Abstract:
A method of drug delivery utilizes a transdermal device that contains a phase change material and a first material such as a drug, a pharmaceutical, or a medicament mixed with or disposed near the phase change material. The phase change material is one that transitions from solid to liquid form when heated. A second material is disposed, suspended, or held in the solid form of the phase change material. The phase change material changes to a liquid state in response to heat and the second material that is disposed, suspended, or held in the phase change material is released and comes into contact with the first material. Advantageously, such second materials may include substances such as pharmaceuticals that boost or supplement the effect produced by a drug delivered transdermally by the device, or drug antagonists, or nicotine.

Description:
PRIORITY 
       [0001]    This application is a divisional of pending U.S. patent application Ser. No. 10/402,023, filed Mar. 27, 2003. 
     
    
     FIELD OF THE INVENTION 
       [0002]    This invention relates to methods of applying pharmacological agents, medicaments, or drugs, including analgesic agents, transdermally, that is, through the skin. More particularly, the invention relates to a method of using a transdermal device incorporating a phase change material that transitions to a liquid phase with the addition of heat. 
       BACKGROUND OF THE INVENTION 
       [0003]    The term “transdermal” refers to introduction or delivery of healing or treatment materials such as pharmacological agents, medicaments, or drugs into a human or animal body through the skin. Transdermal delivery of such materials provides many advantages. For example, such a mode of delivery is comfortable, convenient and noninvasive. With transdermal delivery, the variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences, such as gastrointestinal irritation and the like, are eliminated. Transdermal delivery also makes possible a high degree of control over blood concentrations of any particular agent, medicament, or drug. Over the years the types of materials that can be delivered with a transdermal patch have increased tremendously. For example, many analgesic drug compounds such as fentanyl, sufentanil, alfentanyl, remifentanil, and morphine are administered with a transdermal device. Transdermal devices include, without limitation, bandages, patches, plasters, and other equivalent apparatus. 
         [0004]    Another method of drug delivery through the skin is called iontophoresis. By applying a low-level electrical current to a similarly charged drug solution, iontophoresis repels the drug ions through the skin to the underlying tissue. In contrast to passive transdermal patch drug delivery, iontophoresis is an active method that allows the delivery of ionic drugs that are not effectively absorbed through the skin. 
         [0005]    A representative transdermal device, described in U.S. Pat. No. 4,286,592, is a bandage for delivering drugs to the skin. The bandage consists of a drug reservoir layer sandwiched between an impermeable backing layer and a permeable contact adhesive layer. A drug dispersed in a carrier is disposed in the drug reservoir layer. The drug diffuses through the contact adhesive layer at a rate that is determined by factors common to the drug, the carrier, and the contact adhesive material. 
         [0006]    Currently, transdermal patches are designed to deliver medication slowly through the skin over a long period of time, usually 48 to 72 hours. It is important to know that it may take considerable time, sometimes as long as 12 hours, before the device has reached its full treatment capacity. Depending upon the condition that is being treated, such long-term action can decrease the clinical effectiveness of the treatment. For example, in the treatment of chronic pain, one of the drawbacks with the slow delivery of medication by way of a transdermal patch is that many people experience intermittent flares of pain. Severe flares are called breakthrough pain. The characteristics of breakthrough pain, including the duration of a breakthrough episode, vary from person to person. Generally, breakthrough pain happens quickly, and varies in duration. It may occur unexpectedly and for no obvious reason, or it may be triggered by a specific activity, like coughing, moving, or going to the bathroom. 
         [0007]    Ideally, medication for breakthrough pain should be easily administered and work rapidly. Most people prefer oral medications (taken by mouth), but these are frequently slow to take effect. Further, orally-administered medications are known to cause difficulty in swallowing, nausea or other gastrointestinal problems. Pain medication may also be given by injection, either manually or through a patient-controlled analgesia device (PCA), or through an intravenous tube. But these modes are usually administered by trained personnel and may not be compatible with home care. Accordingly, administration by transdermal means is increasingly favored. 
