezing point above the critical temperature and does not 15 spontaneously wet out the microporous membrane at a temperature at least about 30~C above the desired critical temperature of the object (e.g., pharm:lce~ltical substance, plant material, microorganism, etc.) being monitored; a second component (i.e., the modifying component) that includes at least one compound that has a freezing point below the critical temperature (i.e., it is a liquid at the critical temperature and is 20 used to modify the temperature at which the indicating device is activated); and a third component (i.e., the wetting component~ that incl~l~es at least one compound that has a freezing point below the critical temperature and is capable of spontaneously wetting out the microporous membrane at the critical temperature. The primary organic component, modifying component, and wetting component are miscible liquids above25 the critical tell~pe~L~Ire. They are present in a ratio such that the in-ii,C~ting composition does not spontaneously wet out the microporous membrane at a temperature at least about 30~C (preferably, at least about 45~C, and more preferably, at least about 60~C) above the critical tt;~ re, but does spontaneously wet it out at about the critical temperature upon solidification of a portion of the composition.
At about the critical t~,-.pt;ld~re, at least the primary organic component solidifies out of the inrlic~ting composition, although either or both the wetting component and the modifying component may also solidify with the primary organiccomponent. While not being bound by theory, it is believed that this results in an increase in concentration of the wetting component in the nonsolidified (i.e., ~ g liquid) portion of the indicating composition, which causes spontaneous wet out of the 5 microporous membrane at about the critical temperature. It will be understood by one of skill in the art that the microporous l"~lllbl ane may be wet out by a mixture of the wetting component and other nonsolidified components of the indicating composition;
however, at least the wetting component will wet out the microporous membrane.
An indicating composition that includes a modifying component provides lo advantage over an indicating composition that includes only a primary component that solidifies and a wetting component. Such indicating compositions that include the modifying component provide indicating devices that are capable of being readilymodified to a wide range of critical temperatures. Furthermore, the temperature at which the indicating device is activated can be precisely adjusted by adjusting the 15 relative amounts of the primary organic component, the modifying component, and the wetting component. This provides a greater number of temperatures generally over a broader temperature range to which a combination of any three components can be tailored, as well as a precise adjustment of the temperature.
Thus, the temperature at which the primary organic component solidifies can be 20 modified through the use of the modif~ing component. The pure form of the primary organic component (or pure forms of the individual compounds of the primary organic component if more than one compound is used) has a freezing point above (preferably, at least about 5~C above) the critical temperature for which the indicating device is d~cigned. The pure form of the modifying component (or pure forms of the individual 25 compounds of the modifying component if more than one compound is used) has afreezing point below (preferably, at least about 5~C below) the critical temperature for which the indicating device is designed. The modifying component may cocrystallize with the primary organic component or may simply depress its freezing point. 'rhus, the temperature at which the primary organic component solidifies (i.e., its freezing 30 temperature) when pure is higher than the temperature at which solidification occurs in the indicating composition. Upon the temperature dropping to or below the critical W O g7/18449 PCT~US96/17652 g_ temperature, a portion of the indicating composition solidifies, the concentration of the wetting component in the indicating composition increases, thereby causing the spontaneous wet out of the microporous membrane. This is what is believed to occur when the indicating device is "activated." As stated above, at least the wettings component enters the pores of the microporous membrane, although a mixture of the wetting component and other nonsolidified components of the indicating composition may also enter the pores of the microporous membrane with the wetting component.This wetting out of the microporous membrane can cause the membrane to become generally transparent (i.e., to transmit visible light), or at least tr~n.cll-c.ont lo Thus, as in U.S. Patent No. 4,846,095 ~F.mcl~nder), the device is a visual indicator in that the membrane is initially opaque and becomes transparent, or at least translucent, when it is wetted out. Under normal conditions of use (i.e., temperatures of about 0-60~C without a pressure gradient across the membrane), the membrane will stay generally transparent or tran~ cent If colorant, such as a dye or pigment, is present, 5 however, the melnl)~ e will not necessarily become transparent or even tr~n.~ c~nt Rather, the colorant can be carried into the pores of the membrane and thereby change the color of the membrane. This change in opacity and/or color indicates that the tt;,.,~e,~ure has dropped to, or below, the critical temperature to be indicated.
The indicating device of the present invention can be in a variety of 20 configurations. That is, means for cont~ining the indicating composition and microporous membrane can be in the form of a pouch, a blister pack, etc. The container is formed from one or more materials that can be shaped and sealed to form a reservoir to hold the indicating composition and microporous membrane. These materials are preferably barrier materials for holding out moisture and environmf~nt~l 25 gases. Barrier materials are typically used when one or more of the components of the indicating composition is hygroscopic.
Referring now to Figure 1, the temperature indic~ting device 10 inr.l-ldes two layers 12 and 13 of barrier material, each of which is bonded to a microporous - membrane 14 and 15, thereby forming reservoir 16 between microporous membranes 30 14 and 15. The microporous membranes may be bonded to the barrier layers about their periphery, or across the entire membrane. That is, microporous membrane 14, W O 97/18449 PCT~US96/17652 for example, can be bonded to barrier layer 12 about the periphery of the membrane.
Alternatively, the entire surface of the membrane can be bonded to the barrier layer Barrier layers 12 and 13 are preferably bonded to microporous membranes 14 and 15 by hea$ sealing, although an adhesive or alternative means of bonding could be used.
s Reservoir 16 contains the indicating composition. It is believed that once the indicating device is exposed to the critical temperature for which it is designed, at least the primary organic component solidifies (which may cocrystallize with either the modifying component or the wetting component or both) and the concentration of the wetting component increases in the liquid phase to a point where this nonsolidified portion of the indicating composition (at least the wetting component) spontaneously wets out the microporous membrane. If the indicating composition inr.l~ldes a colorant, the indicating composition becomes visible as a result of the microporous membrane losing its opacity and/or as a result of the colorant entering the pores of the microporous membrane.
S The indicating device shown in Figure 1 can be in a variety of shapes, such as a rec.t~n~ r, square, or circular flat pouch. One surface of the indicating device can have a layer of adhesive disposed thereon for ~tt~-.hing to a surface of the object to be monitored. In such embodiments, there may only be one microporous membrane.
That is, the reservoir 16 would be formed between a barrier layer and a layer ofmicroporous membrane on one side and simply a barrier layer on the other side. When in position on the object to be monitored, the side of the indicating device with only the barrier layer would be closest to the object to be monitored.
The reservoir can also be formed by a washer (i.e., a flat ring) made of a nonporous material, such as a thermoplastic, thermoset, or metallic material. This washer is adhered to a layer of a barrier material on one side, and a second layer of a barrier material with a microporous membrane adhered thereto is adhered to the other side of the washer. The reservoir is thereby formed for pls~f~çm~nt of the in-lic~ting composition.
