A) Optimal Medication Monitor(s) and Method of Retrieving  Adherence Record.

or



Alternative Communication Means are found in Alternative displays for Retrieval of Data from the Monitor This includes Retrieval of  Clinical Data on the Patient.

B) Other Dose Removal Monitors.







Cover Opening Monitors with Spring Loaded Cover without Opening Tabs

While the following three figures show what we think is the best Cap Opening Monitor it is still provides less detailed surveillance than a Dose Removal Monitor and is more likely to lead to treatment failure than a Dose Removal Monitor.

The previous images, Figures 1 and 2, suffer from the fact the patient could leave the cover open defeating the purpose of the monitor. The images in Figures 3, 4, 5, and 6 with a spring to close the cover have protruding tabs that children could play with or the patient could use to see how much medication remains, and create multiple openings of the cover and an inaccurate adherence record.

The spring-loaded device shown in Figure 7 depicts a way of largely avoiding these problems by incorporating an extension on one side of the cover, which can be used to hold the cover open. This extension is roughly parallel to the side of the box and incorporates a flanged groove. There is a corresponding flanged groove in the side of the box. To open the box, the patient would hold the box with the left hand, lift the cover with the right thumb, and slide the thumb along the extension until it reaches the flanged grooves. When the thumb is in the grooves it will hold the cover open. At this point the patient can grasp the box with the rest of the right hand and free up the left hand to remove a dose of medication.
Cover and Cap Opening Monitors

The simplest form of a medication monitor detects when the cover of a container of medication is opened. The patient is instructed to open the container to remove the prescribed doses of medication and to close the cover after the medication has been removed. A record of when the container is opened or not opened then provides reasonable evidence of when the medication was taken. It is the cheapest to construct, but it has the limitations that 1) the caregiver does not know how much medication is removed when the cover is open, 2) the cover may be left open, or 3) if the cover is not opened for several days, the patient may claim he took medicine out for several days to take on a trip when in fact he did not take any medication , 4) a child or patient my play with device especially if a spring is incorporated, and 5) if an LED is included to alert the patient to take medication, this helpful feature would be lost on those days when the cover is opened without removing medication before it is opened to remove medication. This helpful function is described later . Of all the possible devices described below we believe the Cover Opening Monitors with Spring Loaded Cover without Opening Tabs shown in Figures 7, 8, and 9 will be least likely to cause some of these problems.  However, since it does not fully solve these problems a Dose Removal Monitor would provide better surveillance and less chance of a treatment failure.

As of August, 2011 many Cap Opening Monitors are commercially available, and are designed to have their data retrieved by an electronic data collection system, either a computer or a PDA. The data collection system may be periodically connected directly to the monitor, or data may be transferred to a remote data collection system through a telephone or other data link.

Cover and Cap Opening Monitors, and all medication monitors, could be made much more applicable to developing countries if they didn’t require an electronic data collection system or data link to retrieve the compliance record. This could be achieved simply by including an inexpensive built in LED display that could remind and instruct the patient and be used by the caregiver to retrieve the adherence record. The details of this display and the multiple functions it could achieve are presented in the section entitled Communications Functions. The section on Retrieval of Adherence Record in Patient’s home using Red/Green/Yellow LED and
Retrieval of the Adherence Record with Audible Tones in the Clinic or Transmitted to the Clinic by Mobile Phones are particularly attractive ways of retrieving the adherence record.  Other ways are described in   Alternative Displays for Retrieval of Data from the Monitor.

With this cover or cap opening monitors, however,  it would not be possible to determine whether medication was removed when the container was opened, how much medication was removed, or whether medication was returned to the container. Like all medication monitors it would not prove that the medication was ingested.

Description of Cover Opening Monitors:

Possible cover opening monitors include an unlimited range of design variations. The four monitors described here are boxes approximately 5.60"x 6.10"x 1.75" inches (14.2 x 15.5 x 4.5 centimeters), about the size of a thick small to medium book.  These are designed to accommodate a two week supply of strips each containing up to 5 caplets of the four-drug combination tablet of isoniazid (INH), rifampin, (RMP), pyrazinamide (PZA), and ethambutol (EMB) used in the initial phase of therapy, or a four week supply of smaller strips also containing up to 5 pills of the INH and RMP combination tablet used in the continuation phase of treatment. (Both of these preparations are supplied by WHO's Global Drug Facility.)

Cover Opening Monitor Without Spring Loaded Cover

Figure 1 shows a cover opening monitor having a simple, integral, hinge without spring closure, which contains a two-week supply of the four-drug combination tablet.

The monitor shown in Figure 3 incorporates a hinged cover with a spring to hold the cover closed. With this design, the spring acts against two protruding tabs, one on the box and one on the cover. These tabs are designed so that they can be grasped with one hand in order to open the box, as shown in Figure 4.  While the cover is thus held open by one hand, the other hand can remove a dose of medication.

