WO2002049856A1

WO2002049856A1 - Delayed message systems using polymeric membranes

Info

Publication number: WO2002049856A1
Application number: PCT/US2001/049222
Authority: WO
Inventors: Edith Mathiowitz; Jules S. Jacob; Benjamin A. Hertzog
Original assignee: Brown University Research Foundation
Priority date: 2000-12-19
Filing date: 2001-12-19
Publication date: 2002-06-27

Abstract

A time delay messaging device and methods for making the device are described. The device contains at least five layers. These layers are: (1) a clear film, (2) an indicator, (3) a diffusion barrier, (4) an activator, and (5) a backing. p.H-sensitive inks, volatile acids and bases, and iodine vapors can be used to display the message. The device may include additional layers to form a selectively activated device.

Description

DELAYED MESSAGE SYSTEMS USING POLYMERIC

MEMBRANES CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No. 60/256,832, filed December 19, 2000.

BACKGROUND OF THE INVENTION

This invention is generally in the field of the use of time delayed ink messaging systems useful in a variety of applications, including in kits for determining when to stop/begin administering a drug. Time-delayed ink message systems are described in U.S. Patent No.

5,633,836, to Langer et al. Langer uses Red 60 ink in the pH sensitive message systems. This ink is colored, with a pink tint. Thus Red 60 ink does not work on white paper since a printed message will always be visible, even before an activator migrates to the layer that contains the ink. It is therefore an obj ect of the present invention to provide a time- delayed in the system which is colorless and durable.

BRIEF SUMMARY OF THE INVENTION A device comprising at least five different layers displays a message after a time delay of up to 14 days. pH sensitive inks, volatile acids and bases, and iodine vapors can be used to display the message. The main layers include: (1) a clear film, (2) an indicator (which can be part of the clear film), (3) a diffusion barrier, (4) an activator, and (5) a backing. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph of time in minutes versus mass diffused. Figure 2a is a graph of time in days versus weight of film in grams for measuring the diffusion of water (0.1 ml) through a diffusion barrier (layer 3) formed of S225 R film.

Figure 2b is a graph of time in days versus weight loss of film in grams for measuring the diffusion of water (0.1 ml) through a diffusion barrier (layer 3) formed of S225 R film. Figure 3 a is a graph of time in days versus weight of film in grams for measuring the diffusion of water (0.05 ml) through a diffusion barrier (layer 3) formed of S225 R film.

Figure 3b is a graph of time in days versus weight loss of film in grains for measuring the diffusion of water (0.05 ml) through a diffusion barrier (layer 3) formed of S225 R film.

Figure 4a is a graph of time in days versus weight of film in grams for measuring the diffusion of water (0.05 ml) through a diffusion barrier (layer 3) formed of S225 R film. The back of each layer of film in the diffusion barrier contained aluminum foil.

Figure 4b is a graph of time in days versus weight loss of film in grams for measuring the diffusion of water (0.05 ml) through a diffusion barrier (layer 3) formed of S225 R film. The back of each layer of film in the diffusion barrier contained aluminum foil. Figure 5a is a graph of time in days versus weight of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of S225 R film.

Figure 5b is a graph of time in days versus weight loss of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of S225 R film.

Figure 6a is a graph of time in days versus weight of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of ZW44 film.

Figure 6b is a graph of time in days versus weight loss of film in grains for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of ZW44 film.

Figure 7a is a graph of time in days versus weight of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of ELV400 film. Figure 7b is a graph of time in days versus weight loss of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of ELN400 film. Figure 8a is a graph of time in days versus weight of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of CN600 film.

Figure 8b is a graph of time in days versus weight loss of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of CN600 film.

Figure 9a is a graph of time in days versus weight of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of white polypropylene (PP) film, without an adhesive. Figure 9b is a graph of time in days versus weight loss of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of white polypropylene (PP) film, without an adhesive.