- A layer of adhesive on a release liner could also be a temporary barrier, thereby 30 ~ p the need for a barrier layer at least on one side of the in-lic~tin~ device.
Once the release liner is removed, the adhesive could be placed against a glass W O 97/18449 PCT~US96/17652 container, or some other obiect, that could act as a barrier. Alternatively, if the adhesive is sufficiently hydrophobic (e.g., a rubber-based adhesive), it may serve as a barrier even when place on a porous substrate.
The barrier material not only provides the container for the indicating 5 composit;on and microporous membrane, but it can provide a barrier to retard the evaporation of the components of the indicating composition and it acts to seal out water and water vapor, which may adversely affect the reproducibility and precision of the indicating device. The barrier material is typically at least partially tr~n.qmi~cive to visible light so that the visible indicator may be seen therethrough once the inclic~tin~
o device has been activated. If the barrier material is attached to a surface of the object being monitored and is therefore on the "backside" of the indicating device, however, it does not need to be tr~ncmicsive to visible light. Thus, an incii-.~ting device can include more than one type of barrier material, as long as at least a portion of the barrier material is at least partially tr~ncmicsive to visible light.
Referring now to Figure 2, the temperature indicating device 20 in~h~des a thermoformed barrier material 22 and a microporous membrane 24 bonded thereto, and backing 28 bonded to the periphery of the thermoformed barrier material 22, thereby forming reservoir 26 for the indicating composition. Therrnoformed barrier material 22 is preferably bonded to microporous membrane 24 using a layer of 20 adhesive (not shown) about the periphery of the membrane, although other means of bonding can be used (e.g., thermal and ultrasonic welding). Generally, if the entire surface of microporous membrane 24 were bonded to thermoformedl barrier material22~ this would not necessarily prevent it from being wetted out. In this embodiment, backing 28 is not tr~ncmi.csive to visible light, although it could be if desired. In fact, 2~ backing 28 could be made of the same material as thermoformed barrier material 22, although it is generally pl ~rel . ed that the backing 28 be made of a metallic foil, plastic, or a 13min~te that has a sufficiently low water vapor tr~n.cmiicion rate and that prevents the tr~ncmiCcion of visible light. The backing 28 can be coated with a heat sealable material such that it can be thermally bonded to the thermoformed barrier material 22, 30 although an adhesive could be used.
W O 97/1844g PCT~US96/17652 Again referring to Figure 2, the backing 28 can bear an image (e.g., ~EJECT"
or "FROZEN") thereon that cannot be seen through microporous ,--el--b, ~ne 24 prior to the indicating device being activated. Once activated, however, the image could be seen through the thermoformed barrier material 22 and the microporous membrane 24.
s Alternatively, the indicating composition could include a colorant that would be seen upon wetting out of the microporous membrane, or the indicating composition could be colorless and backing 28 could be colored.
Referring now to Figure 3, the temperature indicating device 30 in~ des a layer 32 of barrier material, thermoformed barrier material 33, and microporous 0 membrane 34. The microporous membrane 34iS bonded to the barrier material 32, preferably by heat sealing, although an adhesive layer or other means of sealing could be used. The barrier material 32iS bonded to thermoformed barrier material 33, thereby forming reservoir 36 for the indicating composition. Alternatively, the microporous membrane 34 can be fused between the barrier material 32 and the thermoformed barrier material 33 depending on the materials used. Thermoformed barrier material 33iS backed with an adhesive layer 38 forming hollow space 39.
Adhesive layer 38iS used to attach the indiç~ting device to the surface of the object to be monitored. Thus, barrier material 32iS at least partially tr~n.emi.c~ive to visible light because that is the portion of the indicating device through which a person would look.
Generally, the indicating composition in this embodiment would include a colorant, such that it would become visible as a result of the microporous membrane losing its opacity and/or aS a result of the colorant entering the pores of the microporousmembrane.
~eferring now to Figure 4, the temperature indicating device 40 incllldes a 2s layer 42 of barner material, thermoformed barrier material 43, and microporous membrane 44. The microporous membrane 44iS bonded to the barrier material 42, preferably by heat sealing, although an adhesive layer or other means of sealing could be used. The barrier material 42iS bonded to thermoformed barrier material 43, ~ thereby forming reservoir 46 for the indicating composition. Alternatively, the 30 rnicroporous membrane 44 can be fused between the barrier material 42 and thethermoformed barrier material 43 depending on the materials used. Indicating device W O 97/18449 PCT~US96/17652 40 is positioned against container 47 and held in place by extensions 48 and 49 of thermoformed barrier material 43. Alternatively, or additionally, intiic~fin,~ device 4 can be held in place by adhesive positioned between the surfaces of the indicating device and the container that are in contact.
Polymeric microporous membranes (depicted as, for example, 14 and 15 in Figure 1 ) may be made from polyolefins such as polypropylene and polyethylene, polysulfones, polytetrafiuoroethylene (PTFE), polyamide, polyester, cellulose acetate and other cellulose derivatives, and the like, as well as ~om combinations of these polymers. Pleîe"ed microporous membranes include polyolefins such as polyethylene o or polypropylene. Microporous membranes may be produced by solvent casting ofpolymers, or by a phase separation processes, for example. The surface energy of the membranes can be modified by corona treating, flame treating, or by adding a surface active agent, for example.
Suitable microporous ",e-l.b.~nes have a void volume of about 20-90%, more preferably about 40-85%. Preferably, the structure is characterized by having open porosity with interconnected ~h~nnelc. An example of a material that is suitable for use as the microporous membrane is described in U.S. Patent No. 4,726,989 (Mrozinski). This microporous membrane includes a multiplicity of spaced, randomly dispersed, nonuniformly shaped, equiaxed (i.e., app~o~hllately equal dimensions in all 20 directions) particles of a crystallizable thermoplastic polymer (e.g., a polyolefin such as polypropylene) coated with a compound with which the thermoplastic polymer is miscible. These particles are separated from one another to provide a network ofinterconnected micropores, yet they are connected to one another by fibrils of the thermoplastic polymer. Furthermore, these particles include a nucleating agent in the 25 interior of the particles. They are made by a phase separation process and are often referred to as thermally induced phase separation membranes (i.e., "TIPS"
membranes). Such membranes are commercially available from Mir~inesota Mining and mlf~ctl~ring Company of St. Paul, MN.
