Abstract:
A programmable transdermal patch non-invasively delivers pharmaceuticals or other bio-active agents through the skin of a living body. The patch contains one or more agent storage pads and one or more active drivers that apply an electric current to the skin or produce ultrasound to drive the agent into the skin. A digital data processor controls the drivers to match administration of the agents to the needs of the body. The patch may contain a sensor, coupled to the data processor, for monitoring the concentration of a substance in the body in order to vary dosage of a therapeutic agent. A radio contained in the patch enables control by medical personnel from a remote location and/or transmission of sensor data to the remote location. The pads, drivers, sensor, data processor, radio and a battery are all contained within a unitary patch and need no physical connection to external devices.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a divisional application of Ser. No. 10/728,660, filed Apr. 13, 2004, for which the benefit of priority filing date is claimed. 
     
    
     FEDERALLY SPONSORED RESEARCH 
       [0002]    Not applicable. 
       SEQUENCE LISTING, ETC ON CD 
       [0003]    Not applicable. 
       BACKGROUND OF THE INVENTION 
       [0004]    1. Field of the Invention 
         [0005]    This invention relates to transdermal patches for delivering bio-active agents through the skin of a living body and to apparatus for controlling the rate and timing of transdermal delivery of medicinal drugs or other bio-active agents through the skin. 
         [0006]    2. Description of Related Art 
         [0007]    Non invasive transdermal delivery has been used to administer a variety of different drugs, examples of which include nicotine to assist persons in stopping smoking, estrogen for hormone therapy, nitroglycerin for angina, scopolamine for motion sickness, fentanyl for pain control, clonidine for hypertension and ethinylestradiol and norelgestromin for contraception purposes. 
         [0008]    The conventional transdermal patch contains an adhesive pad which is fastened to the skin and which serves as a permeable reservoir containing a drug which is to be administered. Molecules of the drug pass through minute gaps between skin cells and through the skin&#39;s pores. Patches of this kind have a number of advantages over other methods of administering drugs or other agents. The process is non-invasive. It does not require physical penetration of the skin as in the case of hypodermic injections or intravenous administration of drugs. It bypasses the digestive and other metabolic processes which can alter and consume drugs which are ingested orally. In its original and simplest forms the patch can be small and flat and needs no connections to external control devices, drug containers or the like. Thus the patch can be inconspicuous and does not restrict the mobility of the wearer. 
         [0009]    Other characteristics limit usage of the original forms of transdermal patch to administration of only a small number of drugs. For example, diffusion of the drug out of the reservoir and into the skin is a passive process relying only on a concentration gradient. The stratum corneum or outer layer of the skin forms a barrier of dead cells which can adversely affect the rate at which substances pass through the skin by unaided diffusion. Drug molecules must be small enough to pass between the cells in order to reach capillaries deeper in the skin. The stratum corneum varies in thickness and porosity from person to person, so the drug should have a broad range of acceptable concentrations. Only a small number of drugs have characteristics which enable un-aided diffusion through the stratum corneum at an adequate rate. 
         [0010]    The rate of dosage by the above described original transdermal patches is not adjustable and falls off over a period of use as the concentration of the drug in the reservoir pad diminishes. The rate at which drug is released is dependent on the composition of the reservoir pad, on characteristics of the particular drug and on properties of the area of skin to which it is applied. Designing a conventional patch of this kind to maintain a desired concentration of a particular drug in the body can be very exacting and in many cases is not practical. Further, the conventional patch does not enable any programmed variation of dosage rate over a period of time and dosage cannot be adjusted by medical personnel after the patch is in place. This is of particular significance in the case of administration of certain drugs of which the administration of insulin to diabetic patients is one example. A patient&#39;s need for insulin depends on the current concentration of glucose in the body and this may vary in an unpredictable manner during a period of time. Traditionally, diabetic patients have been required to prick their skin periodically in the course of a day, perform an analysis of the glucose concentration in a drop of blood and to self administer insulin if needed. This is a painful and sometimes unreliable procedure. The above described characteristics of the original transdermal patches make them unsuitable for administering insulin or other drugs which are subject to a variable dosage requirement. 