Figure 10a is a graph of time in days versus weight of film in grams for measuring the diffusion of water (0.05 ml) through a diffusion barrier (layer 3) formed of white polypropylene (PP) film, without an adhesive.

Figure 10b is a graph of time in days versus weight loss of film in grams for measuring the diffusion of water (0.05 ml) through a diffusion barrier (layer 3) formed of white polypropylene (PP) film, without an adhesive.

Figure 1 la is a graph of time in days versus weight of film in grams for measuring the diffusion of water (0.05 ml) through a diffusion barrier (layer 3) formed of Tevlar film, without an adhesive.

Figure 1 lb is a graph of time in days versus weight loss of film in grams for measuring the diffusion of water (0.05 ml) through a diffusion barrier (layer 3) formed of Tevlar film, without an adhesive.

Figure 12a is a graph of time in days versus weight of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of Tevlar film, without an adhesive. Figure 12b is a graph of time in days versus weight loss of film in grams for measuring the diffusion of ammonia (0.05 ml) through a diffusion barrier (layer 3) formed of Tevlar film, without an adhesive. DETAILED DESCRIPTION OF THE INVENTION I. Description of Device

The basic device consists of multiple layers of materials. The main layers include: (1) a clear film, (2) an indicator, (3) a diffusion barrier, (4) an activator, and (5) a backing. The clear film is at the top of the device and allows a user to view the message. The indicator contains the message. The diffusion barrier controls the time delay. The activator contains a volatile agent which diffuses through the diffusion barrier to the activator. The backing layer is at the bottom of the device and is impermeable to al of the contents within the device.

The devices can be designed to be activated as soon as they are manufactured. Optionally, the devices may be designed to be selectively activated. Selectively activated devices contain additional peelable backing layers and adhesive layers. Such devices contain layers in the following order: (1) a clear film, (2) an indicator, (3) a diffusion barrier, (4) a peelable backing, (5) an adhesive, (6) an activator, (7) a bacldng, (8) an adhesive, and (9) a peelable backing. Layers 1-3 form an indicator pack, while layers 6-9 form an activator pack. To activate this device, the user peels layer 4 away, and then sticks the indicator pack (layers 1-3) to the adhesive layer (5) on the activator pack (layers 6-9). The entire device may then be adhered to any surface by peeling away layer 9. Layer 1: Clear Film

The top layer of the device is a clear film that allows the user to view the underlying message printed on the top of layer 2. Layer 1 should be as impermeable as possible to both moisture, needed in the indicator layer (layer 2), and to the volatile agent found in the activator layer (layer 4). Suitable films for Layer 1 include Mylar (polyester) (FLEXMARK^® PM 100 Clear P/T/P No PS), fluorinated ethylene propylene (FEP), clear polypropylene (PP) (FLEXMARK^® PP 200 H Clear), and fluorinated vinyl (Tevlar) (OT 100 Clear No PS). In the preferred embodiment, layer 1 is formed from clear polypropylene. Clear polypropylene is highly impermeable to moisture and the volatile agents that are used in the activator layer. Additionally, polypropylene film heat-seals well to the other components of the device (see Table 2).

Minimizing diffusion of water is critical to the selection of the top layer material. A small amount of moisture is needed in the pH ink, which may be used in the indicator layer (layer 2). If this moisture can diffuse through layer 2 into the atmosphere, the indicator layer will dry out, and the pH ink will not change color. Results from permeability studies indicate that most of the moisture is lost from the four films listed above within the first few days. The clear polypropylene has better water retention properties than the other films. Fluorinated vinyl (Tevlar) film did not performe as well as clear PP in the permeability studies described in Example 1.