Commercially available microporous membranes include a particle-filled 30 polyethylene col.lln~-~;ially available under the trade clesi~n~tion "EXXAlRE FILM"
from Exxon Chemical Co. of Florida, TX, and polypropylene membranes commercially available under the trade dçcign~tion "AKZO" from Akzona of Germany or "CELGARD" from EIoechst Celanese of Sommerville, NJ. Also available are particle-filled rnicroporous membranes available under the trade design~tiQn "EXEPORE" from Mitsubishi Chemical of Yokohama, Japan.
s The micropores of the microporous membrane cause scattering of incident light, causing the microporous membrane to appear opaque. When the voids are substantially filled with a liquid having substantially the same index of refraction as the material of the microporous membrane, the substantially filled voids result in adramatic decrease in scattering, thus rendering the microporous layer tr~n~mic~ive to 0 visible light. If, however, the indicating composition of the present invention includes a colorant, the wetting compound does not have to have substantially the same index of refraction; rather, it merely needs to be able to wet out the microporous membrane.
Even if the temperature exceeds the critical temperature for which the indicating device was de~igne-l, after it has been activated (yet is still within a reasonable te~l~pe~-Lure of 15 about 0-60~C and there is no pressure gradient across the membrane), the wetting compound is generally unable to leave the pores, thereby rendering their microporous membrane generally irreversibly transparent, tr~n~ cçnt, or with colorant therein.
P. ~1. t:d barrier materials provide a barrier to water vapor, environmental gases, etc., such that they do not co"~ e the indic~ting composition in the device.
20 Preferably, the barrier material has a water vapor tr~n~mi~ion rate (WVTR) of less than about 1 gram/meter2 in 24 hours, as measured according to American Society for Testing Materials (AST~I) Test Method F-1249-90 on a MOCON Pe~l~laL~ at 38~C
and 90% relative humidity. More preferably, it has a WVTR of less than about 0. 5 gram/meter2 in 24 hours, and most preferably, less than about 0.1 gram/meter2 in 24 2s hours. It is desirable to keep water vapor ~and water) out of the intlic~tingcomposition ~except for the small amount that may be used as a modifying compound) to ensure reproducibility, precision, and relatively short response times.
Typically, the barrier material is at least partially tr~n~mi~ive to visible light, although it can be completely opa~ue. Suitable barrier materials (depicted as, for 30 example, 12 and 13 in Figure 1) include polymeric films, metallized polytneric films, metallic foils, and l~min~tes comprising films and foils. As stated above, when used W O 97/18449 PCTAUS96/176~2 on both sides of the construction, at least one of the layers of barrier material is at least partially tr~n.cmi~eive to visible light, so that the change in the opacity of the membrane is visible when the critical temperature is reached. The preferred barrier materials are such polymeric films as fluoropolymers, polyolefins such as polyethylene, polyesters, s halogenated polyolefins such as polyvinyl chloride, metallized polyesters, and metallic foils such as ~IIlminllm Suitable comrnercially available barrier materials include l~min~ted materials.
One such l~min~te is a polymeric l~min~te commercially available under the product d.osi~n~tion "MIL-B-22191, Type 1, Class 2" from Georgia P~c~ging, Inc. of l0 Columbus, GA. This material has a WVTR of 0.34 g/m2/24 hours and includes a layer of a therrnoplastic fluoropolymer having high moisture barrier properties commercially available under the trade designation "ACLAR" from Allied Signal of Morristown, NJ.
It also inrll~cle~ two layers of low density polyethylene (PE) and a layer of polyethylene terephth~l~te (PET). Specifically, this material includes a layer of 0.015 mm "ACLAR
RX160" (WVTR = 0.42 g/m2124 hours), a layer of 0.012 mm polyetllylene terephth~l~te (PET), and a layer of 0.064 mm low density polyethylene (LDPE).
Between the layer of "ACLAR RX160" and the layer of PET is a layer of 0.017 mm LDPE, which acts as an adhesive to bond these two films together. Other suitablepolymeric l~min~tes include one formed from a layer of 0.19 mm polyvinyl chloride 20 (PVC), 0.051 mm PE, 0.015 mm "ACI,AR RX160," and 0.051 mm PE, which is available under the product desi~n~tion "VPA 760," and one formed from a layer of 0.19 mm PVC, 0.051 mm LDPE, 0.015 rnm "ACLAR RX160," and 0.051 mm LDPE, which is available under the product de.cign~tion "VPA 790," both of which are available from TekniPlex, Inc. of Somerville, NJ.
Preferred barrier materials may be thermoplastic and thus thermoformable.
Thermoforming is used to produce a desired profile for the barrier material, as depicted, for example, in Figures 2, 3, and 4. Thermoforming is carried out by techniq~lPs well known to those in the art. Typically, the material is positioned on a heated, shaped platen and pressed or vacuum formed into a desired shape. The 30 thermoformable material is used in making blister packages. ~or example, such shaped materials are particularly useful for protecting gelatin capsules for the pharm~cellfic~l industry. Examples ofthermofo,..lable materials include polyvinyl chlorides, polystyrenes, polycarbonates, cellulosics, and the like. Preferred thermoformable barrier materials are l~min~ted L'ACLAR" materials, which are commercially available from TekniPlex, Inc. of Somerville, NJ. One such material includes a layer of 0.03g mm '~ACLAR 22A" (WVTR = 0.34 glm2/24 hours), a layer of 0.051 mrn low density polyethylene, and a layer 0.19 mm polyvinyl chloride. Another such material in~ de~
a layer of 0.023 mm "ACLAR SupRx900" (WVTR = 0.26 g/m2/24 hours) and a layer of 0.19 mm polyvinyl chloride. Other l~mm~ted materials can be made to desired specifications. In addition to being thermoformable, these materials are heat sealable.
Other materials that can be used as the barrier material include metallic foils and other materials that are capable of being cold formed. For example, alllmim-m foil (e.g., about 7.5-75 micrometers thick) can be formed into a desired shape and used as the barrier material. If desired, the metallic foil can be coated with a heat sealable coating. Such coating materials are commercially available. Examples include vinylic and acrylic heat seal coatings available under the product desi~n~tions "4506" and '~4514" from Lawson Mardon of Arlington Heights, IL.
Although barrier materials having WVTR values of less than about 1 g/m2/24 hours are p~er~"~d, this is not a requirement. Materials that are permeable to water vapor and/or environmental gases can be used to form the containment means;
however, such materials are not suitable for highly hygroscopic indicating compositions. Thus, a wide variety of materials can be used to form the barrier material. Examples include, a polyester copolymer available under the trade de~ign~tion "SCOTCHPAK 146" from Minnesota Mining and ~mlf~ct~ring Company of St. Paul, MN as well as other "SCOTC~'AK" ~ Jpable lid films.
The barrier material may have an image applied thereto~ which will be masked when the pores of the microporous membrane are not wetted out (i.e., when the microporous membrane appears opaque), but will be visible when the pores ofthe microporous membrane are wetted out ~thus ~ppea~ g ~ ,ale.l~ or tr~n~hlc~nt).
