Abstract:
A transdermal patch having a top region containing an antagonist followed by a bottom region containing an agonist, whereby the bottommost end of the bottom region is secured to the skin of the patient for delivering a prescribed dosage of agonist to the patient over a predetermined period of time, the antagonist will be released by migrating or moving from the top region through the bottom region to the patient to prevent overdose. Visual indicators are provided in the patch for changing color to separately indicate the operation of the patch, delivery of prescribed dosage, and/or overdosage.

Description:
RELATED APPLICATIONS 
       [0001]    This is a Continuation-in-Part Application of Ser. No. 11/482,206, filed on Jul. 7, 2006, for “Transdermal Patch.” This Application is also related to Ser. No. 11/333,602, filed on Jan. 17, 2006, for “Abuse Resistant Transdermal Drug Delivery,” the teachings of which are incorporated herein by reference to the extent they do not conflict herewith. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to drug delivery systems, and more particularly to a transdermal drug delivery system in the form of a transdermal patch. 
       BACKGROUND OF THE INVENTION 
       [0003]    Transdermal drug delivery systems have been developed for administration and delivery of pharmaceuticals including therapeutic agents at desired sustained levels by absorption through the skin. Such systems are typically embodied in the form of a transdermal patch, and offer advantages, which are not readily achievable by other modes of administration. The transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a sustained- or time-released dose of medication through the skin and into the bloodstream. Transdermal patches are used to deliver a wide variety of pharmaceuticals. 
         [0004]    One widely used type of transdermal patch is the “matrix” type, which generally includes a backing material, a drug reservoir, and an adhesive. The backing material is inert to the pharmaceutical or drug formulation contained in the patch, and prevents migration of the pharmaceutical. The drug reservoir is a matrix in which the pharmaceutical is dispersed and through which it migrates by diffusion or microporous flow. The matrix material may simultaneously act as an adhesive as well, in which case only an occlusive, removable covering or liner is required to complete the system. The transdermal patch provides a relatively simple dosage regimen, and it also provides a relatively slow and controlled route for release of the pharmaceutical into the systemic circulation. 
         [0005]    The transdermal patch possesses some limitations including determining when it is time to change the patch for a fresh one or when a possible overdosing is about to occur. Dosing of any medication by almost any route of administration, has largely been one of “approximation” and “trial and error.” This is especially so with respect to ambulatory patients and long term medication. For this reason, there is a constant need to ensure that the pharmaceutical administered by the transdermal patch is implemented safely and effectively. 
         [0006]    Accordingly, there is a need for a transdermal patch designed to deliver a pharmaceutical through the skin and into the circulatory system. There is a further need for a transdermal patch that continuously monitors the proper functioning of the patch as intended. There is a further need for a transdermal patch that is designed to recognize and indicate when a patch is not functioning properly, when the supply of pharmaceutical has been exhausted, or when an overdose is imminent in order to prevent or halt such overdose event. 
       SUMMARY OF THE INVENTION 
       [0007]    The present invention relates generally to a transdermal drug delivery system in the form of a transdermal patch. The transdermal patch of the present invention is adapted to deliver a therapeutic agent generally in the form of an agonist such as an opioid to the patient. In accordance with the present invention, the transdermal patch is adhesively applied to the skin of the patient. Perspiration containing moisture, ions, electrolytes, and other secretions, will diffuse into the patch in a controlled manner, while the therapeutic agent migrates from the patch into the patient through the skin at a predictable rate, according to corresponding gradient forces. The transdermal patch of the present invention includes safeguards to prevent tampering that may lead to abuse, and to prevent problems associated with imminent overdosing by the patient. Furthermore, the transdermal patch of the present invention includes visually perceptible indicating means to keep the patient informed about the operating status of the patch. 
         [0008]    Preferably, the transdermal patch of the present invention includes a therapeutic agent containing matrix composed of first and second regions. The first region includes the therapeutic agent in the form of an agonist dispersed therein, and the second region includes an antagonist to the therapeutic agent dispersed therein. The patient has increased tendency of experiencing an overdose episode when the transdermal patch remains on the patient&#39;s skin for an excessively prolonged period of time. In such an event, the transdermal patch of the present invention is configured to release a corresponding antagonist at the proper time to neutralize the effects of the agonist, thereby ensuring that the patient avoids life-threatening toxicity or adverse effects related to an overdose. Alternatively, an overdose can occur due to a patient&#39;s skin characteristics facilitating a relatively more rapid absorption of the agonist, whereby the present invention&#39;s subsequent delivery of the antagonist provides safeguards against the effects of the agonist, thereby protecting the patient from a dangerous overdose. 
         [0009]    More preferably, the transdermal patch of the present invention further includes a visual indicator located at the top end of the reservoir, wherein the visual indicator is adapted to undergo a visual change in the presence of the perspiration from the patient. Perspiration containing moisture and electrolytes can readily diffuse into the present patch, which at a pre-determined time based on the corresponding diffusion rate, reaches the indicator to effect the visual change. In this manner, the visual indicator can thereby be adapted to inform the patient about the operating status of the transdermal patch. 
         [0010]    The present invention includes the description of a visual indicator that can be designed, through its formulation, to effect a visible change at significant time points in the lifetime of the patch. Since the dynamics of the mechanism effecting the visual change or changes are associated with the release of the drug (i.e., agonist), the configuration of the present patch can be tailored to provide visual indicators representing the status of the drug release from the matrix. For example, the release of a sufficient drug quantity to exert a therapeutic action can be associated with one color change indicator, and the near exhaustion of drug reserves from the matrix or potential imminent overdose in the patient, can be associated with a second color change. This second feature, in particular, will serve as an indicator to the patient that the current patch should be removed and discarded. 
         [0011]    In one aspect of the present invention, there is provided a transdermal patch for administrating an agonist to a patient, where the transdermal patch comprises: 
         [0012]    a) an occlusive wall defining a reservoir with an open bottom end and an opposing top end; 
         [0013]    b) a matrix occupying the reservoir, the matrix comprising:
       a first region having the agonist suspended therein for release through the bottom end of the reservoir to the patient; and   a second region having an antagonist associated with the agonist suspended therein and being configured to release the antagonist at a predetermined time after the initial release of the agonist from the first region; and       
 