Other films which may be suitable for use as layer 1 include PNdC coated films, which, for example, are available from DUPOΝT^® (e.g., Saran Coated PE) and Mobil (e.g., BICOR^® 85 AXT and BICOR^® 110 ASB-X). The Mobil films have a polypropylene base with an acrylic layer on one side and a PNdC coating on the other, and are clear. The acrylic side of the Mobil films accepts water-based inks

Optionally, the message may be printed directly on the underside of layer 1 and layer 2 may be omitted from the device. Layer 2: Indicator Layer

A suitable material for layer 2 has the following properties: (1) a message can be printed on it, and (2) the volatile agent diffuses freely through it. White filter paper with a printed message in special pH sensitive ink may be used for Layer 2. Another important property of layer 2 is color, since the layer needs to mask the message until it changes. Thus the selection of paper and ink is important. pH sensitive ink Suitable inks include pH sensitive inks, such as phenolphthalein or phenol red inks. The preferred ink is phenolphthalein ink. Phenolphthalein ink is almost colorless and there is no problem hiding an image made with it on white paper. For hydrophobic inks, it is preferable to print the message directly on the top of the diffusion barrier (layer 3). The pH sensitive inks are made with ethanol and water, and they do not print well on the hydrophobic polymers used as the diffusion barriers (layer 3).

Adding glycerol to the ink allows one to produce devices with longer time delays, regardless of the water permeability properties of the top layer (layer 1).

One pH sensitive ink is an aqueous solution of phenol red, which produces a dark red ink at neutral pH (approximately 7.0). Two main problems exist with the phenol red indicator: (1) the ink always has some color regardless of the pH, and (2) the phenol red ink requires a bit of moisture to be active.

Because of the color, the message is always visible when it has been printed on a white paper background. A yellow ink (for bases), formed with the addition of acid, can be used to make a hidden message if it is printed on yellow paper that will mask the message. When the ink is activated it turns dark red/purple and the message can clearly be seen. In contrast, a purple ink (for acids), formed with the addition of base, is not as useful because it does not show up on a purple background after it has turned yellow. pH sensitive litmus paper (Precision Laboratories, West Chester, Ohio) may be used as the indicator. Red paper can be used to indicate bases (turns blue), and blue paper can be used to indicate acids (turns red). The litmus paper is easy to use. It contains no written message. The litmus paper requires moisture to work. Thus, the paper strips are moistened before they are placed in the device. For example, an electric humidifier can be used to moisten the paper strips immediately before they are laminated between layers 1 and 3. A 1% phenolphthalein solution, which is almost completely colorless, turns a very distinct dark red when activated. Messages, in the form of words or pictures, can be written on white paper with the 1.0% ink and are invisible until activated with the volatile base. However, the 1% phenolphthalein is not quite dark enough in printed form. The maximum amount of phenolphthalein that will dissolve in a standard printing solution containing 9 parts 70% ethanol (EtOH) and 1 part glycerol is 2.5%, which also was not dark enough. Therefore in the preferred embodiment, the indicator is formed from 9 parts 100% EtOH and 1 part glycerol with 5% (w/v) phenolphthalein. This solution results in a darker and more vibrant printed message when activated. The phenolphthalein indicators require moisture to work. Anhydrous System Anhydrous systems can be formed. In these devices, the message on layer 2 is written with oil or a polymer-based "ink". When reacted with a iodine, the ink changes to reddish brown. Layer 3: Diffusion Barrier Layer 3 acts as a diffusion barrier. This layer is used to control the time delay of the message activation. Layer 3 may actually consist of multiple layers of the same film, depending on how long of a time delay is required. Generally, the greater the total thickness of layer 3, whether using one layer or a combination of layers, the longer the time delay. In the preferred embodiment, a single thick film, instead of multiple thinner ones, is used. Several different films have been evaluated as diffusion barriers. .

These films include: vinyls, such as Cling Vinyl CN-600 (50% plasticizers), Extra-Life Vinyl ELN-400 (40% plasticizers), N-325, and S225; polypropylenes, such as Optiflex S 225 R White TC-391 44PP-8, ZW44 Optiflex EZWhite 44PP-8 (PP with EVA skin), and FLEXMARK^® PP 240 F White No PS; and polyethylenes, such as FLEXMARK^® PE 350 F White No PS (FLEXICON^®).