When the cover is closed, as in Figure 3, it depresses a button which opens a switch mounted on the monitor's circuit board. When the patient opens the cover, as shown in Figure 4, the button is released and the switch closes. This causes the monitor's microcontroller to direct the LED to flash red if the box had not been opened that day or green if it had been opened that day.  If the box had not been opened earlier in the day, the microcontroller would record the box-opening event as representing medication removal. (If the box is opened again during the day, it is assumed that the patient was not removing additional medication since the LED would be instructing the patient not to take additional medication.)

Since it might be difficult for the caregiver to use the button which senses opening of the cover as the button with which the microcontroller is directed to display the adherence record, a second query button may be provided, as shown in Figures 3 and 4. This query button would also activate a switch on the monitor's circuit board. It would be accessible without opening the cover through a query button access hole in the cover as shown in Figure 3. The patient could also use this query button to query the monitor as to whether medication had been taken, without opening the container. This might reduce extraneous openings by patients who wanted to know if they had taken medication but did not intend to take medication immediately if they had not already taken it.

The protruding tabs shown in Figures 3 and 4 might invite children or an adult to "play" with the device by grasping the tabs, opening the device, and creating a false record of medication removal. The device in Figure 5 and 6 should reduce this occurrence, by substituting a downward directed vertical opening wall for the upward protruding vertical opening tab. The patient would open this device by placing his fingers into the pocket behind the vertical opening wall and bring the two tabs together with his thumb on the horizontal opening tab. Otherwise the device would function the same as shown in Figures 3 and 4.
Figure 8 shows the other side of the device with a hole in the cover for the patient or caregiver to push the query button.
While it shouldn’t be overly difficult for the patient to hold the cover open with his thumb in the thumb groove while removing medication, the caregiver may find that holding the cover open in this manner makes it difficult to fill the device. Figure 9 shows how a rod such as a pencil could be inserted into an opening between the extension of the cover and the device to hold
the cover open. While the patients might learn this maneuver and leave the cover open it is unlikely to occur because it would be easier to use his thumb.

Finally, it should be stressed that the device should be made of transparent material so the patient doesn’t have to open the cover to see how much medication remains, which would create an inaccurate monitor record.
If it is necessary to use the device for medications that are placed in packages in the clinic, the type of package shown in Figure 10 could be used. However, packages filled in the clinic may not provide adequate protection against moisture for those medications where moisture protection is needed.


Various Cap and Cover Opening Monitors:

Two companies produce medication monitors that determine when a cap is removed from a bottle of medication. These monitors require a computer or PDA to retrieve the compliance record.

Aprex Inc.  http://www.aardexgroup.com/

Information Mediary Inc. www.informationmediary.com/

One company,  Shanghai Guifan Digital Technology Co. Ltd in Shanghai China, makes a simple Cover Opening Monitor  that requires a computer or PDA to retrieve the adherence record.

Two companies market an advanced Cover Opening Monitor, which sends a mobile phone signal to a server each time the Cover of a Container is opened:  

Simpill Inc.    www.simpill.com  

Wisepill Technologies  www.wisepill.com

The server keeps the adherence record and can automatically notify the patient, the caregiver, and/or the supervising office every time the patient fails to take medication. They should prove to be useful in the developed countries, but because of the added cost of the built in mobile phone capability, it may be difficult to justify in poor developing countries.

Figure 2. shows the same monitor as Figure 1 with a four-week supply of the INH and RMP combination tablet.

To motivate the patient to close the cover the LED could start flashing yellow 15 seconds after the cover was opened, and or a buzzer could initiate a buzzing sound 30 seconds later if the cover was not closed.

Cover Opening Monitors with Spring Loaded Cover and Opening Tabs

As noted above, Cover and Cap Opening Monitors with built in displays would be more applicable in developing countries. Figure 11 shows a conceptual design for a Cap Opening Monitor incorporating a LED for presenting compliance data in the same manner as for the Cover Opening Monitor.

The Cap Opening Monitor has advantages relative to the Cover Opening Monitor since it is slightly less expensive and less bulky, which makes it easier to take on a trip.

However, since it dispenses loose pills rather than strips of packaged medication there is a greater likelihood for the patient to take an incorrect dose. Also, since the medication is not packaged, it provides less adequate moisture protection for hygroscopic medications. On the other hand this type of device might be suitable for the continuation phase of therapy, since Rifamate* (The Fixed Dose Combination of Isoniazid and Rifampin) is usually dispensed in bottles in the United States.