         [0016]    c) a permeable adhesive layer covering at least a portion of the bottom end of the reservoir, the adhesive layer being adapted for maintaining the matrix in communication with the skin of the patient. 
         [0017]    Preferably, the second region is configured to release the antagonist in the event of imminent overdose of the agonist released from the first region. 
         [0018]    In a further aspect of the present invention, there is provided a transdermal patch for administrating an agonist to a patient, where the transdermal patch comprises: 
         [0019]    a) an occlusive wall defining a reservoir with a bottom end and an opposing top end; 
         [0020]    b) a matrix permeable to perspiration from the patient occupying the reservoir, the matrix comprising:
       a first region having the agonist suspended therein for release through the bottom end of the reservoir to the patient; and   a second region located at the top end of the reservoir, the second region having an antagonist associated with the agonist suspended therein and being configured to release the antagonist at the onset of imminent overdose of the agonist by the patient;       
 
         [0023]    c) a permeable adhesive layer covering at least a portion of the bottom end of the reservoir, the adhesive layer being adapted for maintaining the matrix in communication with the skin of the patient; and 
         [0024]    d) at least one visual indicator located at the top end of the reservoir, the at least one visual indicator being adapted to undergo a visual change upon contact with the perspiration from the patient. 
         [0025]    In an even further aspect of the present invention, there is provided a transdermal patch for administrating an agonist to a patient, where the transdermal patch comprises: 
         [0026]    a) an occlusive wall defining a reservoir with a bottom end and an opposing top end; 
         [0027]    b) a matrix permeable to perspiration from the patient occupying the reservoir, the matrix comprising:
       a first region having the agonist suspended therein for release through the bottom end of the reservoir to the patient; and   a second region located at the top end of the reservoir, the second region having an antagonist associated with the agonist suspended therein and being configured to release the antagonist at the onset of imminent overdose of the agonist by the patient;       
 