For example, the image can be a printed message on at least one major surface. The printed layer is typically formed from an applopliate printing ink and/or embossed directly into the material. In such embodiments, this layer of barrier material is W O 97/18449 PCT~US96/17652 referred to as a backing (see Figure 2~, and the barrier material is opaque. Pre~,~ly, the barrier material (e.g., the backing) is a metallic foil such as alllmim-m foil. Thus, the metallic foil may have paper adhered to one surface to allow placement of the text or graphics.
To prepare the indicating device shown in Figure 1, a l~m;n~te is formed comprising a first microporous membrane adhered to a first barrier layer. It may be adhered with adhesive or by heat sealing about the outer periphery. Two pieces of this l~min~te are then placed in a facing relationship such that the microporous membrane sides face each other and sealed about the outeT periphery. This creates a reservoir for Lo the in~lic~ting composition. Alternatively, the microporous membrane is adhered to a first barrier layer and used with at least one other barrier layer to form a receptacle.
For example, the membrane is heat sealed to a first transparent barrier layer7 and then this construction is heat sealed to a second barrier layer, such as heat sealed ~Inminllm foil The reservoir is formed by the microporous membrane and the second barrier 15 layer.
The indicating composition contains less than about 10 wt-% water.
Preferably, it contains less than about 1 wt-% water. Compositions with less than about 10 wt-% water, and particularly with less than about I wt-%, provide indicating devices with good precision and reproducibility. For example, they will preferably be 20 reproducibly activated within about ~2~C, and more preferab~y, within about +1~C, of the desired critical temperature, using the test method described in the examples section, which generally involves a cooling rate of 1~C/ 30 minutes. Compositions with less than about 10 wt-% water provide indicating devices with relatively short response times. For example, the indicating devices of the present invention preferably 25 respond in no greater than about 60 minllte.~, more preferably, in no greater than about 45 minllt~, and most preferably, in no greater than about 30 minutes. Furthermore, they make it possible to indicate at temperatures other than 0~C.
The primary organic component ;nclndes compounds that do not wet out the microporous membrane under normal use and/or transportation conditions Typically, 30 suitable compounds for use in the primary organic component do not spontaneously wet out the microporous ,nt;~ ne at a temperature at least about 30~C above the W O 97/18449 PCT~US96/17652 critical temperature. Preferred such compounds do not spontaneously wet it out at a temperature at least about 45~C (and more preferably, at least about 60~C) above the critical temperature. The wetting component includes compounds that do spontaneously wet out the rnicroporous membrane at about the critical temperature.
In its initial state (i.e., prior to being activated), the indicating composition does not spontaneously wet out the rnicroporous membrane at a temperature at least about 30~C above the critical temperature for which the indicating device is d~ci~ned. It is believed that at or below about the desired critical temperature (i.e., the temperature to be avoided), a sufficient amount of the primary organic component solidifies, causing 0 the concentration of the wetting component to increase, allowing the r ~ g liquid portion (i.e., the nonsolidified portion) of the indicating composition ~at least the wetting component) to wet out the pores of the microporous membrane by reducing the surface tension of the indicating composition.
When the nonsolidified portion of the indicating composition (i.e., the wetting 15 component or a mixture of the wetting component and other components of the ~ndicating composition) enters the pores ofthe microporous .l.~-nl,.~e, the membrane becomes at least partially tr:~ncmic.cive to visible light. If a colorant (i.e., a pigment or dye) is present, the color will be appa-~ when the membrane becomes transparent. If a soluble colorant is in the indicating composition, the colorant can be carried into the 20 pores ofthe microporous ..-e-.-b-~ne. The microporous membrane then changes from opaque (white) to the color of the colorant (e.g., dye).
When a colorant is used, it is preferably soluble in the in(lic~ting compositionwithin the temperature range over which the indicating device is to be used. Thecolorant, typically in the form of a pigment or dye, can penetrate the pores of the 25 microporous ~-l~.llbl ane once the telllp.,l ~ure has dropped to about the critical temperature. It can also remain in the pores even if the indicating device is exposed to elevated temperatures within normal use and transportation conditions. The colorimparted to the device by the colorant should be easily seen by the unaided eye.Preferably, the colorant is generally safe for human contact, such as a food-grade dye.
30 Preferred dyes are commercially available under the product d~cign~tions "ERIOGLAUCINE" (blue CI 42090), "ERITHROSIN B" (red CI 45430), W O 97/18449 PCT~US96/17652 "TARTRA~ " (yellow CI 19140), and "FAST G~EEN FCF"(green CI 42053) from Aldrich Chemical Co. of Milwaukee, WI. The colorant is added in an amount ~llffi~i~nt to color the indicating composition and make the color change appa~ to the ~ln~ ed eye when the indicating device has been exposed to the critical S te~llpel~ re. Typically, this ranges from about 0.01 wt-% to about 0.5 wt-%, based on the weight of the indicating composition. It is preferred to use small amounts of colorant because they may affect the freezing point of the solution and because they are expensive.
The primary organic component includes at least one organic compound that 10 does not enter the pores of the microporous IllGlllbl ~ne when in the pure state at least in the absence of a pressure gradient across the membrane at a temperature at least about 30~C above the critical temperature for which the indicating device is designed.
Preferred such compounds do not spontaneously wet it out at a temperature at least about 45~C (and more preferably, at least about 60~C) above the critical temperature.
15 Such compounds have a generally high dipole moment resulting in a generally high surface tension. Preferably, the surface tension is greater than about 30 dynes/cm, more preferably, greater than about 35 dynes/cm, and most preferably, greater than about 40 dynes/cm, as measured using ASTM Test Method D1331-89, Method A, at 23~C for materials that are liquid at this temperature. For materials that are solids at 20 this temperature, the surface tension is measured at 5~C above the freezing point. The surface tension of the primary organic component is greater than the surface energy of the microporous membrane chosen. For ~,~aln~lc, for a microporous membrane made of polypropylene, the surface energy is about 30 dynes/cm. Thus, suitable compounds for the primary organic component have a surface tension greater than about 30 25 dynes/cm when the microporous membrane is polypropylene. Preferably, compounds used in the primary organic component have a viscosity greater than about 10 centipoise, more preferably, greater than about 30 centipoise, and most pl~ bly,greater than about 50 centipoise, measured at 23~C for materials that are liquid at this temperature. For materials that are solids at this tel,.pel ~LIlre, the viscosity is measured 30 at 5~C above the freezing point (i.e., melting point).