Some of the test films such as the adhesive-backed ZW44 film or FLEXMARK^® PP 240 (No PS) in Table 1 had an adhesive backing on one side, which makes it easier to manufacture the devices. A heat-sealer can also be used to manufacture the devices. Films without an adhesive layer were used in these tests, because the adhesive layer resulted in unpredictable heat-seals (see Table 1). Polypropylene films provided the longest delay under most circumstances (see Table 1). Layer 4: Activator Layer The activator layer can be formed of any number of different thin films or reservoirs containing the active agent, which usually is a volatile acid or base. The primary functions of the activator layer are to contain the volatile agent, protect it from manufacturing conditions, and in some cases retard release of the agent to further slow message activation.

Two types of activator layers are generally used: (1) solvent-cast films, and (2) filter-paper reservoirs. In most cases, the volatile agent is in the fomi of a liquid, which generally can be difficult to handle. Both the solvent-cast film and filter-paper techniques are designed to make the volatile agent easy to incorporate into the finished product. Additionally, both techniques result in an activator layer that easily can be laminated between other layers of the finished device. The activator layer may be a film made from a polymer, such as polycaprolactone (PCL). PCL films are solvent-cast in a solvent such as methylene chloride.

The volatile agent can be a volatile base, such as triethylamine or amylamine, a volatile acid, such as acetic or butyric acid, ammonia, or ammonium carbonate. In the preferred embodiment, the volatile agent is ammonium carbonate.

Triethylamine and amylamine are very volatile and highly toxic. Thus films cast with these bases dry quickly. Acetic acid or butyric acid take longer to dry than the than films cast with the organic bases. Thus by the time the films have dried, and can be peeled off of the glass plate, the butyric acid has almost completely evaporated. However, the acetic acid film retains enough of its original loading to quickly turn a phenol red indicator bright yellow. Ammonia is preferred as the volatile agent, since it is relatively inexpensive, compatible with the PCL film casting technique, highly volatile, and less toxic than the other two organic bases. Volatile Gas Forming Agents

An alternative activating agent is a volatile gas forming or releasing agent such as ammonium carbonate, commonly used as the active ingredient in "smelling salts." Ammonium carbonate, which is 30% by weight ammonia, provides a compact reservoir of active ammonia vapors, eliminating the requirement to absorb liquid ammonium hydroxide onto solid matrices, such as filter paper. Ammonium carbonate solid sublimes, producing ammonia (base) and carbon dioxide gases that can diffuse through polymer membranes and activate a pH-sensitive indicator message. However, carbon dioxide can recombine on the message side of the system to form the Lewis base, carbonic acid, which can, in turn, inhibit activation of the pH sensitive ink.

Introducing carbon dioxide adsorbent materials in the greatly enhances the efficiency of the device. Carbon dioxide adsorbent materials may be either mixed directly with the ammonium carbonate agent or introduced as a separate layer between the ammonium carbonate (layer 4) and pH sensitive message (layer 3) layers. Carbon dioxide adsorbent materials include carbon dioxide "scrubbing agents". Examples of carbon dioxide scrubbing agents are alkali hydroxides, such as barium hydroxide, lithium hydroxide, sodium hydroxide, and aluminum hydroxide. Collins CO2 absorbent Granules (Warren E. Collins Inc., Braintree, Massachusetts), which are commonly used to absorb carbon dioxide in spirometer device, is particularly effective. This product contains barium hydroxide and an indicator dye to show the status of the absorptive pellets. Addition of a one- to ten-fold excess of scrubbing agent by weight, with respect to ammonium carbonate, greatly increases the diffusion of ammonia through the polymer membranes, lowering the amount of volatile solid required to activate the message.

A significant advantage of an ammonium carbonate system is that small amounts of the material, either laminated between polymer membranes or encapsulated as solids in a polymer film, can generate tremendous quantities of ammonia gas. Working quantities of 25-50 mg can activate a 2" by 3" message packet. Consequently, small loses during storage are essentially unimportant. Such a message system offers substantial benefits in product shelf-life applications.