         [0008]    The transdermal administration of some drugs is advantageously assisted by the addition of heat. For example, U.S. Pat. No. 6,261,595 describes a transdermal patch with an attached pocket for receiving a heating device. Distinct advantages enjoyed with the application of heat include a decrease in the time required for the transdermal patch to reach steady-state serum concentrations, and the ability to change the serum concentration of the drug being delivered for a short period of time in response to the changes in the magnitude of applied heat. Of course, increasing the rate at which medication is administered from a transdermal patch may mean more frequent changing of the patch. 
         [0009]    There is sometimes a social price paid for the convenience of administering medication by transdermal means. In this regard, transdermal devices are frequently stolen and then processed to extract narcotic drugs for unauthorized use. A drug may be easily obtained from a transdermal patch by boiling the patch in water. The diluted drug may then be concentrated, aggregated with a larger supply and ingested. One method to combat such abuse is disclosed in U.S. Pat. No. 5,149,538 in which an analgesic antagonist is added to a transdermal patch containing an analgesic drug. Initially, the antagonist is separated from the analgesic drug by a barrier that is soluble in water, alcohol or an organic solvent. In use, if the transdermal patch is immersed in water, the barrier dissolves, releasing the antagonist to mix with, and neutralize, the analgesic drug. One disadvantage of this design is the soluble barrier, which may release the antagonist prematurely if the patch gets wetted accidentally, or is disposed in a humid environment, such as when a user showers or bathes. 
         [0010]    It would be advantageous to elaborate or enhance the ability of a transdermal patch to alter the characteristics of drug delivery with the addition of heat, by, for example, sharply increasing or decreasing the rate of drug administration to a patient beyond that which is achievable presently. For example, treatment of breakthrough pain can be enhanced by a steeply accelerating rate of delivery in response to an increase in heat. 
         [0011]    It also would be desirable to defeat abuse of a transdermal patch in response to elevation of the temperature of the patch beyond a threshold that approaches the temperature of water heated to, or near, boiling. 
       SUMMARY OF INVENTION 
       [0012]    The present invention is directed to a transdermal device that contains a phase change material and another material. The transdermal device may also contain a drug, a pharmaceutical, or a medicament mixed with or disposed near the phase change material. The term “phase change material” denotes a substance that changes state in response to heat. In particular, a phase change material is one that transitions from solid to liquid form with the addition of heat. The other material is disposed, suspended, or held in the phase change material when the phase change material is in its solid form. When heat is applied to the transdermal device the phase change material changes to a liquid state and the material that is held or suspended in the phase change material is released. Advantageously, such materials may include substances such as pharmaceuticals, drug antagonists or agonists. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS  
         [0013]      FIG. 1  is a sectional view showing one embodiment of the invention; 
           [0014]      FIG. 2  is a sectional view showing an embodiment similar to  FIG. 1  using an alternate adhesive layer; 
           [0015]      FIG. 3  is a sectional view showing another embodiment of the invention; and 
           [0016]      FIGS. 4-6  are sectional views showing more embodiments of the reservoir and phase change material layer. 
       
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS  
       [0017]    In this description, a transdermal device is presented and discussed. For convenience, the device is referred to as a “transdermal patch” or simply as a “patch”; however, use of these terms is not intended, and should not be taken, to exclude from the scope of this invention other devices that are designed to be placed on the skin to enable the transdermal administration of a drug, a pharmaceutical, or a medicament. 
         [0018]      FIG. 1  illustrates one embodiment of this invention. A transdermal patch  10  is comprised of a backing layer  12 , a reservoir  14  containing a drug  15  and a phase change material preferably having a particulate form including particles  16 . The particles and the drug are mixed so that the particles are dispersed throughout the drug  15 . A material  18  is held or suspended in the phase change material particles  16  in their solid state. In this condition, the material  18  is immobilized and is substantially out of contact with the drug  15 . This is the state that is illustrated in  FIG. 1 . When the phase change material transitions from solid to liquid form, the material  18  emerges, or is released, from the phase change material at which time it becomes mobile and comes into contact with the drug  15 . This is not shown, but is inherent in, and readily conceivable from FIG.  1 . The patch  10  may also have an adhesive layer  20  connected to the backing layer  12  directly, or through intermediate structure not shown in  FIG. 1 . The adhesive layer  20  may also contain a permeable barrier material  21 . A release liner  22  may be provided on the adhesive layer  20 . The release liner layer  22  may be removed to expose the adhesive layer  20  before the transdermal patch  10  is applied to a patient&#39;s skin. In addition to the drug  15 , the phase change material particles  16 , and the material  18 , the reservoir  14  may also contain other materials, such as permeation enhancers, thickeners, solvents, stabilizers, excipients, carriers and the like. 