W O 97/18449 PCT~US96/17652 The freezing point of the compounds suitable for use in the primary organic component is above (preferably, at least about 5~C above, more pl ~fe~ ~ly, at least about 10~C above, and most preferably, at least about 15~C above) the desired critical temperature. Generally, the freezing point of such compounds are no more than about 5 60~C above the desired critical temperature. Suitable compounds include polyfunctional alcohols such as 1,3-propanediol, ethylene glycol, di(ethylene glycol), glycerol, tripropylene glycol, as well as polyethoxylated derivatives of these glycols, and polyethylene glycol. Other suitable compounds include very polar esters and amides, for example. Preferably, the primary organic component comprises at least 0 one polyfunctional alcohol.
The modifying component incl~-dç.~ at least one compound that has a freezing point below (preferably, at least about 5~C below, more preferably, at least about 10~C
below, and most preferably, at least about }5~C below~ the desired critical temperature. Generally, the freezing point of such compounds are no more than about 5 60~C below the desired critical temperature. Preferably, such compounds do notspontaneously enter the pores of the microporous membrane when in a pure state in the absence of a pressure gradient across the membrane at a temperature at least about 30~C above the critical temperature ~although when mixed with the wetting component, the modifying component may contribute to the wet out of the 20 membrane). More preferably, compounds suitable for use in the modifying component do not spontaneously wet out the microporous membrane at a t~ pe~lure at least about 45~C (and most preferab~y, at least about 60~C) above the critical temperature.
Preferred compounds suitable for use in the modifying component have a generally high dipole moment resulting in a generally high surface tension. Preferably, 25 the surface tension is greater than about 30 dynes/cm, more preferably, greater than about 35 dynes/cm, and most pl ~re. ~Iy, greater than about 40 dynes/cm, as measured using ~STM Test Method D 13 3 1 -8g, Method A, at 23 ~C for materials that are liquid at this temperature. For materials that are solids at this temperature, the surface tension is measured at 5~C above the freezing point. The surface tension of the 30 preferred modifying component is greater than the surface energy of the microporous membrane chosen. For example, for a microporous melllbl~lle made of polypropylene, W O 97/18449 PCT~US96tl7652 the surface energy is about 30 dynes/cm. Thus, suitable compounds for the modifying component have a surface tension greater than about 30 dynes/cm when the microporous membrane is polypropylene.
Preferably, compounds used in the modifying component have a viscosity s greater than about 10 centipoise, more preferably, greater than about 30 centipoise, and most preferably, greater than about 50 centipoise, measured at 23~C for materials that are liquid at this temperature. For materials that are solids at this temperature, the viscosity is measured at 5~C above the freezing point. Suitable compounds include polyfunctional alcohols such as 1,3-butanediol, 1,4-butanediol, ~,3-butanediol, 1,3-10 propanediol, triethanol amine, ethylene glycol, di(ethylene glycol), tliethylene glycol,propylene glycol, glycerol, tripropylene glycol, as well as polyethoxylated derivatives of these glycols, polyethylene glycol, and block copolymers of ethylene glycol and propylene glycol. Other suitable compounds include very polar esters and amides, for example. Preferably, the modifying component comprises at least one polyfunctional 5 alcohol.
The wetting component incl~des at least one organic compound that is capable of wetting out the pores of the microporous membrane when in the pure state at about the critical temperature in the absence of a pressure gradient across the membrane.
Such compounds have characteristics such as a generally low viscosity and a generally 20 low surface tension. Preferably, the viscosity is less than about 50 centipoise, more preferably, less than about 25 centipoise, and most preferably, less than about 10 centipoise, at 23~C for materials that are liquid at this temperature. For materials that are solids at this temperature, the viscosity is measured at 5~C above the freezing point. For effective wet out, the surface tension of the wetting component is less than 2s the surface energy of the microporous membrane chosen Preferably, the surfacetension of compounds used in the wetting component is less than about 30 dynes/cm, more preferably, less than about 27 dynes/cm at 23~C for materials that are liquid at this temperature. For materials that are solids at this temperature, the surface tension is measured at 5~C above the freezing point. Suitable wetting compounds include 3û alcohols, ketones, ethers, halogenated or nonhalogenated ~Ik~ne~ halogenated or nonhalogenated alkenes, amines, and combinations thereof. Preferably, the wetting CA 02236032 l998-04-27 W O 97/18449 PCTrUS96/17652 compounds include propylene glycols having a weight average molecular weight of less than about 2000, (Cl-C8)alcohols (e.g., meth~nol, ethanol, propanol, and butanol), (Cz-C8)ketones (e.g., acetone, 2-butanone), (C2-C8~ethers, (c5-cls)alkanes (e.g., heptane), halogenated (C5-C~8)alkanes (e.g., trichloroethane), (cs-cls)alkenes~
5 halogenated (C5-CI8)alkenes, and (Cl-Cg)amines (e.g., ethylamine and diethylamine).
When selecting the compounds to be used in the primary organic component, the modifying component, and the wetting component, the following parameters aretypically considered. First, the freezing point of the primary organic component(whether one primary organic compound or a mixture of such compounds is used) 10 should be at a higher temperature than the critical indicating temperature. Second, an amount of the wetting component (whether one wetting compound or a rnixture of such compounds is used~ is used to ensure wetting of the microporous membrane atabout the critical indicating temperature, but not at useful temperatures greater than the critical indicating temperature. Third, the freezing point of the modifying 1S component (whether one modifying compound or a mixture of such compounds is used) should be at a lower temperature than the critical indicating t~ pe~ re.
Fourth, an amount of the modif~ing component (whether one modif~ing compound or a mixture of such compounds is used) is used to adjust the indicating tt",l)e- aLllre of the device to the critical indicating temperature for the desired application. In practice, 20 the order of addition of these components does not matter.
Typically, at least about 50 wt-% of the primary organic component is used in an indicating composition. Preferably, at least about 70 wt-% (more prerel~bly, at least about 80 wt-%) and no greater than about 98 wt-% of the indicating composition is the primary organic component. Typically, at least about 1 wt-% of the wetting 25 component is used in an indicating composition. Pler~.~bly, at least about 3 wt-% and no greater than about 20 wt-% (more preferably, no greater than about 15 wt-%, and most pl~rt;l~bly, no greater than about 10 wt-%) ofthe in(1ic~ting composition is the wetting component. Typically, at least about I wt-% of the modifying component is used in an indicating composition. Preferably, at least about 10 wt-% and no greater 30 than about 40 wt-% (more preferably, no greater than about 3 0 wt-%) of the indicating composition is the modifying component. If water is used in the modifying W O 97/18449 PCTrUS96/17652 component, no greater than about 10 wt-% of water is used. In pl erc;l, ed indicating compositions, there is less than about 1 wt-% water (whether intentionally added or through absorption by hygroscopic components of the composition~. All weight percents are based on a percentage of the weight of the total indicating composition.
s The desired ratio of these components depends upon the desired critical temperature. Furthermore, the ratio of any three components can be varied to obtain a wide variety of critical temperatures. This can be readily determined by a minoramount of experimentation. For example, for an indicating device that activates at the critical temperature of-0.5~C, the in~lic~t;ng composition includes about 81 wt-% 1,4-butanediol (primary organic component), about 14 wt-% propylene glycol (modifying component), and about S wt-% isopropanol (wetting component). For an indicating device that activates at the critical temperature of 3 .0~C, the indicating composition inr.llldes about 85 wt-% 1,4-butanediol, about 10 wt-% propylene glycol, and about 5 wt-% isopropanol. For an indicating device that activates at the critical tenll)el ~l~re of -5.0~C, the indicating composition inc~udes about 75 wt-% 1,4-butanediol, about 20 wt-% propylene glycol, and about 5 wt-% isopropanol.