Iodine Vapor: Anhydrous System Anhydrous systems which do not require water for activation of a hidden message, can be used in layer 4. Metallic iodine crystals, either enclosed in plastic "pouches" or encapsulated in polymer films (PCL) were formed. Iodine metal "sublimes" into a gas phase and has the additional property of reacting and binding to compounds with unsaturated double bonds in their chemical structure. Some examples of unsaturated compounds are oils (corn, safflower, olive oil) and polymers (polystyrene, polybutadiene, etc). Iodine vapor reacts with colorless unsaturated compounds and turns them eitlier brown or red. This reaction does not depend on water.

The principle of the system remains the same: delay the diffusion of iodine vapor by interposing polymer film barriers until iodine reacts with the message written with oil or polymer-based "inks". A slight drawback of the system is the "non-specificity" of iodine binding, i.e., iodine binds to many of the polymer films and adhesives and discolors them in the process. Optionally the device may contain an opaque masking layer surrounding the message to hide the discoloration of the device.

A great advantage of the system is that a small amount of iodine metal or encapsulated film generates substantial amounts of iodine vapor, so consequently small losses during storage are not significant. This offers a great benefit for product shelf-life. Additionally, iodine has low toxicity and can be used as an antiseptic, a food additive and a dietary supplement.

Layer 5: Backing Layer

The purpose of the backing layer (layer 5) is to serve as a diffusion barrier to both the volatile agent and moisture. Ideally, layer 5 should be completely impermeable to the volatile agent. Suitable films include Extra-Life Vinyl (ELV-400), Fluorinated Ethylene Propylene (FEP), Fluorinated Vinyl (Tevlar), and Peelable Foil (PE backed aluminum foil).

Previously, many of the devices were made with ELV-400 backings simply because the extra life vinyl (ELV) had the lowest percentage of plasticizers of all the films being used at the time. In early experiments, the ELN-400 films also appeared to be the best barrier. Since it soon became apparent that the vinyl films were rather permeable to both the organic bases and moisture, FEP was laminated between the adhesive ELN film and the activator layer (layer 4), in the following order: (i) Activator Layer (layer 4), (ii) FEP (layer 4a), and (iii) Backing Layer (adhesive up) (layer 5). FEP is highly impervious to most solvents, and was assumed to be a much better diffusion barrier than the ELN film alone. However, the FEP film does not have an adhesive layer, nor can it be heat-sealed. Consequently, there is no easy way to test the permeability of the film to moisture or to the volatile agents.

The peelable foil is the preferred material for the backing layer, since foil containing films are often used commercially in applications where a barrier layer is required. The films used in our experiments have a PE bacldng that enables them to be heat-sealed. A number of devices manufactured with heat-sealed foil backings currently are being studied.

Devices

Table 1 provides a summary of the different layers in each film that was tested, the loadings, the barriers, and the time delays. Films which did not contain an adhesive layer are designated "No PS". Packets that have not turned, but are expected to do so are indicated in Table 1 with an asterisk (*).

Table 1

Key:

Gly = Gly

Phen = phenolphthalein (NH )₂C0₃ = ammonium carbonate Ba(OH)₂ = barium hydroxide

FP = FP PS = PS Amyl = amyl Satd = saturated Methods of making the Devices

Layer 1

The clear layer is applied using standard techniques.

Layer 2 pH sensitive inks The ink was either drawn onto filter paper squares with the tip of a glass pipette or the filter paper squares were simply dipped in the ink solution and allowed to air dry. (The dried paper had to be remoistened before it could be used in the devices.) To make the color change associated with the volatile agent more noticeable, the phenol red ink was titrated with HCL to turn it bright yellow or NH₄OH to turn it dark purple. The yellow indicator ink was used with volatile bases (it turns dark red or purple) and the dark purple with acids (turns bright yellow or orange).