         [0030]    c) a permeable adhesive layer covering at least a portion of said bottom end of the reservoir, the adhesive layer being adapted for maintaining the matrix in communication with the skin of the patient; and 
         [0031]    d) primary, first, second and third visual indicators each located at the top end of the reservoir, the primary, first, second and third visual indicators each being adapted to undergo a visual color change upon contact with the perspiration from the patient. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0032]    The following drawings, in which like items may have the same reference designations, are illustrative of embodiments of the present invention and are not intended to limit the invention as encompassed by the claims forming part of the application, wherein: 
           [0033]      FIG. 1  is cross-sectional view of a transdermal patch for one embodiment of the present invention; and 
           [0034]      FIG. 2  is a cross-sectional view of a transdermal patch for another embodiment of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0035]    The present invention is directed generally to a transdermal drug delivery system in the form of a transdermal patch. The transdermal patch of the present invention is adapted to deliver a therapeutic agent generally in the form of an agonist such as an opioid to the patient. In accordance with the present invention, the transdermal patch is adhesively applied to the skin of the patient. Perspiration containing moisture, ions, electrolytes, and other secretions, will diffuse into the patch in a controlled manner, while the therapeutic agent migrates from the patch into the patient through the skin, according to corresponding gradient forces. The transdermal patch of the present invention includes safeguards to prevent tampering that may lead to abuse, and to prevent problems related to overdosing by the patient. The transdermal patch of the present invention is specifically constructed to prevent illicit diversion of the opioid agonist for non-medical or non-therapeutic use. Furthermore, the transdermal patch of the present invention includes visually perceptible indicating means to keep the patient informed about the operating status of the patch. 
         [0036]    In accordance with the present invention, the transdermal patch includes a matrix having a first region with a therapeutic agent, preferably an agonist, and more preferably an opioid agonist, dispersed therein, and a second region with an antagonist capable of neutralizing the pharmacological effects of the therapeutic agent in the patient&#39;s body, dispersed therein. Each of the regions is formulated and positioned to release its respective contents under different timing circumstances  and  conditions during usage. This arrangement provides an effective mechanism to substantially minimize or prevent overdosing when the transdermal patch remains on the patient&#39;s skin for an excessively prolonged period of time. The latter condition may occur especially in elderly and ambulatory patients. This arrangement provides a further mechanism to prevent unacceptable tampering that may lead to abuse. The agonist and antagonist are retained in the present patch in a manner, which effectively restricts the user&#39;s ability to illicitly extract the agonist without contamination by the antagonist. Accordingly, this combination of illicit diversion prevention and overdose protection yields a drug delivery system with an enhanced safety profile and therapeutic effectiveness, while at least maintaining or preserving the efficacy of the administered agonist. 
         [0037]    In a general embodiment of the present invention, there is provided a transdermal patch for administrating an agonist to a patient. The transdermal patch includes an occlusive wall defining a reservoir with an open bottom end and an opposing top end, and a matrix occupying the reservoir. The matrix includes a first region having the agonist suspended therein for release through the bottom end of the reservoir, and a second region including an antagonist associated with the agonist suspended therein. The second region is configured to release the antagonist at a predetermined time after the initial release of the agonist from the first region of the matrix. The transdermal patch further includes a permeable adhesive layer covering at least a portion of the bottom end of the reservoir, and the adhesive layer being adapted for maintaining the matrix in communication with the skin of the patient. 
         [0038]    In accordance with the present invention, the consistencies and the migration characteristics of the matrix and its regions can be altered or modified to provided different delivery times and rates depending on the agonist and antagonist combination. In addition, the concentrations of the agonist and antagonist can be varied to delivery different doses, rates and potencies. 
         [0039]    Preferably, the transdermal patch of the present invention further includes a visual indicator located at the top end of the reservoir, wherein the visual indicator is adapted to undergo a visual change in the presence of the perspiration from the patient. Perspiration containing moisture and electrolytes can readily diffuse into the present patch, which at a pre-determined time based on the corresponding diffusion rate, reaches the indicator to effect the visual change. In this manner, the visual indicator can thereby be adapted to inform the patient about the operating status of the transdermal patch. 