Cap Opening Monitor with Buzzer to Motivate Patient to Close and Tighten Cap to Prevent Moisture from Reaching the Medication

Ethambutol is hygroscopic. This means the fixed dose combination of isoniazid, rifampin, pyrazinamide, and ethambutol is also hygroscopic. There is evidence which suggests that when this combination of drugs gets moist, the effectiveness of the preparation is reduced. Therefore, the amount of ambient moisture reaching the medication should be reduced to the greatest extent possible. This is usually done by placing a desiccant in the bottle of medication.

However, if the patient leaves the cap open after removing a dose the desiccant can become saturated with moisture rendering it ineffective. Therefore, additional measures may needed to make sure the cap is closed and fully tightened after each dose is removed.

Other reasons for making sure the cap is closed is to reduce the chance that the medications will be spilled or some other substance will get into the bottle.

One way of encouraging the patient to close the cap would be to build a buzzer into the cap that would start buzzing a short interval after the cap was removed (15 seconds) and continue to buzz until the cap was closed. This should remind the patient to close the cap. If the patient failed to do this, the continued buzzing noise would most likely prove to be a sufficient annoyance that some one in the family would be motivated to close the cap.

It may be necessary to go one step further and create a means that motivates the patient to tighten the cap after it has been closed.

A mechanism to achieve this objective is shown in Figures 12, 13, 14, and 15
Figure 12 shows a bottle cap shell with a ring around the cap with a small ring for attaching a strap or chain to connect the cap to the bottle while the cap is removed. It also shows a query button for the patient and caregiver.

Figure 13 shows how the cap incorporates a seal plate with an elastomer seal, which seals against the rim of the bottle. The seal plate is able to move within the cap shell, as will be described later.

Figure 14 shows that the seal plate has a central projection, which contacts a switch lever to actuate a switch. Around this projection is a spring. As the cap is screwed onto the bottle, the seal plate moves up in the cap shell compressing the spring between the seal plate and a spring support plate. The spring force is the force pressing the seal against the lip of the bottle. When the spring compression is sufficient, the projection has moved far enough to open the switch, signaling that the bottle is sealed. There is a thrust washer between the end of the spring and the seal plate which allows the seal plate to rotate relative to the cap shell without "winding up" the spring.

When the cap is unscrewed, the projection moves away from the switch lever closing the switch and signaling that the bottle has been opened. If the cap remains unscrewed for some period of time (perhaps 15 seconds) a buzzer sounds reminding the patient to screw the cap onto the bottle.

The closing of the switch signals a microcontroller to record when the cover is opened and medication presumably removed. Time information is derived from a real time clock (not shown).
Figure 13: Cut away view of closure warning bottle cap showing seal.

Figure 14 also shows that the top of the warning cap has a screw cap that can be removed to change the batteries. As indicated in Figure 15, the query button extends through the top of the cover. If the query button was constructed with enough travel, it could be pushed down below the inner surface of the top cover allowing the cover to be unscrewed. Otherwise it would function as a lock when it was not pushed down to a sufficient extent.  This would normally prevent the patient from unscrewing this cover.

Figure 15 shows the circuit board with the microcontroller, buzzer, batteries, query button, and LED. The query button along with the microcontroller and LED can be used by the patient for instructions when to take medication and by the caregiver to retrieve the adherence record as described in the Simple Red/Green LED section.

Summary

Cover and Cap Opening Monitors provide a much better means of determining compliance than current approaches: pill counts, appointments kept, urine tests, staff judgments, etc and are less expensive to build.  However, since they don’t determine how many if any pills are removed when the cover is open, they are clearly inferior to dose removal monitors.
Figure 15: Cut away view of closure warning bottle cap showing multiple elements
Figure 14: Cut away view of closure warning bottle cap showing means for sensing required sealing force.
Figure 12: Closure warning bottle cap which can be attached to bottle
Figure 11: Cap Opening Monitor with built-in display
Figure 10: Package for multiple different pills to be filled in the clinic.
Figure 5: Cover Opening Monitor with spring loaded cover and alternative opening tabs.
Figure 3. Cover Opening Monitor with spring loaded cover, for dispensing Global Drug Facility packaged TB medication.
Figure 2. Cover Opening Monitor for the Isoniazid and Rifampin Tablet.
Figure 1. Cover Opening Monitor for Four-Drug Combination Tablet.
Figure 4: Opened Cover Opening Monitor showing the use of protruding tabs to open the cover.
Figure 6: Opened Cover Opening Monitor showing the use of Alternative Opening Tabs to open the cover.
Figure 8: Back side of Cover Opening Monitor with a spring loaded without tabs.
Figure 9: Back side of Cover Opening Monitor with a spring loaded without tabs with rod to hold cover open for filling the device.
Figure 7: Cover Opening Monitor with a spring loaded cover without tabs.