If many indicator squares are made at one time and allowed to dry so they could be used at a later date, the squares must be moistened prior to placement in the device. pH sensitive inks require a small amount of moisture to change color. If the filter paper squares were allowed to dry completely then the pH inks would not change color when exposed to the volatile agent from layer 4. Consequently, when devices are made with the dried filter paper squares, the indicators are moistened slightly, e.g., using an electric humidifier or spray gun, before they are laminated between layers 1 and 3.

Ink can be applied to the filter paper using inkjet printing. In one embodiment, the black ink is flushed from a cartridge of an inkjet printer, such as one made by Hewlett Packard, and the cartridge is loaded with pH sensitive ink, such as phenolphthalein ink. Using this method, words and messages can be printed in the "invisible" ink directly onto plain white printer paper. The messages are then cut out and placed in the device. Printer paper works as well as filter paper.

A method for printing phenolphthalein ink with a Hewlett Packard inkjet printer is described below. An inkjet cartridge was washed out with distilled water to remove all remaining traces of the black ink. A 1.0% phenolphthalein solution was made with 70% EtOH so that there would be a small amount of water in the indicator. In addition to the water, glycerol was added to the ink to increase its viscosity slightly and minimize the chance of the printed ink bleeding into the paper. The final concentration of the ink was 1.0% phenolphthalein dissolved in 10% glycerol, 27% water, and 63% EtOH. The ink printed very well with this technique. Furthermore, the glycerol acts as a humectant, and it retains a sufficient amount of moisture to render the printed ink active with out any additional humidification. For example, one of the indicator paper strips exposed to atmospheric air for over a week still changed color upon exposure to NH₄OH. Since the glycerol retained sufficient moisture, the device does not have to rely on the water barrier properties of layer 1 to work effectively. Allowing for a broader range of materials to be used in layer 1.

Methods of Forming layer 4

PCL film casting techniques can be used. However, the PCL film casting teclinique is very time consuming. Further, a large percentage of the ammonia was lost as the film dried.

In a second manufacturing technique for producing the activator layer, ammonia was loaded onto small squares of filter paper to form the activator layer. A known quantity (typically 50 μl) of ammonia was placed on a 1 cm² piece of filter paper immediately before it was laminated between layers 3 and 5. The filter paper technique saved a considerable amount of time, and unlike the PCL film casting technique, a known quantity of volatile agent could be placed in each device. Knowing the quantity of volatile agent loaded is important since it enables one to accurately assess permeability/barrier properties of the films through weight loss experiments. It also permits one to determine when all of the volatile agent has been lost to the environment (see Example 1).

Examples Example 1: Film Permeability Studies. A number of film permeability studies were performed to test the barrier properties of the top (layer 1), diffusion barrier (layer 3), and backing (layer 5) layers to water and ammonia. The films were made into double- sided pouches by using two layers of each film and either sealing using adhesive layer or heat-sealing the films together, if the film did not have an adhesive layer.

The pouches were loaded with a filter paper square (1cm²) containing 50 μL of water or ammonia. The filter paper was placed between the two layers of film. The pouches were weighed immediately after they were sealed, and again at later time points. Table 2 contains the data for each type of film tested and the amount of time for the water or ammonia to pass through the film. Data and graphs of the individual permeability studies is shown in Figures 2-12. Table 2: Layer 3 Film Permeability