         [0019]    A similar embodiment is shown in  FIG. 2 . The difference between this embodiment and the one shown in  FIG. 1  is the adhesive layer. In this embodiment, an adhesive layer  23  is along a perimeter of the transdermal patch  10  leaving an opening  24  exposing the permeable barrier material  21 . When the release liner layer  22  is removed, both the adhesive layer  23  and the permeable barrier material  21  are in contact with the patient&#39;s skin. The rest of the description for the transdermal patch is the same as  FIG. 1 . 
         [0020]    The backing layer  12  prevents the materials in the reservoir layer  14  from being released or transported through the top or side surfaces of the patch  10 . This layer is preferably substantially impermeable with regard at least to the drug  15  used in the patch  10 , if not to all of the materials in the reservoir  14  layer. Thus, the backing layer  12  also prevents the phase change material particles  16  or the material  18  from being released or transported through the top or side surfaces when the patch is unheated and also when heat is applied. The materials of which the backing layer  12  can be made include polymers such as polyethylene, polypropylene, polyvinylchloride, polyurethane, polyesters such as poly (ethylene phthalate), coated flexible fabrics such as paper or cloth, and foils such as laminates of polymer films with metallic foils such as aluminum foil. The backing layer  12  can be produced or provided in any thickness appropriate to providing the desired barrier and support functions. For example, a suitable thickness may be in a range from 10 to 200 microns. The backing layer may also be painted or coated to enhance its absorption of IR radiation. 
         [0021]    The backing layer  12  and adhesive layer  20  must be able to position and retain the contents of the reservoir  14 . The adhesive layer  20  must also be permeable to the drug  15  and to the material  18  when the material  18  is released from the phase change material  16 , such that the drug  15  and the suspended material  18  diffuse osmotically through the adhesive layer  20 . The adhesive layer  20  may be made from acrylics, synthetic rubbers, silicone or other suitable materials. The backing layer  12  may extend over the sides of, and be contiguous with, the adhesive layer  20 , fully encapsulating the reservoir  14 , as shown in  FIG. 1 . 
         [0022]    The drug  15  may include one or more of many pharmacological agents or narcotic analgesics such as fentanyl, sufentanil, alfentanyl, remifentanil, morphine or other drugs known in the art suitable for use in a transdermal patch or any drugs that can be treated with naloxone or nalmefene. The drug  15  should be permeable through the adhesive layer  20 , the permeable barrier material  21 , and also permeable through the skin to which the transdermal patch is applied. The drug may be contained in a gel, cream, paste, slurry, or other suitable pharmaceutical carrier. 
         [0023]    The phase change material, preferably in the form of particles  16 , includes, holds, suspends, or contains the material  18 . The phase change material  16  also acts as a barrier between the drug  15  and the suspended material  18  and must be impermeable to both of them. At room temperature, the phase change material is in a solid phase. With the addition of heat, the phase change material becomes liquid, releasing the material  18  into the reservoir  14 . In one embodiment, the material  18  is mixed or blended into the phase change material creating the phase change material particles  16 . In another embodiment, the material  18  may be blended with the phase change material to form a phase change material layer  16   a , see  FIGS. 3-6 . In still another embodiment, the material  18  may be microencapsulated in the phase change material, rendering the particles  16  as microspheres. The microencapsulation process can be physical or chemical. The phase change material may be any material having the described characteristics and abilities. For example, high molecular weight alkanes (waxes) that melt at high temperatures, such as paraffin wax, may be utilized and are available with melting points or temperatures between 21.9° C. and 61.2° C. Other suitable materials include polylactones. 
         [0024]    It may be desirable that the phase change material comprise one material having one melting point or temperature, with one material suspended therein. In other, more functionally rich applications, there may be multiple phase change materials having one or more melting points or temperatures and/or one or more materials suspended therein. The melting points or temperatures of the phase change materials may be tailored to initiate release of the suspended material at a specific phase change material melting point or multiple melting points. 