Other materials (preferably, those which are soluble in the indicating composition) can be added to control the freezing point and/or alter the viscosity of the solution. For example, immobilizing agents can be added to control the rate of diffusion and/or build viscosity. Immobilizing agents such as thickeners and viscosifiers can be added to increase the viscosity of the indicating composition, and even forrn a gel. A gel is desirable because it would be easier to dispense into a pouch of the device and it would leak less if there were a failure in the pouch seal. Examples of such thickeners and viscosifiers include modified celluloses; starches; proteins;
~5 polymers prepared from ethylenically unsaturated monomers such as acrylates, acryl~mides, vinyl pyrrolidine, vinyl acetate, acrylonitrile, styrene, and the like;
polyurethanes; fumed silicas (such as that available under the trade df?cign~tions "AEROSIL" from Degussa AG of Frankfort, Germany or "Cab-O-Sil M5" from Cabot - Corp. of Tuscosa, IL); and clays. Other immobilizing agents include imrnobilizing 30 matrices such as fibrous materials made from woven or nonwoven natural or synthetic materials, such as Kraft blotter papers (such as that available under the trade de~ign~tion "VERIGOD" blotting paper available from James River ~orp. of Richmond, VA), sponges, or flocked porous materials, and polypropylene nonwoven material (such as that available under the trade dç~ign~tiQn "THINSULATE" from Minnesota Mining and ~nllf~ctllring Company of St. Paul, MN); air laid web such as 5 paper towels; and nonwoven hydrophilic materials (such as filter paper available from Whatman of Maidstone, F.ngl~rlcl) N~r.le~ting agents can also be added ~although it is envisioned that they are not necçS~ry) to prevent super-cooling and improve reproducibility. Examples of suchmlcle~ting agents include AgI, silica, fumed silica, ground glass, or other materials 0 having a high surface area with a rough topology.
The indicating devices of the present invention are relatively easy to make.
Generally, the only precaution that needs to be taken is to ensure that the indicating composition does not include any significant amount of water absorbed from the atmosphere. Standard h~n~llin~ technig~les for this are known to one of skill in the art.
15 Once the in~lic~ting composition is prepared, it is placed in the desired container, typically via pipette or microsyringe. Preferably it is filled in a way which elimin~te- air bubbles, ~lt~lo~lgh this is not a requi,GI,lGll~. The container is sealed together completely, and the device is ready for use.
As ~li.scll~sed above, the container can be in a variety of shapes and sizes, as20 shown in Figures 1-4. The only requirement is that as the indicating composition and rnicroporous membrane should be in contact prior to activation. Thus, the intiicating device can include separate compartments to avoid activation during shipping from the point of m~nllf~ct-lre to the point of use. For example, the in~ic~ting composition can be encased in a rupturable container, which is impermeable to the indicating 2s composition. A pl ~rGI l ed rupturable container is formed of polymeric material, and can be sealed by means of heat or adhesive. Prior to using the indicating device, the rupturable container should be broken, typically by hand pressure, so the indicating composition and microporous ll~G~llbl~ne come in contact.
~ When adhesive is used to bond various components together or to affix the 30 indicating device to a substrate, the adhesives are preferably pressure-sensitive adhesives, such as, for example, silicone-based adhesives, e.g., polysiloxanes, acrylic-W O 97/18449 PCT~US96/17652 based adhesives, e.g., isooctyl acrylate/acrylic acid copolymers7 rubber-based adhesives, e.g., styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, and nitrile rubbers, e.g., aclylonitrile-but~liçnç~ and rnixtures of these. Pressure-sensitive adhesives are well-known to one of ordinary skill in the art.
S Also useful are foam adhesives and double sided tapes (such as "957g" tape or "409"
carpet tape, which are commercially available from Minnesota Mining and M:~m~f~ctl~ring Company of St. Paul, MN). Also useful are curable adhesives such as epoxies, silicones, cyanoacrylates, and the like. Hot melt and curable hot melt adhesives are also suitable. It is hllpol lant when s~lecting and adhesive to ensure that 0 the composition does not solubilize or soften the adhesive resulting in bond failure.
The indicating device may be attached to a product via adhesive. For example, it can be adhered to the top, bottom or side of a vial, can, jar, carton, or box.
It can be customized with graphics and have a visible window on either front or back of the container to allow for inspection. For example, a word, phrase, or graphic 5 could be imprinted in the inner side of the indicating device, such as on the microporous membrane, which would be obscured by the opacity of the membrane.
Upon reaching the critical temperature, the membrane would become transparent (or at Ieast tr~n~ll-cent) making the word, phrase, or graphic visible. Alternatively, when colorant is incorporated into the device, there is a change in color in the microporous 20 film which indicates the critical temperature has been reached. A word, phrase, or mess~ge could be imprinted on the ,l,t;".b,~ne such that it is visible prior to activation.
Upon activation, if the indicating composition contains a colorant of the same color as the printed message, the message would disa,opeal~.
The indicating device is useful when used as an indicator for flash frozen foods25 (such as poultry), paints, water-based adhesives, dairy products, plants, pharm~ceuticals or water-based chemicals. It can be used to indicate when the product is exposed to undesirably low temperatures. It is useful as an indicator on foodproducts, for in~t~ncç~ where it is important that the temperature remain cold but not so cold that the product freezes, such as fresh poultry or frozen meat. It is also useful 30 on pharm~cellticals and medicines, where the temperature should remain about +5~C.
W O 97/18449 PCT~US96/176S2 For example, at 5~C, vaccines are stable for up to one year; if exposed to temperatures of about 0~C, the reliability of the vaccines is questionable.
Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples as well as other conditions and details, should not be construed to unduly limit this invention. All materials are commercially available except where stated or otherwise made apparellL.
