CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.

62/732,952, filed September 18, 2018, to U.S. Provisional Application No. 62/580,884, filed November 2, 2017, to U.S. Provisional Application No. 62/616,340, filed January 11, 2018, and to U.S. Provisional Application No. 62/580,895, filed November 2, 2017, the entireties of which are incorporated by reference herein.

[0002] This application may also be related to International Application No.

PCT/US 17/54093, filed September 28, 2017, the entirety of which is incorporated by reference herein.

INCORPORATION BY REFERENCE

[0003] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

BACKGROUND

[0004] Transdermal drug delivery patches are typically made by dissolving the drug in a pressure-sensitive adhesive. This adhesive layer is sandwiched between a backing and a release liner. The user then removes the release liner and applies the patch on the skin for the prescribed duration of wear. In typical patches, the dissolved drug in the drug formulation may undergo degradation (e.g. oxidation) and/or separate from the pressure-sensitive adhesive during storage or wear (e.g., precipitate out of adhesive due to crystallization). Further, the physical properties of the adhesive (e.g., adhesion) may change over time during product storage prior to use.

[0005] Moreover, transdermal drug delivery is not currently a safe method of delivery for certain medications, such as opioids. Opioid-containing products are prone to abuse, and current state-of-the-art lacks an abuse-deterrent transdermal drug delivery system containing opioids. Currently, the transdermal patches available in the market can be easily manipulated to extract the opioid by means of a suitable household solvent or can be abused/misused by administering the formulation in an unintended way.

[0006] Accordingly, a transdermal drug delivery system that solves some or all of these problems is desired. SUMMARY OF THE DISCLOSURE

[0007] Described herein is a transdermal drug delivery system that includes a chemical means of abuse-deterrence. In some embodiments, the transdermal drug delivery system can be used for opioid delivery. In such systems, the chemical means may be, for example, a modified opioid antagonist such as an opioid antagonist encapsulated in polymer or a prodrug form of antagonist. The transdermal drug delivery systems described herein can also be applied to other compounds that are abused, such as prescription stimulants, benzodiazepines, etc., in which there exists an antagonist that can be co-formulated.

[0008] In some embodiments, the drug delivery system can include a reservoir to hold solvent, a porous membrane to hold a dry formulation of agonist and antagonist, and a chamber to mix the solvent and agonist/antagonist.

[0009] In some embodiments, the drug delivery system can include a gel formulation having agonist and antagonist dispersed therein.

[0010] In some embodiments, the drug delivery system can include a gel formulation having opioid agonist dissolved therein.

[0011] In some embodiments, the drug delivery system can include a multilayer patch having agonist and antagonist dissolved and/or dispersed in separate layers.

[0012] In some embodiments, the drug delivery system can include smart abuse-deterrent systems that may communicate information regarding use and patient compliance to a device, such as smartphone, with which the device is paired. This information can also be used to provide psychosocial behavioral support to aid in the treatment of chronic pain, anxiety, or addiction/dependence, depending on the indication.

[0013] In some embodiments, the drug delivery system can also include the ability to track the dosage forms during supply chain and prevent diversion.

[0014] In general, in one embodiment, a transdermal drug delivery device includes a reservoir, a transdermal drug delivery membrane, and a fluid pathway between the reservoir and the transdermal drug delivery membrane. The reservoir includes a gel formulation having an opioid agonist and opioid antagonist. The transdermal drug delivery membrane is configured to contact skin of a patient to provide the opioid agonist to the skin.

[0015] This and other embodiments can include one or more of the following features. The opioid antagonist can include antagonist encapsulated in polymer particles. The polymer particles can be nano-particles or micro-particles. The polymer particles can include