         [0040]    The present invention includes the description of a visual indicator that can be designed, through its formulation, to effect a visible change at significant time points in the lifetime of the patch. Since the dynamics of the mechanism effecting the visual change or changes are associated with the release of the drug (i.e., agonist), the configuration of the present patch can be tailored to provide visual indicators representing the status of the drug release from the matrix. For example, the release of a sufficient drug quantity to exert a therapeutic action can be associated with one color change indicator, and the near exhaustion of drug reserves from the Matrix or potential imminent overdose in the patient, can be associated with a second color change. This second feature, in particular, will serve as an indicator to the patient that the current patch should be removed and discarded. 
         [0041]    Referring to  FIG. 1 , there is shown a cross-sectional view of a transdermal patch, designated generally by the reference  10  for one embodiment of the present invention. The patch  10  comprises a translucent occlusive wall, or backing layer  12  with a top face portion  26 . The wall  12  provides a reservoir  14  having an open bottom end  15  and an opposing top end  17 . The wall  12  can be composed of a medically approved plastic material including plastic composites formed by any suitable technique. Other suitable materials, generally of plastic polymeric composition, can be used for the wall  12 , and are known to those skilled in the art. The reservoir  14  includes a matrix  20 , which is formulated to absorb several times its own weight in water, and capable of suspending a drug for subsequent release. 
         [0042]    In a preferred embodiment of the present invention, the matrix  20  may be composed of guar, acacia, or xanthan gum, or a gelling agent or polymer such as carboxypolymethylene, hydroxyethylcellulose or polyacrylamide. In the case of guar gum, for example, the matrix  20  can be formulated to absorb from about 5 to 10 times its own weight. The matrix  20  includes a first region  20   a  and a second region  20   b  located at the top end  17  of the reservoir  14 . The first and second regions  20   a  and  20   b  can be composed of the same material or different materials exhibiting different diffusion rates and/or chemical properties. The sensitivity of the matrix material to the permeation of moisture is controlled by the choice of materials or formulation. The matrix  20  is designed to allow moisture, ions, electrolytes and the like, typically, present in perspiration, to diffuse or permeate in order to release the therapeutic agent for delivery to, and subsequent passage through the skin of the user as will be described hereinafter. 
         [0043]    The first region  20   a  of the matrix  20  comprises a therapeutic agent  21 , preferably an agonist, suspended therein. The agonist can be an opioid agonist useful for treating or preventing a disease, condition or symptoms thereof including alleviation of pain in a warm-blooded animal including a human. The second region  20   b  of the matrix  20  comprises an antagonist  23  to the therapeutic agent  21 , which is a pharmaceutical agent that inhibits or blocks the biologically active effects of the agonist  21  contained in the first region  20   a . The first and second matrix regions  20   a  and  20   b  are suitably formulated and positioned with one another to provide differential rates and times of delivery, while obstructing tampering for illicit diversion as will be further described hereinafter. 
         [0044]    The term “opioid agonist” is defined for purposes of the present invention to mean any opioid-based compound including opioid peptides, opium alkaloids, semi-synthetic and fully synthetic opioids, capable of binding to an opioid receptor and triggering a response in a cell, and include bimodally acting opioid agonists. The term “opioid agonist” can be used interchangeably with the term “opioid.” 
         [0045]    Suitable examples of opioid agonists  21  useful in the present invention, include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, combinations thereof, salts thereof, and the like. 
         [0046]    Preferred examples include hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, salts thereof, and combinations thereof. 
         [0047]    The term “opioid antagonist” is defined for purposes of the present invention to mean any opioid-based compound capable of binding to the same opioid receptor of a corresponding opioid agonist, and preventing or blocking the activation of the receptor. Suitable examples of opioid antagonist  23  useful in the present invention include naltrexone, nalmefene, cyclazacine, levallorphan and mixtures thereof. Preferably, the opioid antagonist is naloxone or naltrexone. 