         [0011]    More recent advances in transdermal drug delivery address the problems discussed above. Delivery of bio-active agents through the skin has been enhanced by active driving processes which enable drugs of larger molecular size to be administered and which provide for control of the rate of drug delivery. In one such process, known as iontophoresis, electrodes are used to transmit a small electric current through the reservoir pad and into the underlying skin. The current is thought to temporarily enlarge porosities in the stratum corneum. Drugs dissolved in the reservoir pad tend to be ionized and the electrical field impels the charged ions through the enlarged porosities. Diffusion of agents into the skin has also been actively controlled by another driving process, known as phonophoresis, in which ultrasound is used to increase the porosity of the stratum corneum. 
         [0012]    Some more recent transdermal drug delivery systems also make use of a digital data processor to control the action of the active drivers. This enables programmable variation of the timing and rate of drug delivery to accommodate to different drugs and to the needs of different patients. 
         [0013]    Sensors which monitor the concentration of a substance in a patient&#39;s body in a non-invasive manner have been coupled to the digital data processor. Such sensors typically employ a process known as reverse iontophoresis. Electrodes produce an electrical current in the skin which extracts interstitial fluid, including glucose for example, through the skin. Glucose concentration in the interstitial fluid is detected by infrared spectography for example. This enables computer controlled variation of insulin dosage to match the needs of the particular patient. 
         [0014]    These recent advances have greatly expanded the versatility and effectiveness of transdermal drug delivery but have also created problems which can restrict usage of the technique. Instead of a single unitary patch, the newer systems variously require that multiple components be fastened to the skin, require interconnecting cables and/or require bulky external housings containing controls or other components. Operation may require the presence of medical personnel or may be dependent on actions taken by the patient. Unlike the original and simpler transdermal patches, these drug delivery systems are not free of physical connections to external devices and are not fully mobile. 
         [0015]    The present invention is directed to overcoming one or more of the problems discussed above. 
       BRIEF SUMMARY OF THE INVENTION 
       [0016]    In one aspect the present invention provides a transdermal patch for delivery of a bio-active agent into the skin of a living body which patch is fastenable to a surface of the skin. The patch contains at least one agent storage pad positioned to dispense agent into the skin and contains electrically operated driver means for causing delivery of the stored agent from the storage pad into the skin. A battery supplies electrical current to the driver means and other electrical components of the patch. A programmable digital data processor controls dispensing of the agent by the reservoir pad and driver means. An analysis unit monitors the concentration of a substance in the body. The analysis unit provides concentration signals to the digital data processor enabling dispensing of the agent into the skin when the concentration is outside of a particular range of concentrations. The battery, programmable digital data processor and the analysis unit are all contained within the patch itself. 
         [0017]    In another aspect of the invention, the patch may contain a plurality of the agent storage pads, each storing a different agent, and a plurality of the electrically operated driver means each being operative on a separate one of the agent storage pads in response to actuating signals from the data processor. 
         [0018]    In still another aspect, the invention provides a transdermal patch for delivery of a bio-active agent into the skin of a living body which patch is fastenable to a surface of the skin. The patch contains an agent storage pad positioned to dispense agent into the skin and contains electrically operated driver means for causing delivery of the stored agent from the storage pad into the skin. A battery supplies electrical current to the driver means and other electrical components of the patch. A programmable digital data processor controls dispensing of the agent by the reservoir pad and driver means and a radio receiver enables input of programming signals to the data processor from a remote location. The programmable digital data processor, radio receiver and battery are contained within the patch. 
         [0019]    The invention provides an “intelligent” transdermal patch which regulates release of pharmaceuticals or other bio-active agents into the body to establish and maintain a preferred dosage over a period of time. Administration of the bio-active agent through the skin is controlled by application of an electrical current or application of ultrasound to one or more agent storage pads. A digital data processor chip contained within the patch may variously be programmed to match the administration of the agent to a known rate at which the agent is consumed by metabolic processes or may respond to a sensor in the patch which monitors the concentration of a substance in the body. In some usages of the invention, the data processor is programmed to vary the rate of release of the bio-active agent to conform to normal variations of the rate at which hormones or other substances are produced by the body during the course of a day or other time period. The patch may contain a radio receiver for delivering programming signals, originating at a remote radio transmitter, to the data processor. This enables control of the patch by medical personnel or other persons from a location which is away from the patch. The patch may contain a plurality of agent storage pads each holding a different bio-active agent which agents may be released jointly or independently of each other as might be needed. The patch may be used to administer diverse different pharmaceuticals, vaccines or other bio-active substances without significant pain or inconvenience to the person wearing the patch and without requiring the wearer to self regulate dosage of the bio-active substance. The unitary patch requires no physical connection to external devices and thus allows the wearer to be fully mobile. 