hydroxypropyl methyl cellulose phthalate. The polymer particles can include cellulose acetate phthalate. The polymer particles can include cyclodextrin, poly-ethylene glycol, poly lactic acid, poly glycolic acid, poly caprolactone, poly(lactic-co-glycolic acid), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate succinate, methacrylic acid-methyl methacrylate copolymer, amino methacrylate copolymer, or gelatin. The gel formulation can include a hydro-alcoholic gel. The gel formulation can include hydroxypropyl cellulose. The gel formulation can include polyvinyl pyrolidone. The gel formulation can include propylene glycol, lauryl alcohol, levulinic acid, or propylene glycol monolaurate. The opioid agonist can include fentanyl, morphine, oxycodone, hydromorphone, tramadol, oxymorphone, alfentanil, sufentanil, methadone, buprenorphine, or hydrocodone. The opioid antagonist can include Naloxone, Naltrexone, Nalmefene, or Samidorphan. The transdermal drug delivery device can further include a controller configured to control delivery of the opioid agonist from the reservoir to the transdermal drug delivery membrane. The opioid agonist can be dissolved in the gel formulation. The opioid antagonist can be dispersed within the gel formulation. The opioid agonist can include 1-10% w/w of the gel formulation. The opioid agonist can include 2-6% w/w of the gel formulation. The transdermal drug delivery device can further include a biometric sensor configured to detect a patient biometric parameter. The transdermal drug delivery device can further include a controller configured to activate delivery of the opioid agonist from the reservoir to the transdermal drug delivery membrane based upon a trigger from the sensor. The biometric sensor can include a temperature sensor, a gait sensor, a motion sensor, a pulse oximeter, a fingerprint scanner, a heart rate sensor, an ECG sensor, a skin sensor, a blood flow sensor, an impedance sensor, a retina scanner, a voice recognition sensor, or a facial recognition sensor. The transdermal drug delivery device can further include a piston configured to deliver the gel formulation from the reservoir to the transdermal drug delivery membrane. The transdermal drug delivery device can further include a spring configured to activate the piston. The transdermal drug delivery device can further include a bolus chamber having a smaller volume than the reservoir. The transdermal drug delivery device can further include a valve having a first position in which the gel formulation flows from the reservoir to the bolus chamber and a second position in which gel formulation flows from the bolus chamber to the transdermal membrane. The reservoir can be a sealed reservoir. The transdermal drug delivery device can further include a breaking element configured to break the sealed reservoir to deliver the gel formulation to the transdermal drug membrane.

[0016] In general, in one embodiment, a transdermal drug delivery device includes a reservoir, a transdermal drug delivery membrane, and a fluid pathway between the reservoir and the transdermal drug delivery membrane. The reservoir includes a gel formulation including poly(lactic-co-glycolic acid) and an opioid agonist. The transdermal drug delivery membrane is configured to contact skin of a patient to provide the opioid agonist to the skin. [0017] This and other embodiments can include one or more of the following features. The gel formulation can further include propylene glycol. The gel formulation can further include n- methylpyrrolidone. The opioid agonist can include 1-10% w/w of the gel formulation. The opioid agonist can include 2-6% w/w of the gel formulation. The drug delivery device may not include an opioid antagonist. The opioid agonist can include fentanyl, morphine, oxycodone, hydromorphone, tramadol, oxymorphone, alfentanil, sufentanil, methadone, buprenorphine, or hydrocodone. The transdermal drug delivery device can further include a controller configured to control delivery of the opioid agonist from the reservoir to the transdermal drug delivery membrane. The opioid agonist can be dissolved in the gel formulation. The transdermal drug delivery device can further include a biometric sensor configured to detect a patient biometric parameter. The transdermal drug delivery device can further include a controller configured to activate delivery of the opioid agonist from the reservoir to the transdermal drug delivery membrane based upon a trigger from the sensor. The biometric sensor can include a temperature sensor, a gait sensor, a motion sensor, a pulse oximeter, a fingerprint scanner, a heart rate sensor, an ECG sensor, a skin sensor, a blood flow sensor, an impedance sensor, a retina scanner, a voice recognition sensor, or a facial recognition sensor. The transdermal drug delivery device can further include a piston configured to deliver the gel formulation from the reservoir to the transdermal drug delivery membrane. The transdermal drug delivery device can further include a spring configured to activate the piston. The transdermal drug delivery device can further include a bolus chamber having a smaller volume than the reservoir. The transdermal drug delivery device can further include a valve having a first position in which the gel formulation flows from the reservoir to the bolus chamber and a second position in which gel formulation flows from the bolus chamber to the transdermal membrane. The gel formulation can further include dimethylsulfoxide or polyethylene glycol. The reservoir can be a sealed reservoir. The transdermal drug delivery device can further include a breaking element configured to break the sealed reservoir to deliver the gel formulation to the transdermal drug membrane.