         [0025]    The choice of material  18  depends on its intended purpose or role. One purpose of the material  18  may be to prevent unauthorized extraction and use of an analgesic drug from the patch  10 . In this role, the material  18  is an antagonist to the drug  15 , and those skilled in the art will appreciate that there must be an amount of the antagonist contained in the phase change material which is effective to counteract or neutralize the drug  15 . In this configuration, when the transdermal patch  10  with phase change material is placed in boiling water to extract the drug  15 , the heat would cause the phase change material to transition to a liquid, thereby releasing the antagonist material to counteract or neutralize the drug  15 . As an example, presume the drug  15  is morphine. Accordingly, the material  18  is or includes a compound selected from the group of compounds that are antagonistic to morphine, which includes naloxone hydrochloride (Narcan) and nalmefene (Revex). 
         [0026]    In another embodiment of this invention, the patch  10  may be used to assist a patient with a burst of an analgesic drug to treat breakthrough pain. Here, the material  18  may be identical to the drug  15  but in a more concentrated form than the drug  15 , or it may comprise another analgesic drug that is more potent or effective for breakthrough pain. In use, the transdermal patch  10  is placed on the patient that is experiencing pain with a normal dosage of analgesic drug  15 . When the patient experiences breakthrough pain heat is applied to the transdermal patch  10 . In this case, heat may be applied by means of any one of a plurality of heat producing means including, without limitation, a resistance heater, a heating pad, a radiator, a concentrated beam of energy, or any equivalent means. When the melting point or temperature of the phase change material is reached, the phase change material transitions to liquid form, and the material  18  is delivered transdermally by the patch  10 . 
         [0027]      FIG. 3  illustrates another embodiment of this invention. The patch  10   a  is comprised of a backing layer  12 , a reservoir  14   a  with a drug layer  15   a  and a phase change material layer  16   a  with a material  18  suspended or held in the phase change material while the phase change material is in its solid state, an adhesive layer  23  along a perimeter of the transdermal patch  10  and a release liner  22 . One difference between the patch  10  of  FIGS. 1 and 2  and the patch  10   a  of  FIG. 3  is that in transdermal patch  10 , the phase change material  16  is dispersed in the drug  15  while in transdermal patch  10   a , the phase change material  16   a  is maintained or disposed separately from, but adjacent to, the drug  15   a.    
         [0028]      FIG. 4  is a sectional view looking down and illustrates another embodiment of this invention similar to  FIG. 3 , the difference being in the reservoir and phase change material layers. The patch  10   b  has a circular shape with a reservoir  14   b  with a drug layer  15   b  surrounding a phase change material layer  16   b  with a material  18  suspended or held in the phase change material while the phase change material is in its solid state. 
         [0029]      FIG. 5  is a sectional view looking down and illustrates another embodiment of this invention similar to  FIG. 3 , the difference being in the reservoir and phase change material layers. The patch  10   c  has a circular shape, with a pie shape portion being a reservoir  14   c  with a drug layer  15   c  with a complementing pie shape portion being a phase change material layer  16   c  with a material  18  suspended or held in the phase change material while the phase change material is in its solid state. 
         [0030]      FIG. 6  is a sectional view looking down and illustrates another embodiment of this invention similar to  FIGS. 3 and 5 , the difference being in the reservoir and phase change material layers. The patch  10   d  has a circular shape, with a pie shape portion being a reservoir  14   d  with a drug layer  15   d  with a complementing pie shape portion being a phase change material layer  16   d  with a material  18  suspended or held in the phase change material while the phase change material is in its solid state. One difference between the patch  10   c  of  FIG. 5  and the patch  10   d  of  FIG. 6  is that near a center is another drug layer  26 . This additional layer may be the same drug, a different dosage of the drug, another drug or another phase change material layer with another material suspended or held in the phase change material. 
         [0031]    In still another embodiment, the reservoir of the patch may contain only the phase change material with a material suspended or held in the phase change material while the phase change material is in its solid state (i.e., no drug or drug layer in the reservoir). In this case, the patch may be used for specific applications or circumstances, such as the application of an analgesic drug. The analgesic drug would be mixed or suspended in the phase change material while the phase change material is in its solid state. For example, if a person needs a dose of pain reliever, a patch containing the phase change material with the suspended analgesic drug may be placed on the person&#39;s skin. Heat is then applied to the patch to liquefy the phase change material and release the suspended analgesic drug for transdermal introduction into the circulatory system of the patient. 