         [0020]    The invention, together with further objects and advantages thereof, may be further understood by reference to the following detailed description of the invention and by reference to the accompanying drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWING 
         [0021]      FIG. 1  is a broken out side view of a controlled dosage transdermal patch depicting a first embodiment of the invention which enables controlled administration of any of a plurality of different bio-active agents. 
           [0022]      FIG. 2  is a broken out view of the underside or skin facing surface of the transdermal patch of  FIG. 1  taken along line  2 - 2  of  FIG. 1 . 
           [0023]      FIG. 3  is a is a graph depicting a typical variation of the concentration of a pharmaceutical drug within the body of a medical patient over a period of time during controlled administration of the drug by a transdermal patch embodying the invention. 
           [0024]      FIG. 4  is a section view taken along line  4 - 4  of  FIG. 2  and which depicts an analysis unit within the patch which monitors the concentration of substances in interstitial fluid extracted through the skin. 
           [0025]      FIG. 5  is a schematic diagram illustrating characteristics of the infrared absorption spectra of substances in extracted interstitial fluid which are detected by the analysis unit of the patch which is shown in  FIG. 4 . 
           [0026]      FIG. 6  is an enlarged view of a corner region of the transdermal patch of the preceding figures depicting a patch activating switch. 
           [0027]      FIG. 7  is a section view taken along line  7 - 7  of  FIG. 6  showing internal components of the switch in the open condition. 
           [0028]      FIG. 8  is a section view of the activating switch of  FIG. 7  showing components of the switch in the closed condition. 
           [0029]      FIG. 9  is a broken out view of a modification of a portion of the transdermal patch of the preceding figures wherein administration of the drug is controlled by a membrane which is permeable when subjected to an electrical current and impermeable in the absence of the current. 
           [0030]      FIG. 10  is a broken out view of the underside of an embodiment of the transdermal patch in which controlled diffusion of a bio-active agent into the skin is effected by ultrasound generators within the patch. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0031]    Referring jointly to  FIGS. 1 and 2  of the drawings, a controlled dosage transdermal patch  11  embodying the invention is adhered to the skin  12  of a person who is to be administered one or more pharmaceutical drugs or other bio-active agents. The patch  11  of this example includes an outer cover  13  forming a thin chamber  14  having an open underside that faces the person&#39;s skin. Agent storage pads  16  at the underside of the patch  11  may be of any of the known hydrophilic compositions and are preferably hydrogel pads of the type that adhere to the skin. Retention of the patch may be augmented by a skirt  17  of adhesive tape which extends outward from the periphery of cover  13  at the underside of the cover. Chamber  14  is divided into upper and lower regions by a circuit board  18  which supports electronic components, to be hereinafter described, within the upper region of the chamber. 
         [0032]    The patch may be designed to administer a single bio-active agent or to administer any selected one or selected ones of a plurality of agents. The patch  11  of this particular example enables administration of three different bio-active agents. Partitioning  19  divides the lower region of chamber  14  into four square sectors  21 ,  22 ,  23  and  24 . The first three sectors  21 ,  22  and  23  contain square agent storage pads  16  situated at the lower region of chamber  14  in position to contact the skin  12 . Each such pad  16  functions as an agent reservoir and is initially saturated with a bio-active agent that is to be administered by the particular pad. The fourth sector  24  of this embodiment contains an analysis unit  25  which extracts interstitial fluid through the skin  12  and which detects the concentration of a substance in the extracted fluid as will hereinafter be described in more detail. 
         [0033]    The stratum corneum or outermost layer of the skin  12  is normally impermeable or semi-impermeable to many bio-active agents, particularly agents having relatively large molecular structures. Consequently, many drugs or other bio-active agents do not diffuse through the outer layer of the skin  12 , at least at a medically desirable rate, simply as a result of the concentration gradient between a drug saturated storage pad  16  and the adjacent skin. This originally limited the use of transdermal patches to a small number of drugs or other agents. Electrically operated drivers can make the stratum corneum temporarily more permeable and can actively drive bio-active agents from the pad  16  into underlying tissue. One known form of active driver performs a process known as iontophoresis in which electrodes create a small and painless electrical current in the skin which increases permeability of the stratum corneum. Drugs dissolved in hydrogel pads exhibit an ionic charge and the electrical field created by the energized electrodes actively drives drug ions into porosities in the skin. Another form of active driver, using a process known as phonophoresis, generates acoustic pulses of ultrasound to increase permeability of the stratum corneum. 