[0018] In general, in one embodiment, a transdermal drug delivery device includes a reservoir including an opioid agonist therein, a transdermal drug delivery membrane configured to contact skin of a patient to provide the opioid agonist to the skin, a biometric sensor configured to detect a patient biometric parameter, and a controller configured to activate delivery of the opioid agonist from the reservoir to the transdermal drug delivery membrane based upon a trigger from the sensor.

[0019] This and other embodiments can include one or more of the following features. The sensor can be a motion sensor. The sensor can be a temperature sensor. The sensor can be a gait sensor, a pulse oximeter, a fingerprint scanner, a heart rate sensor, an ECG sensor, a skin sensor, a blood flow sensor, an impedance sensor, a retina scanner, a voice recognition sensor, or a facial recognition sensor. The opioid agonist can include fentanyl, morphine, oxycodone,

hydromorphone, tramadol, oxymorphone, alfentanil, sufentanil, methadone, buprenorphine, or hydrocodone. The transdermal drug delivery device can further include a piston configured to deliver the gel formulation from the reservoir to the transdermal drug delivery membrane. The transdermal drug delivery device can further include a spring configured to activate the piston. The transdermal drug delivery device can include a bolus chamber having a smaller volume than the reservoir. The transdermal drug delivery device can further include a valve having a first position in which the gel formulation flows from the reservoir to the bolus chamber and a second position in which gel formulation flows from the bolus chamber to the transdermal membrane. The reservoir can be a sealed reservoir. The transdermal drug delivery device can further include a breaking element configured to break the sealed reservoir to deliver the opioid agonist to the transdermal drug membrane when activated by the controller in response to the trigger from the sensor.

[0020] In general, in one embodiment, a transdermal drug delivery device includes a first layer including an opioid antagonist therein and a second layer including an opioid agonist, an acrylate adhesive, and a silicone adhesive.

[0021] This and other embodiments can include one or more of the following features. The second layer can further include dimethylisosorbide, levulinic acid, or glycerol monooleate. The opioid agonist can include fentanyl, morphine, oxycodone, hydromorphone, tramadol, oxymorphone, alfentanil, sufentanil, methadone, buprenorphine, or hydrocodone. The opioid agonist can include 3-15% w/w of the second layer. The opioid agonist can include 5-12% w/w of the second layer. The opioid antagonist can include Naloxone, Naltrexone, Nalmefene, or Samidorphan. The first layer can further include a silicone adhesive or an acrylic adhesive. The opioid antagonist can include 1-5% w/w of the first layer. The opioid antagonist can include 2- 3% w/w of the first layer. The transdermal drug delivery device can further include a membrane separating the first layer from the second layer. The transdermal drug delivery device can further include a biometric sensor configured to detect a patient biometric parameter. The biometric sensor can include a temperature sensor, a motion sensor, a gait sensor, a pulse oximeter, a fingerprint scanner, a heart rate sensor, an ECG sensor, a skin sensor, a blood flow sensor, an impedance sensor, a retina scanner, a voice recognition sensor, or a facial recognition sensor. The second layer can be a transdermal layer configured to contact skin of a patient to provide the opioid agonist to the skin.

[0022] In general, in one embodiment, a method of delivering an opioid agonist to the patient includes: (1) attaching a transdermal membrane of a transdermal delivery device to skin of a patient; (2) moving a gel formulation comprising an opioid agonist and opioid antagonist from a reservoir of the transdermal delivery device to the transdermal membrane; and (3) passing the opioid agonist and not the opioid antagonist from the transdermal membrane across the skin.

[0023] This and other embodiments can include one or more of the following features. The opioid antagonist can include antagonist encapsulated in polymer particles. The polymer particles can be nano-particles or micro-particles. The polymer particles can include

hydroxypropyl methyl cellulose phthalate. The polymer particles can include cellulose acetate phthalate. The polymer particles can include cyclodextrin, poly-ethylene glycol, poly lactic acid, poly glycolic acid, poly caprolactone, poly(lactic-co-glycolic acid), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate succinate, or gelatin. The gel formulation can include a hydro-alcoholic gel. The gel formulation can include hydroxypropyl cellulose. The gel formulation can include polyvinyl pyrolidone. The gel formulation can include propylene glycol, lauryl alcohol, levulinic acid, or propylene glycol monolaurate.