       EXAMPLE 1 
     Abuse Prevention 
       [0032]    In this example, a patch  10  contains an analgesic drug  15 , such as morphine, for relieving pain in a patient. The dosage of morphine is selected to provide sustained and continuous delivery of the drug through the skin and into the circulatory system. There are cases where the transdermal patches are stolen to extract the analgesic drug  15  from the transdermal patch  10 . One method of extracting the analgesic drug  15  is by boiling the transdermal patch  10  in water. To prevent this abuse, the transdermal patch  10  contains a morphine antagonist  18  suspended in a phase change material. When the transdermal patch  10  is heated in the boiling water, the phase change material changes to a liquid, releasing the antagonist  18 , which then mixes with the morphine to counteract the morphine&#39;s effect. The amount of antagonist  18  in the phase change material should be enough to counteract the morphine. This antagonist may  15  also be released from the transdermal patch  10  if the patient tries to accelerate the dosing of the analgesic drug  15  by heating the transdermal patch  10 , again preventing abuse. 
       EXAMPLE 2 
     Breakthrough Pain Relief 
       [0033]    In this example, a transdermal patch  10  contains an analgesic drug  15 , such as morphine, for relieving pain in a patient. The dosage of morphine is selected to provide sustained and continuous delivery of the drug through the skin and into the circulatory system. In some instances, an additional amount of analgesic drug is needed by the patient for pain or for breakthrough pain episodes. To relieve breakthrough pain episodes, the transdermal patch  10  contains an additional dose of pain medication  18  suspended in a phase change material. To release the medication  18 , heat is applied to the transdermal patch  10 , changing the phase change material to a liquid, releasing the medication  18 , which then migrates through the skin and into the circulatory system. In use, the release liner  22  is removed and the transdermal patch  10  is affixed to a patient&#39;s skin by the adhesive  20 . The analgesic drug  15  is then delivered through the skin into the circulatory system of the patient, relieving pain. When a breakthrough pain episode occurs, sufficient heat is applied to the transdermal patch  10 , for example by a resistance heater, or by a heating pad, to transition the phase change material from a solid to a liquid form, thereby releasing the additional dose of the medication  18 . The additional dose may be the same as the drug  15 , a more concentrated form of the drug  15 , or a different drug altogether. Once the additional dose of the medication  18  is released from the phase change material, it migrates through the skin and into the circulatory system. 
       EXAMPLE 3 
     Nicotine Relief 
       [0034]    In this example, a patch  10  is a transdermal nicotine patch that contains a nicotine compound  15  for relieving nicotine urges in a patient trying to quit a nicotine habit. The dosage of the nicotine is selected to provide sustained and continuous delivery of the nicotine through the skin and into the circulatory system. In some instances, an additional amount of nicotine is needed by the patient to overcome an increased urge or craving. To relieve such a yen, the transdermal nicotine patch  10  may contain an additional dose of nicotine  18  suspended in a phase change material. To get this additional dose  18 , heat is applied to the transdermal nicotine patch  10 , changing the phase change material to a liquid, releasing the additional dose of nicotine  18 , that is then delivered through the skin and into the circulatory system. In use, the release liner  22  is removed and the transdermal nicotine patch  10  is affixed to a patient&#39;s skin by the adhesive  20 . The nicotine drug  15  is then delivered through the skin into the circulatory system of the patient, relieving the urge or craving associated with nicotine addiction. When a increased urge or craving episode occurs, sufficient heat is applied to the transdermal nicotine patch  10 , for example with a heating pad, to change the phase change material from a solid to a liquid, releasing the additional dose of the nicotine  18 . The additional dose of the nicotine  18  may be the same as the nicotine drug  15 , a higher dose of the nicotine drug  15  and/or a different dose or drug completely. Once the additional dose of the nicotine  18  is released from the phase change material, it is delivered through the skin and into the circulatory system the same as the nicotine drug  15 . 
         [0035]    Many modifications and variations of the invention will be evident to those skilled in the art. It is understood that such variations may deviate from specific teachings of this description without departing from the essence of the invention.