         [0034]    The transdermal patch  11  depicted in  FIGS. 1 and 2  contains active drivers  26  of the iontophoresis type to control dosage of the bio-active agents. A separate first driver electrode  27  is disposed against the upper surface of each storage pad  16  and each such electrode preferably conforms in outline with the underlying pad. A single second driver electrode  28  is spaced apart from each of the first driver electrodes  27  to enable creation of an electrical current within the skin between one or more of the first driver electrodes  27  and the second electrode  28  In this embodiment, the second driver electrode  28  is situated in the fourth sector  24  of chamber  14  against the top surface of another hydrogel pad  29  which assures good electrical contact between the second driver electrode and skin  12 . 
         [0035]    Administration of the bio-active agent in any of the storage pads  16  is initiated by applying voltage of a first polarity to the one of the first driver electrodes  27  that contacts that pad while applying voltage of opposite polarity to the second driver electrode  28 . The electrical field which is created in this manner repels ions having a polarity similar to that at the first driver electrode  27  and thus drives such ions out of pad  16  and into the underlying skin  12 . Thus a positive voltage is applied to the first driver electrode  27  if ions of the drug are of a type which exhibits a positive charge and negative voltage is applied if the drug ions are negatively charged. Administration of the drug stops when application of the voltage to the first driver electrode  27  is terminated. 
         [0036]    The electrical force necessary to cause a particular drug to be dispensed from a hydrogel material is dependent on electrical characteristics of the molecules of the drug and is proportional to both the viscosity of the hydrogel and the current within the hydrogel. Additives known to those skilled in the art can be added to the hydrogel material of storage pads  16  to fix the viscosity of the material at a value at which a drug is retained in the pad in the absence of electrical current The degree of viscosity which is needed to stabilize a particular drug in this manner can easily be determined by testing. In this condition, the pads  16  may be characterized as being impermeable in the absence of an electrical current while being permeable in the presence of electrical current. The electrical current which is created by an active driver  26  is dependent on the voltages which are applied to the driver electrodes  27  and  28 . The particular voltages that are needed to drive a particular amount of a drug out of the pad  16  in a particular time period can also be determined by testing. 
         [0037]    Electrical power for operating the driver electrodes  27  and  28  and for operating other electrical components to be hereinafter described is provided by a battery  30 . Other electrical components include a voltage regulating module  32  which provides selectable voltages to a switching module  33 . Switching module  33  enables application of selected voltages of either polarity to any or all of the driver electrodes  27  and  28 . The voltage regulating module  32  and switching module  33  may be solid state circuits which are controlled by digital signals produced by a programmable digital data processor  34 . Data processor  34  is a semiconductor microchip of one of the known forms and includes the standard computer components such as a central processing unit, memory arrays, data buses and input/output interfacing. Data processor  34  is programmable to control the timing and duration of successive administrations of bio-active agent at any of the pads  16  in any of a variety of modes of operation which will hereinafter be discussed. Battery  30 , voltage regulating module  32 , switching module  33  and data processor  34  are all contained within the transdermal patch  11  on circuit board  18  within the upper region of chamber  14 . 
         [0038]    The patch  11  also contains a radio transmitter and receiver  36  which enables input of instructions to data processor  34  and monitoring of data produced by the processor with a remote control unit  37  which may be located away from the patch. The remote control unit  37  in this embodiment includes another radio transmitter and receiver  38 . The remote control unit  37  also includes a data input device  39  and a monitor  40  for displaying data received from the patch  11 . The data input  39  may be a keyboard for example and monitor  40  may be a data display screen of one of the known forms. Remote control unit  37  enables transmission of signals, which are preferably encrypted, to the internal radio transmitter and receiver  36  of patch  11  for such purposes as selecting a mode of operation of the patch and for programming or reprogramming the timing and duration of successive administrations of a bio-active agent. Monitor  40  displays information produced by data processor  34  such as readings of the concentration of a substance in a patient&#39;s body that are detected by the analysis unit  25 . This allows medical personnel to control treatment of a patient without removal of the patch  11  from the patient or other manipulations at the actual patch and without necessarily being in proximity to the patient. 