* No data taken

Example 2: Studies of Layer 2 with Phenolphthalein Inks. For the majority of the pH experiments, a phenolphthalein indicator was used. Two pH sensitive dyes, were used: Direct Yellow #4 and phenolphthalein, supplied as dry powder. The Direct Yellow changes only very slightly when exposed to a strong base (NH OH), but the phenolphthalein changes from an almost colorless solution in water to a dark purple. Phenolphthalein is somewhat soluble in water, but it is much more soluble in ethanol (EtOH). Phenolphthalein was dissolved in EtOH at varying concentrations to determine the optimal concentration needed to produce an indicator that was both colorless and produced a distinct color change with pH. Table 3 below illustrates results obtained using 0.1% (10 mg/ml EtOH), 1% (100 mg/ml EtOH), and 5% (500 mg/ml EtOH) phenolphthalein solutions, which were tested on 1cm² pieces of wliite filter paper. The filter paper squares were dipped in the respective solutions and then air-dried. Neither the 0.1% or 1.0%) solutions resulted in any noticeable tint, but the 5.0%> solution left a slight yellow/orange tint on the white paper. Next, the filter paper squares were humidified and exposed to NH OH. The 0.1 % squares turned a light shade of pink, and the 1.0% and 5.0% squares turned a very distinct dark purple. There was no distinguishable difference between activated color of the 1% and 5% indicators. Table 3: Phenolphthalein Inks

* Does not require additional humidifϊcation Example 3: Properties of Volatile Agents.

A number of different volatile agents have been used with varying degrees of success. Table 4 lists agents and their corresponding properties.

Table 4: Volatile Agents

The activator layer (layer 4) was originally conceived as a thin film of pofy(caprolactone) (PCL) containing the active agent. PCL is generally solvent-cast using methylene chloride (MeCl ), so the active agent must be miscible in the MeCl₂ for it to be distributed evenly throughout the PCL film.

The first volatile agent tested was triethylamine, a highly volatile organic base. Unfortunately, triethylamine is so volatile, that, most of the amine had evaporated from the PCL film by the time the solvent was gone and the film was ready to be cut.

The next agent tested was amylamine, another organic base with a lower volatility than triethylamine. The amylamine was cast in 50% (by weight) films of PCL on a glass plate. To minimize losses of the amylamine, the films were incorporated into the devices as soon as they were dry enough to be peeled from the glass plate and cut to size (10-15 minutes).

Two volatile acids, acetic acid and butyric acid, were identified as compatible with the PCL/MeCl film-casting technique. Films cast with both of these acids take significantly longer to dry. A few devices were manufactured using the acetic acid loaded PCL films with CN-600 diffusion barriers. The acetic acid prototype resulted in time delays of 2-3 days. Results In general, the organic bases performed relatively well, although triethylamine proved to be too volatile. A number of successful devices were manufactured with the amylamine using the ELV-400 vinyl films as the diffusion barrier. The longest delay obtained to date, 14 days, was achieved with amylamine. Amylamine unfortunately is fairly toxic and its odor is offensive.

Example 4: Testing Material for Layer 5.

A number of devices were made using heat-sealed Tevlar for both layers 1 and 5. A permeability study was started using heat-sealed pouches of Tevlar containing either ammonia or water. However, the Tevlar did not perform nearly as well as the polypropylene films previously tested. The

Tevlar pouches lost all of their contents within the first 4-5 days, whereas the polypropylene pouches lasted closer to 2-3 weeks.

It is understood that the disclosed invention is not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

Claims

We claim:

1. A time-delay message system comprising a plurality of layers of materials comprising a clear film, an indicator, a diffusion barrier, an activator, and a backing, wherein a message appears on the indicator only following controlled diffusion of the activator through the diffusion barrier to contact the indicator.

2. The message system of claim 1 wherein the indicator comprises a pH-sensitive ink.

3. The message system of claim 2 wherein the indicator is a phenolphthalein ink.

4. The message system of claim 1 wherein the activator is selected from the group consisting of volatile acids, volatile bases, and iodine.

5. The message system of claim 4 wherein the indicator comprises an anhydrous ink and the activator is iodine.

6. The message system of claim 1 further comprising a peelable backing and an adhesive layer between the diffusion barrier and the activator and an adhesive with a peelable backing attached to the backing layer.

7. The message system of claim 1 wherein the clear film and the indicator are formed in a single layer.

8. A method for printing a message on a layer of a message system comprising effecting a reaction between the activator and the indicator in the message system of any of claims 1-7.

9. A method of making a message system comprising laminating the layers of the message system of any of claims 1-7 to form a single device.