         [0048]    Referring back to  FIG. 1 , the matrix  20  is maintained in contact with the patient&#39;s skin during administration via a permeable adhesive layer  16  in one embodiment of the present invention. The permeable adhesive layer  16  can be composed of a suitable pressure-sensitive adhesive material, and is located at the bottom end  15  of the reservoir  14  overlaying the bottom portion of the matrix  20 . The adhesive layer  16  enables the matrix  20  and the wall  12  to be secured to the skin of the patient, while permitting free passage of molecules (e.g., perspiration and drug) in between the patch  10  and the patient&#39;s skin. It will be understood that when the patch  10  is provided to the patient, the adhesive layer  16  is normally covered with a disposable protective layer  18  that the patient must remove prior to application. When attached to the skin of the patient, the wall  12  provides an occlusive covering, which enhances hydration of the skin area covered by the patch  10 , and diffusion of the perspiration into the matrix  20 . Hydration of the skin fosters release and absorption of the drug associated with the patch  20 . In another embodiment of the present invention, substantial portions of the adhesive layer  16  can be removed or eliminated to provide direct contact of the matrix  20  with the patient&#39;s skin for enhancing ease of delivery. 
         [0049]    In a preferred embodiment of the present invention, the patch  10  further includes a visual indicator  24  within the top end  17  of the reservoir  14 . The visual indicator  24  is adjacent to and operatively associated with the top face portion  26  of the wall  17 , and visible through the wall  12 . Preferably, the visual indicator  24  is a microencapsulated color indicator, wherein the color agent is encapsulated within a coating material. The coating material may be selected from arylate resins or methylmetacrylic acid co-polymers, or from formulations of hydrophilic ethylcellulose derivatives and hydrophobic methylcellulose derivatives. 
         [0050]    The indicator  24  is adapted to change color in response to the presence of water, moisture, electrolyte, ions, or other secretions present in perspiration, and can be produced from inorganic salts, which change color upon hydration such as, for example, anhydrous copper sulfate or cobalt chloride. In an alternative embodiment of the present invention, colorful dyes such as amaranth or mercurochrome can be microencapsulated to effect a color change when released. The microencapsulation can be formulated for selective timing of the activation of the color change in the presence of water, moisture, electrolyte, ion or other secretion. This enables the indicator  24  to be tailored to accurately reflect the status of drug release from the patch  10 , either by an appropriate choice of coating material or by manipulation of the components in the matrix  20 . This feature is advantageous in instances where the timing of events such as the onset, peak, decline and end of the therapeutic delivery of the drug is an important consideration in the proper use of the patch  10 . Indicator  24  can be provided by any indicator which reacts to changes in ion concentration about or near the physiological range, for example, erythrolimin, bromothyol blue, neutral red, phenol red, thymol blue, phenolthalein or other appropriate acid/base indicators. 
         [0051]    The material of the matrix regions  20   a  and  20   b  can be selected or formulated to control of the rate of drug release from the matrix  20 , as well as the diffusion rate of the perspiration through which the corresponding matrix regions  20   a  and  20   b  are activated for release of their associated pharmaceutical agent such as agonist  21  and antagonist  23 , respectively. As shown in  FIGS. 1 and 2 , the matrix regions  20   a  and  20   b  are positioned in direct abutting contact with one another in the absence of or without any barrier to fluid flow therebetween. Although the matrix regions  20   a  and  20   b  can be formulated to exhibit the same or different rates of release for the corresponding actives, the junction positioned between the matrix regions  20   a  and  20   b  allows unimpeded passage of fluid therebetween. 
         [0052]    The matrix regions  20   a  or  20   b  can be formulated to be relatively impervious to moisture, for example, one that is thicker or less permeable because of its physico-chemical properties, or one that contains a higher content of hydrophobic elements in its composition, will result in a more gradual drug release over a sustained time period and gradual diffusion of the patient&#39;s perspiration therethrough. In contrast, a matrix region  20   a  or  20   b  that is relatively permeable to water will rapidly release the drug over a relatively shorter time period. 
         [0053]    Once the patch  10  is properly applied to the patient&#39;s skin, the occlusive wall  12  entraps the patient&#39;s perspiration produced from the covered area of the skin. The perspiration permeates through the adhesive layer  16  into the first matrix region  20   a  in one embodiment, or directly thereinto in an alternative embodiment of the present invention. As the perspiration solvates the matrix material, the suspended agonist  21  is released and flows to the patient&#39;s skin for delivery. The diffusion rate of the perspiration through the first matrix region  20   a  is selected to provide adequate time for administering a full dose of agonist  21  to the patient. 