         [0039]    Remote control of the patch  11  can be useful in circumstances other than in medical treatment of an ill patient. For example, there is much concern in military operations about the possible use of chemical or biological weapons. Patches  11  containing one or more antitoxins, vaccines or the like can be fastened to the skin of soldiers and other persons who may be at risk but not be activated until use or imminent use of such weapons is detected. Upon detection of such a threat, military commanders may then immediately and simultaneously use remote control  37  to initiate administration of appropriate counter agents to all persons equipped with the patch. 
         [0040]    Data processor  34  may be programmed to cause administration of a pre-determined amount of a drug or other agent at predetermined intervals following activation of the patch and the amount and interval can be changed by instructions transmitted by remote control  37  if necessary. The concentration of a therapeutic drug in the body diminishes following each administration as the drug is consumed by body processes. The rate at which the concentration of most particular drugs decreases is known to medical practitioners and dosage is repeated at intervals to maintain the concentration within a desired range. This can be a somewhat erratic process when the repeated doses require attention and efforts by the patient or medical personnel. The present invention provides for a more precise maintenance of the desired concentration in an automatic manner. In particular, data processor  34  can be programmed to provide an initial dosage of a drug or the like which brings the concentration up to or near the maximum value of the desired range and to provide a smaller dosage at appropriate intervals thereafter which restores the concentration to the initial value. 
         [0041]    In particular, the following values can be entered into the memory of the data processor: 
         [0042]    (t 0 )=the time following activation of the patch at which the driver is to be energized to begin administration of the drug; 
         [0043]    (N)=the initial dosage which is to be administered to the particular patient in order to achieve an initial concentration of the drug in the body; 
         [0044]    (t on )=the period of time that the driver electrodes are to remain energized in order to deliver the initial dosage (N); 
         [0045]    (V)=voltage to be applied to the driver electrodes in order to deliver the initial dosage (N) in time period (t on ); 
         [0046]    (1/n)=a fraction of the initial concentration by which the concentration is to be allowed to diminish before a replenishment dosage is administered. For example, (1/n) may be the half life of the initial dosage of the drug in the body in which case n=2; 
         [0047]    (t shut )=the period of time that the driver electrodes are to be unenergized following each on period (t on ). Time period (t shut ) is the time required for the concentration of the drug in the body to diminish by fraction (1/n) of the initial concentration; 
         [0048]    (t off )=the period of time following (t 0 ) after which the patch is to stop administering the drug. 
         [0049]    At time (t 0 ) following activation of the patch, the program signals voltage regulator  32  and switching circuit  33  to apply voltage V to the driver electrodes. After elapse of time t on  the program signals the switching circuit to de-energize the driver electrodes. Subsequently, after elapse of time period t shut , the program signals the switching circuit to reapply voltage V to the driver electrodes for a time period equal to (t on )×(1/n) in order to administer the first replenishment dose. The program then continues to energize the driver electrodes with voltage V for cyclical time periods having a duration equal to (t on )×(1/n) and which are separated by time periods equal to t shut . The program terminates administration of the drug after time period t off  has elapsed. 
         [0050]      FIG. 3  graphically depicts the above described pattern of administration of a typical drug. For purposes of example  FIG. 3  depicts the administration of testosterone which has a 12 minute metabolic half life in the human body and which is to be replenished each time that the concentration has declined to one half of the original value. 
         [0051]    The patients need for some drugs may vary in a known cyclical fashion during the course of a day. Data processor  34  may be programmed to vary the dosage during the day or other time periods in the optimum manner. 
         [0052]    The need for some other drugs or agents does not follow a predictable pattern of the kind described above. The need for such drugs may vary in a seemingly random manner dependent on the patient&#39;s activities, food consumption or other variables. The need for insulin by diabetic patients is a well known example. Referring again to  FIGS. 1 ,  2  and  4 , analysis unit  25  may be activated to monitor the concentration of a substance in a patient&#39;s body in a non-invasive manner. This enables variation of the timing and amount of successive dosages of one or more drugs to accommodate to an unpredictable need for a drug. 