Examl~les o Determination of Indicatin~ Teml)erature To test for indicating temperatures, devices of the present invention were prepared and then tested at desired temperatures in a water bath. The devices were conditioned by holding for one hour in a desiccator prior to the test.
To determine the temperature at which the composition results in penetration 15 of the pores of the membrane to render it transparent, a water bath (commercially available as NESLAB RTE-11 l from Neslab Instruments of Newington, NH~
controllable to temperatures + 0.1 ~C, was used. The temperature was set at a desired testing temperature and equilibrated for 30 min--tes prior to testing a sample. The samples were placed on clips and completely irnmersed into the bath. They were held 20 for 30 minutes in the bath, and then (~ mined to see if any changes in the transparency of the microporous membrane had occurred. If the device had not been activated, the temperature was reduced l~C and held for 30 minutes. This procedure was repeateduntil activation occurred. A minimllm of three samples were tested and averaged.Typically, five samples were used.
The membrane in the indicating device chs~r~es from opaque to transparent at the critical temperature, or if a dye is present, the membrane may change color to that of the dye.
Wet Out Test To determine the utility of the components in the indicating composition, tests were carried out using microporous membrane available as an "oil-out" polypropylene W O 97/18449 PCT~US96tl76',2 microporous membrane from Minnesota Mining and Manufacturing Company of St. Paul, MN to determine wetting and non-wetting characteristics. The tests were carried out at room temperature.
Test 1: A section of microporous membrane was cut into 2.5 cm squares. The ~ "lb~ne was placed on a bench top. A 0.33 ml sample of the component was deposited via microsyringe onto the membrane. If the rnicroporous membrane became transparent in 5-10 minl-tec, the component was considered to be a wetting component. If the membrane did not become transparent in this time interval, thecomponent was considered a primary organic component or a modifying component.
lo For components that are solids at room temperature (22-25~C), exactly the same procedure was carried out, except that the component was warmed up until it was liquid and then tested with the liquid and membrane lllainlained at a temperature just above the freezing point (i.e., melting point).
Test 2: If the component was observed to wet out the membrane, the 15 component was placed into an indicating device prepared as described in Example 1, below. The effect of the component was readily observed by seeing the changes in the membrane, which was covered by a ~l anspal ~ barrier layer. If the microporous membrane became transparent in 5-10 minlltec the component was considered to be a wetting component. If the membrane did not become Ll ~Ln~pa. ~n~ in this time interval, 20 the component was considered a primary organic component or a modifying component. For components which were solids at room temperature (22~ - 25~C), exactly the same procedure was carried out, except that the component was warmedup until it was liquid and then deposited into the reservoir in the indicating device, which was also held at this elevated te---pe-~ re.
Test 3: If the component passed both Tests 1 and 2 (i.e., it wetted out the membrane), it was used as a wetting component in an indicating composition. Several suitable in-iic~tin~ solutions are shown in Table 2. Indicating compositions were made up and deposited via microsyringe into the device pl ~pal ed as described in Example 1.
To test the critical temperature of the device, it was placed in a freezer at a 30 temperature of-15~C. It was checked at 30 minute intervals to see if the in~iiC~t;ng W O 97/18449 PCT~US96/17652 composition had wet out the microporous membrane (thus rendering it L,~l~spa,t;
and if it was solid rather than liquid.
E~ample 1 s This example illustrates the preparation of a device of this invention wherein a receptacle is formed between two layers of microporous film. This construction is similar to that depicted in Figure 1.
1) Adhering the microporous membrane to a barrier layer O A piece of microporous polypropylene membrane, commercially available as"oil-out" microporous membrane from Minnesota Mining and M~nllf~cttlring Company of St. Paul, MN, was cut to about 2.5 cm by about 305 cm. ~ piece of balrier layer material, available under the trade design~tion "MIL SPEC B22191, Type 1, Class 2" from Georgia Pacl~ging Inc. of Columbus, GA, which consisted of a layer 15 of O.Ol5 mm "ACLAI?. RX160", a layer of 0.018 mm low density polyethylene, a layer of 0.012 mm polyethylene terephth~l~te7 and a layer of 0.064 mm low density poiyethylene, was cut to about 2.8 cm by about 33 cm. The microporous membrane was placed on the lower jaw of a laboratory heat sealer (commercially available under the trade desiP~n~tion Sentinel Heat Sealer from Sentinel Corp. of Hyannis, MA).20 The barrier film was positioned on top of the microporous membrane such that the membrane was about 0.63 cm from the edge of the barrier film. The sealer was activated; the settings were 121.1~C + 2.8~C, û.28 MPa, 2 seconds dwell time.
2) Preparing a pouch 2s The heat sealer was adjusted to a higher temperature, 221.1~C + 2.8~C, 0.28 MPa, 2 seconds dwell time. Two pieces, prepared as described in step l, were placed together with the membrane side (depicted as layers 14 and 15 in Figure 1) in a face to face relation. The barrier layer formed the outside of the pouch (depicted as layers 12 and 13 in Figure 1). This was heat sealed to form a strip about 0.63 cm wide, thus 30 forming the base of the pouch. This strip was cut into about 3.8 cm by about 3.8 cm squares. Two edges of each square were heat sealed together, leaving one edge open.
CA 02236032 l998-04-27 -2~-The ends ofthis open section were heat sealed about 0.63 cm in from each edge to~ yield about a 2.5 cm section along the center section of one edge of each pouch which was not sealed.
s 3~ Filling the pouch Using the same heat settings from step 2), the pouch was filled with the desiredinrlic~tin~ composition by using about 0.3 cm3 of desired indicating mixture, care being taken to remove all air bubbles from the pouch. The top of the pouch was heat sealed, as in step 2). The device was then ready for testing (as described above) or forpl,~c~m~nt on a container by use of a pressure sensitive adhesive (commercially available under product number 467 from Minnesota Mining and M~nllf~etl-ring Company of St. Paul, MN).
4) Indicating Compositions The following indicating compositions were prepared by combining the compounds in Table 1 in the weight percentages indicated. Each of the components, some of which are very hygroscopic, was stored in a sealed container with molecular sieve under an atmosphere of nitrogen. All compositions were prepared in air and then purged with nitrogen. Each of composition included 0.1 gram Euroglaucine dye from Aldrich Chemical Co. of Milwaukee, WI~ 1,4-Butanediol (99% pure, 0.35% water), 1,2-propanediol (99% pure)~ triethylene glycol (99% pure), and diethylene glycol (99%
pure) were obtained from Aldrich ~hernical Co. of Milwaukee, WI; isopropanol (reagent grade, 99.7% pure) was obtained from EM Science of Gibbstown, NJ;
glycerol ~99.5% pure, 0.5% water) was obtained from Mallinckrodt Baker, Inc. of St.