         [0054]    As the perspiration flows into the second matrix region  20   b , the antagonist  23  is released therefrom and begins to diffuse through the matrix  20  toward the patient&#39;s skin. Eventually, the perspiration reaches the visual indicator  24  and activates a visual change to notify the patient that the patch  10  has delivered the requisite dose amount and to remove the patch  10  to prevent an overdose. The patient is provided a short time to remove the patch  10  as the antagonist diffuses or migrates through the matrix  20 . If the patient does not remove the patch  10 , the antagonist  23  is subsequently delivered to the patient through the skin. In this manner, the antagonist  23  is administered in sequence after the administration of the agonist  21 . As a result, the administration of the antagonist  23  reverses the therapeutic effects of the agonist  21  previously administered, and prevents or avoids any complications that may arise from the imminent drug overdose. 
         [0055]    The second matrix region  20   b  also operates to deter tampering for the purpose of illicitly diverting the agonist  21  contained in the first matrix region  20   a . The second matrix region  20   b  is fragile and physically disruptable, and also soluble in the presence of any solvent that may be used by abusers to extract the agonist from the first matrix region  20   a . Accordingly, if an abuser attempts to mechanically extract the agonist  21  from the matrix  20 , the antagonist  23  in the second matrix region  20   b  will likewise be extracted and mixed with the agonist  21 . This will counter the expected “high” effect of the agonist  21 . Similarly, if the abuser attempts to use a solvent to extract the agonist  21  from the first matrix region  20   a , the second matrix region  20   b  will dissolve, releasing the antagonist  23  along with the extracted agonist  21 , thereby foiling the diversion attempt. 
         [0056]    The transdermal patch  10 , as described previously, includes the matrix  20  with two regions  20   a  and  20   b , each exhibiting individual diffusion characteristics. The matrix  20  urges the therapeutic agent (e.g., opioid agonist  21 ) to flow towards the patient&#39;s skin based on the concentration gradient. Similarly, the perspiration including moisture, ions, electrolytes and other secretions, produced by the patient, flow into the matrix  20 . The indicator  24  which can be sensitive to any of the perspiration components is positioned proximate the top end  17  of the reservoir  14 . The therapeutic agent, agonist  21  for example, flows to the patient&#39;s skin until such time that a permitted maximum dosage has been administered, at which point the antagonist  23  begins to flow toward the skin to prevent or minimize any potential for an overdose. The matrix  20  is designed so that the perspiration reaches the indicator  24  at about the same time the desired dose is administered to the patient. If the indicator  24  is disregarded, then the patch  10  begins to administer the antagonist  23 . The arrangement of the agonist  21  and antagonist  23  further limits the potential of extracting the agonist  21  without contamination by the antagonist  23 . 
         [0057]    The ratio of the agonist  21  to the opioid antagonist  23  in the transdermal patch  10  is such that the effect of the agonist  21  is at least partially blocked when the patch  10  is chewed, crushed or dissolved in a solvent and heated, and then administered orally, intranasally, parenterally or sublingually. In particular, the amount of opioid antagonist  23  administered is equipotent relative to the corresponding amount of the agonist  21  administered to at least suppress the pharmacological effects of the agonist  21  at a predetermined time after administration of the agonist  21 . 
         [0058]    Since the transdermal patch  10  of the present invention, when used as instructed, does not substantially release the antagonist  23  when the agonist  21  is adminstered properly in the allotted time, the amount of such antagonist  23  can be varied more widely than if the opioid antagonist  23  is available to be released into the gastrointestinal system upon oral administration. For safety reasons, the amount of the antagonist  23  present must not be harmful to humans even if fully released. The ratio of particular agonist  21  to antagonist  23  can be determined without undue experimentation by one skilled in the art. 
         [0059]    In certain embodiments of the present invention, the ratio of the agonist and the antagonist is about 1:1 to about 50:1 by weight, preferably about 1:1 to about 20:1 by weight. In certain preferred embodiments, the ratio is about 1:1 to about 10:1 by weight. In a preferred embodiment of the invention, the agonist comprises an opioid such as oxycodone or hydrocodone and is present in the amount of about 15 mg to 45 mg and the antagonist comprises naltrexone and is present in about 0.5 mg to 5 mg. 
         [0060]    Further examples illustrating the relative neutralizing potency of naltrexone against various commonly used opioid agonists are provided below in Table 1. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                   
                   