         [0053]    Analysis unit  25  operates by the reverse iontophoresis process in which an electrical current extracts interstitial fluid, including glucose for example, through the skin. The analysis unit  25  includes first and second spaced apart hydrogel fluid collection pads  42  and  43  respectively which are disposed at the underside of sector  24  of the patch in position to contact the skin. A flat electrode  44  is disposed against the upper surface of collection pad  42  and a similar electrode  46  is disposed against the upper surface of collection pad  43 . In response to programmed instructions from data processor  34 , switching circuit  33  applies positive voltage to electrode  44  and negative voltage to electrode  46  to create an electrical current in the underlying skin. This enhances porosity of the skin and causes negatively charged ions, such as glucose ions for example, to be drawn through the skin and into collection pad  42  by the current and the positive electrical charge on electrode  44 . Negatively charged drug ions are drawn into the other collection pad  43  by a similar process. 
         [0054]    An infrared source  47  directs infrared energy through collection pad  42  towards an infrared detector  48  which is situated between the two collection pads  42  and  43 . Substances such as glucose absorb discrete infrared frequencies. The frequency absorption patterns for different particular substances, such as glucose, are known to the art and are unique to the particular substance. Thus the infrared intensity data produced by detector  48  for a series of specific infrared frequencies identifies the presence of a substance such as glucose in collection pad  42  and identifies the concentration of the substance in the pad. Detector  48  is of the type which outputs this data in digital form thereby enabling data processor  34  to analyze the detected data and to enable administration of a corrective dosage of an agent, such as insulin derivative, at one or more of the drug administration sectors  22 ,  23  and  24  in the manner previously described. 
         [0055]    Referring jointly to  FIGS. 4 and 5 , data processor  34  may be programmed to sample a substance such as blood glucose “M” times per day starting at a specific hour (t M ) of the day. At time (t M ) the program signals switching circuit  33  to apply voltage to the analysis unit  25  thereby creating an electrical current in the underlying skin. This causes interstitial fluid to be drawn through the skin and into the analysis unit  25  by the reverse iontophoresis process. Ions which carry a positive charge, such as potassium ions, are drawn into collection pad  42  by the electrical current and the negative charge on the overlying electrode  44 . Infrared source  47  directs infrared energy through the collection pad  42  and towards infrared detector  48 . The infrared radiation includes the infrared absorption spectrum frequency range (v 1  to v 2 ) of the substance which is to be detected. 
         [0056]    Prior to use of the patches with particular patients a series of “K” different known concentrations of the substance to be detected, such as glucose for example, are measured and their spectra [G] K  are stored in the permanent memory of data processor  34  in a vector (Q i ) whose successive elements represent detected infrared intensities and their corresponding frequencies. During use of the patch the program compares the detected infrared spectrum [G M ] of the glucose or other substance that is contained in each sampling of interstitial fluid with the stored vectors (Q i ) of intensities and frequencies for each concentration [G] K .  FIG. 5  is a diagrammatic depiction of a detected spectrum [G M ] which lies between two stored spectral values [G U ] and [G L ]. The upper spectrum [G U ] is the stored spectrum which is immediately above detected spectrum [G M ] and the lower spectrum [G L ] is the stored spectrum which is immediately below the detected spectrum. Therefore the difference (A) between the intensity levels of the successive spectra, such as [G U ] and [G L ], that are stored in the data processor memory determines the accuracy of the detected spectrum [G M ]. This difference can be made arbitrarily small to provide a desirable degree of accuracy by storing concentration spectra [G] K  which are arbitrarily closer to each other. 
         [0057]    This form of programming enables determination of the concentration levels of glucose or other substances by the most basic fixed point computer operations instead of more complex floating point operations. This enables a very simple, inexpensive central processor to be employed. 
         [0058]    The stored spectra [G] K  of glucose or another substance include the spectra of the maximum and minimum acceptable concentrations in the patient&#39;s body. If the detected concentration is above the maximum or below the minimum, the program initiates one or more modes of corrective action. In one mode of operation the program causes data processor  34  to signal radio receiver/transmitter  36  to transmit the concentration data to the remote radio receiver/transmitter  38  where medical personnel are alerted to the problem. Using remote control  37 , the medical personnel may then return instructions to data processor  34  to cause administration of a corrective drug from one or more sectors of the patch  11  in the previously described manner. In another mode of operation, the program may cause the cyclical measurements of the concentration of a substance, such as glucose, to be stored in the random access memory of the data processor. Medical personnel may then use remote control  37  to access this information. In another mode of operation, the program may initiate administration of a corrective agent automatically when the detected concentration of a substance is outside of a desired range of concentrations. 