2s Louis, MO; ethylene glycol (99.991% pure, 0.009% water) and methyl ethyl ketone (99.7% pure, 0.02% water) was obtained from JT Baker Inc. of Phillipsburg, NJ. The critical temperature for each is an average of 10 trials. The error for each is less than about 1~C.
W O 97/18449 PCT~US96/17652 Table 1 C~ticalT~ 4.8~C -3.2~C -2.0~C 3.4~C 1.6~C -0.4~C 2~C 2~C ~~C 2~C
1,4-bl-t~n~ ol 75 85 80 8087.5 81 85 90 87 90 (prima~ nt) 1,2-~ 1 20 6 14 8 (mod~ing~
i~u~u~ ol 5 5 5 5 5 5 5 (wetting co~ nt~
mPth:lnnl 5 (welting co,.")~ ~~ ) glycerol 10 (Il.~ry.,.g.
triethylene glycol 5 (modifying ~ n~P.~I) diethylene glycol 7 5 (modii;ing~~-y - ) ethylene glycol 10 5 5 (modifving ~ 0 methyl ethyl ketone 5 5 (welting .,~ )ol~.lL) E~slmPle 2 This example illustrates the p- epai ~lion of a device as depicted in Figure 2. A
5 barrier material (depicted as 28 in Figure 2) is a l~min~te of a layer of polyethylene terephth~l~te (PE), a layer of low density polyethylene (LDPE), a layer of ~luminllm foil, another layer of low density polyethylene (LDPE), and a layer of 0.064 mm linear low density polyethylene (LLDPE), which is commercially available under the trade d~si~n~tion L'BN 48" from Georgia Pack~in~ Inc. of Columbus, GA. In this 10 construction, the LLDPE side of the l~min~te faces the inside of the device and the PET side is on the outside.
A second barrier material (depicted as 22 in Figure 2) is a thermoforrned l~min~te of a layer of 0.19 mm polyvinyl chloride (PVC), a layer of 0.051 mm LDPE, a layerofO.015 mm"ACLARRxl60" fluoropolymer, andalayerO.051 mmLDPE, 15 which is commercially under the trade designation "VPA 760" from Tekni Plex Inc. of Somerville, NJ. In this construction, the LDPE side of the l~min~te faces the inside of the device and the PVC side is on the outside.
The rnicroporous polypropylene Illellll)l~ne (depicted as 24 in Figure 2) described in Exarnple 1 was cut into a I cm diameter disc and heat sealed under the conditions described in Exarnple 1 around the periphery to the bottom of the reservoir formed by the second barrier material. The desired indicating composition was then s placed in the reservoir and the first barrier material was heat sealed to the second barrier material across the top.
Example 3 This example demonstrates the effect of a thickener on the in~iC~ting lo composition and the device. Three indicating compositions were prepared, eachhaving a diLrel~ni thickener concentration. and the time to wet out the membrane was recorded. The in~ic~ting composition incl--dçd 81% 1,4-b~lt~n~riiol, 14% 1,2-propanediol, and 5% isopropyl alcohol. To this was added 0.1 gram of Erioglaucine dye. This in~lic~tin~ composition has a critical indicating temperature of-0.4~C. To 100 grams ofthis dye-cont~ining composition was added 3.75 grams, 2.5 grams, or 1.25 grams, respectively, of fumed silica, which is commercially available under the trade clecign~tiQn "Cab-O-Sil M15" from Cabot Corp. Of Tuscosa, IL. These mixtures were placed in individual jars, purged with nitrogen, sealed, and placed on a shaker overnight to agitate the compositions.
An in-iic~ting device was prepared as described in Example 1. To each of 5 such devices for each concentration of silica, 0.3 ml of the thickened indicating composition was added. The indicating devices were placed in a constant temperature bath at -2~C. The 3.75 wt-% silica sample was activated in 1 hour; the 2.5 wt-% silica sample was activated in 45 minllt~c; the 1.25 wt-% silica sample was activated in 30 2s minutes as did a control sample that contained no silica.
F.Y~mnle 4 This example illustrates the lower level of wetting component and modifying component needed for activation. Indicating devices as described in Example 1 were 30 used. Five samples of each composition were tested at -3~C for 30 minutes. Each of the follo~,ving compositions inçl~lc3ec3 0.1 gram ~uro~3~çine dye. For a composition W O 97/18449 PCT~US96/17652 cont~inin~ 98% 1,4-butanediol, 1% 1,2-propanediol, and 1% isop~opallol, none ofthe samples were activated. For a composition cont~inin~ 97% 1,4-butanediol, 2% 1,2-propanediol, and 1% isopropanol, two ofthe five samples were activated. For a composition co..~ 97% 1,4-butanediol, 1% 1,2-propanediol, and 2% isopropanol,5 five of the five samples were activated. For a composition cont?~ining 98% 1,4-butanediol, 1% propylene glycol, and 1% isopropanol, five of five the samples were activated. Thus, indicating compositions co.,l~ i"g as little as 1% wetting component and 1% modifying component can produce effective indicating devices.
0 E:~ml~le 5 This example illustrates that a three component system can provide indicating devices that activate at a wide variety of temperatures over a relatively broad temperature range. Indicating devices as described in Example 1 were used. Ten samples of each composition were tested. Each of the following compositions 15 included 0.1 gram Euroglaucine dye. Samples were placed in a low temperature bath at a temperature above the critical temperature and the temperature was lowered by 1~C increments every 30 minutes. The tempera$ure at which each ofthe samples activated was recorded. For any one composition. the critical temperature recorded in Table 2, below, was an average of ten samples.
~o Table 2 1,4-Butanediol1,2-Propane IsopropylTemp. ~~C) Standard Glycol Alcohol Deviation 89.0 6.0 5.0 4.5 0.5 87.0 8.0 5.0 4.0 0.0 85.0 1 0.0 5.0 3 .0 0.0 83.0 12 0 5.0 2.0 0.3 81.0 14.0 5.0 -0.4 0.5 80.0 1 5.0 5 .0 -1 . 1 0.3 79.0 16.0 5.0 -1.8 0.4 75.0 20.0 5.0 -4.8 0.4 W O 97/18449 PCT~US96/17652 Although the invention has been described with respect to specific p~ t;d embo~iment~ it should be appreciated that other embodiments lltili7.in~ the concept of the present invention are possible without departing ~om the scope of the invention.
The invention, for example, is not int~n~led to be limited to the specific adhesive s articles discloses in the ple~"ed embo~limP.ntc The invention is not int~nded to be limited to the pr~ d embodiments described herein, but rather the invention is defined by the claims and equivalents thereof.
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