                 Naltrexone 
               
               
                   
                   
                   
                 neutralizing 
               
               
                   
                   
                 Opioid dose 
                 equivalent dose 
               
               
                   
                 Agonist 
                 (mg) 
                 (mg) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Morphine 
                 10.00 
                 12.00 
               
               
                   
                 Hydromorphone 
                 1.30 
                 1.56 
               
               
                   
                 Oxymorphone 
                 1.00 
                 1.20 
               
               
                   
                 Levorphanol 
                 2.00 
                 2.40 
               
               
                   
                 Methadone 
                 10.00 
                 12.00 
               
               
                   
                 Fentanyl 
                 0.10 
                 0.12 
               
               
                   
                 Buprenorphine 
                 0.40 
                 0.48 
               
               
                   
                   
               
             
          
         
       
     
         [0061]    Referring to  FIG. 2 , a transdermal patch designated generally by reference numeral  30  is shown for an alternative embodiment of the present invention. The embodiment of the patch  30  includes features similar to those described for the transdermal patch  10 . The transdermal patch  30  further includes visual indicators  32 ,  34 , and  36  each of which is operatively associated with a corresponding fluid permeable column or timing channels  33 ,  35 , and  37 , respectively. The visual indicators  32 ,  34 , and  36  are the same as described for the indicator  24  in the prior embodiment. The timing channels  33 ,  35 , and  37  are configured generally to provide a timing mechanism for the associated visual indicators  32 ,  34  and  36 , respectively. The timing mechanism is implemented by controlling the diffusion rate and distance in which the patient&#39;s perspiration travels along the length of the timing channel  33 ,  35 , or  37  from the patient&#39;s skin to the corresponding visual indicator  32 ,  34 , or  36 , respectively. 
         [0062]    The timing channels  33 ,  35 , and  37  are each composed of a fluid passing porous material such as, for example, an adsorbent material capable of conveying moisture, ions, electrolytes, and other secretions from the patient at a predetermined rate of diffusion. The adsorbent material can include, but is not limited to, silica, silica gel, alumina, cellulose, and combinations thereof. The diffusion rate of the adsorbent material can be readily adjusted by varying the porosity, pore size and hydrophobicity of the material as known in the art. The fluid passing porous material can also include materials similar to those used to construct the drug containing matrix  20 . 
         [0063]    Each of the timing channels  33 ,  35  or  37  exhibits different rates of diffusion based on the desired timing condition. In this manner, the timing channels  33 ,  35  and  37  are designed to provide a series of different color indicators to change color at time points corresponding, for example, to the time of onset of drug delivery, the time of peak delivery, the time at which delivery should be discontinued, time when risk of overdose is imminent and time when release of the antagonist begins to prevent the imminent overdose. The color changes that indicate the critical events in the life of the patch  30  can be devised very closely to reflect the true status of drug release from the matrix  20  as will be further described hereinafter. 
         [0064]    In one embodiment of the present invention, the visual indicator  32  and the timing channel  33  can be designated to indicate that the patch  30  has been properly applied to the patient&#39;s skin and is operating. The adsorbent material used in the timing channel  33  can be formulated to exhibit a high diffusion rate as compared to the matrix  20 . Accordingly, the activation of the indicator  32  denotes that the adhesive layer  18  is properly bonded to the patient&#39;s skin and that the corresponding delivery of the agonist  21  has been initiated. 
         [0065]    The visual indicator  34  and the timing channel  35  can be designated to indicate that the patch  30  is in peak delivery mode of the agonist  21  to the patient. The adsorbent material used in the timing channel  35  can be formulated to exhibit a medium diffusion rate as compared to the matrix  20 . Accordingly, the activation of the indicator  34  denotes the peak delivery of the agonist to the patient. 
         [0066]    The visual indicator  36  and the timing channel  35  can be designated to indicate that the patch  30  has delivered the desired dose of the agonist  21  to the patient. The adsorbent material used in the timing channel  37  can be formulated to exhibit a slow diffusion rate as compared to the matrix  20 . Accordingly, the activation of the indicator  36  denotes the threshold at which the patient is in danger of receiving an overdose of the agonist  21 , and that delivery of the antagonist  23  is initiated. 
         [0067]    As to the visual indicator  24 , the visual change indicates that successful drug delivery has taken place. The indicator  24  ensures compliance to dosing instructions, since the visual change will not be achieved without continued contact with the skin. Observation, therefore, that a visual change did not occur at the expected time in any of the indicators  24 ,  32 ,  34 ,  36 , respectively, can prompt further investigation. Therefore, the dermal patch  10  or  30  in accordance with this invention preferably includes at least one indicator, designed to change visually when the drug reserves within the matrix  20  is almost exhausted. The indicator  24  is intended to prompt the user to remove and discard the old patch  10  to avoid imminent overdose of agonist  21 , and initiation of the delivery of the antagonist will begin soon after. 
         [0068]    The above-described patches  10  and  30  can be used in conjunction with preparatory skin cleanser, containing, for example, alcohol and a weakly buffered acidic or basic solution. The solvent serves to remove surface grease to eliminate a barrier to absorption at the skin, and a buffered acidic or basic solution can be selected according to the physical or chemical properties of the particular drug to be administered, and to maximize drug stability, while enhancing transdermal penetration. 
         [0069]    The forgoing discussion discloses and describes merely exemplary embodiments of the present invention. One skilled in the art will readily recognize from such discussion, and from the accompanying claims, that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.