         [0059]    Operations of the data processor  34  involving the analysis unit  25  have been described above primarily with reference to the monitoring of glucose in the body of a patient. The patch  11  can be adapted to monitoring other substances in the interstitial fluid of a patient&#39;s body by essentially similar techniques. The patch  11  can be adapted to monitor substances which are drawn towards the positive electrode  46  by reverse iontophoresis by providing another infrared source  50  which directs infrared towards detector  48  through the other collection pad  43 . 
         [0060]    The analysis unit  25  described above uses infrared spectrometry to monitor the concentration of a substance in interstitial fluid. A variety of other techniques are known which detect the concentration of a substance in a fluid. These other techniques may be used in the patch  11  in instances where the components for implementing the process are small enough to be contained in a transdermal patch. 
         [0061]    Referring again to  FIG. 1 , a sizable period of time may elapse between manufacture of the patch  11  and the time that the patch is to be used. It is preferable that battery  30  be disconnected from the electronic components  32 ,  33 ,  34 ,  36  of the patch during this period of time to avoid premature operation of the patch and to avoid unnecessary draining of the battery. An activating switch  51  is provided to maintain the battery  30  in a disconnected state until such time as the patch is intentionally activated. While a simple on-off switch might be used for this purpose, it is preferable that the switch  51  have a specialized construction which blocks closing of the switch until an intentional action is taken to condition the patch  11  for operation. It is also preferable that the switch lock itself in the closed position when it is operated. This prevents accidental inactivation of the patch  11  during use. 
         [0062]    In particular, with reference to  FIGS. 6 ,  7  and  8 , the switch  51  of this example has a depressible switch button  52  which protrudes slightly from cover  13  at a corner of the cover when the switch is in the open condition. A removable plug  53  extends into cover  13  at that corner and prevents button  52  from being depressed until the plug is withdrawn from the cover. A spaced apart pair of metal fixed contacts  54  extend upward from circuit board  18  under button  52 . Button  52 , which is formed of non-conductive material, has a downward extending annular sleeve portion  56  which encircles the upper ends of fixed contacts  54  when the button is in its un-depressed condition. The button  52  also has a central rod portion  57  which extends downward between the upper ends of fixed contacts  54  when the button is in the un-depressed condition. A movable contact  58  is secured to rod portion  57  and has a pair of tangs  59  which extend outward and upward from opposite sides of the rod portion and which are formed of resilient metal. 
         [0063]    The upper ends of fixed contacts  54  have small lips  61  which extend towards each other and which are positioned to deflect tangs  59  towards rod portion  57  temporarily as button  52  is traveled downward. Tangs  59  spring outward after passing between lips  61  and the lips then prevent the tangs and button  52  from being raised. Thus the switch  51  is locked at the closed position at which movable contact  58  forms an electrically conductive path between the fixed contacts  54 . Separate conductors  62  extend from each fixed contact  54  to enable the battery to supply operating current to previously described electronic components of the patch when switch  51  is in the closed condition. At the closed position of the switch, sleeve  56  closes the opening in cover  13  that was created by withdrawal of plug  53   
         [0064]    As previously described, the bio-active agent storage pads  16  are treated with additive to have a viscosity sufficient to retain the drug in the absence of an electrical current.  FIG. 9  depicts an alternate embodiment in which storage pads  16   a  of the patch  11   a  need not be treated in this manner as they are each encased in a thin membrane  64  which is itself impermeable to the drug in the absence of an electrical current and which becomes permeable in the presence of current. The membranes  64  may be thin films of hydrogel material treated with a viscosity adjusting additive in the manner which has been previously described. 
         [0065]    The above described embodiments of the invention have active drivers which rely on the iontophoresis process produced by subjecting the skin to an electrical current. Alternately the patch may make use of the process known as phonophoresis in which pulses of acoustic energy in the ultrasound range act to increase permeability of the outermost layer of the skin. Referring to  FIG. 10 , the driver electrodes of the previously described embodiments of the invention are replaced with small electrically operated ultrasound generators  66  which may be of known design. The ultrasound generators  66  are situated immediately above the hydrogel pads  16   b . The patch  11   b  of  FIG. 10  may otherwise be similar to the patch which has been previously described. 
         [0066]    While the invention has been described with reference to certain specific embodiments for purposes of example, many other variations and modifications are possible and it is not intended to limit the scope of the invention except as defined by the following claims.