[0024] In general, in one embodiment, a method of delivering an opioid agonist to the patient includes: (1) attaching a transdermal membrane of a transdermal delivery device to skin of a patient; (2) moving a gel formulation comprising poly(lactic-co-glycolic acid) and an opioid agonist from a reservoir of the transdermal delivery device to the transdermal membrane; and (3) passing the gel formulation to the skin for transdermal passage of agonist into a bloodstream of the patient. The poly(lactic-co-glycolic acid) is configured to solidify or clump together if the gel formulation is exposed to saliva, other body fluid, or solvent in case of abuse.

[0025] This and other embodiments can include one or more of the following features. The gel formulation can further include propylene glycol. The gel formulation can further include n- methylpyrrolidone. The drug delivery device may not include an opioid antagonist. The gel formulation can further include dimethylsulfoxide or polyethylene glycol.

[0026] In general, in one embodiment, a method of delivering an opioid agonist to the patient includes: (1) attaching a second layer of a transdermal delivery device to skin of a patient, the second layer including an opioid agonist, an acrylate adhesive, and a silicone adhesive, wherein the transdermal drug delivery device further includes a first layer including an opioid antagonist therein; and (2) passing the opioid agonist and not the opioid antagonist from the transdermal drug delivery device to the skin.

[0027] This and other embodiments can include one or more of the following features. The second layer can further include dimethylisosorbide, levulinic acid, or glycerol monooleate. The opioid agonist can include fentanyl, morphine, oxycodone, hydromorphone, tramadol, oxymorphone, alfentanil, sufentanil, methadone, buprenorphine, or hydrocodone. The opioid agonist can include 3-15% w/w of the second layer. The opioid agonist can include 5-12% w/w of the second layer. The first layer can further include a silicone adhesive or an acrylic adhesive. The opioid antagonist can include 1-5% w/w of the first layer. The opioid antagonist can include 2-3% w/w of the first layer. The drug delivery device can further include a membrane separating the first layer from the second layer. The opioid agonist can include fentanyl, morphine, oxycodone, hydromorphone, tramadol, oxymorphone, alfentanil, sufentanil, methadone, buprenorphine, or hydrocodone. The opioid agonist can be dissolved in the gel formulation or adhesive. The method can further include detecting a patient biometric parameter with a biometric sensor of the transdermal drug delivery device. The method can further include activating delivery of the opioid agonist based upon a trigger from the biometric sensor. The biometric sensor can include a temperature sensor, a motion sensor, a pulse oximeter, a fingerprint scanner, a heart rate sensor, a gait sensor, an ECG sensor, a skin sensor, a blood flow sensor, an impedance sensor, a retina scanner, a voice recognition sensor, or a facial recognition sensor. The opioid antagonist can include Naloxone, Naltrexone, Nalmefene, or Samidorphan. The opioid antagonist can be dispersed within the gel formulation or adhesive. The opioid agonist can include 1-10% w/w of the gel formulation. The opioid agonist can include 2-6% w/w of the gel formulation. The method can further include moving a piston of the transdermal drug delivery device to move the gel formulation from the reservoir to the transdermal drug delivery membrane. Moving the piston can include moving the piston with a spring. The transdermal drug delivery device can further include a bolus chamber having a smaller volume than the reservoir, the method further comprising moving the gel formulation from the reservoir to the bolus chamber prior to moving the gel formulation containing the opioid agonist to the skin. The reservoir can be a sealed reservoir. The method can further include breaking the sealed reservoir with a breaking element to deliver the gel formulation to the transdermal drug membrane.

BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative

embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0029] FIG. 1 shows a device with a dry powder formulation and solvent during storage.

[0030] FIG. 2 shows a device with a dry powder formulation and solvent after activation.

[0031] FIG. 3 shows a device with a gel formulation. [0032] FIG. 4 is a graph showing the agonist flux across the skin for various device designs.

[0033] FIGS. 5A-5B show an exemplary two-part transdermal drug delivery system.

[0034] FIG. 6 shows a polymer matrix transdermal drug delivery system.

[0035] FIG. 7 shows a polymer matrix transdermal drug delivery system with a rate- controlling membrane.

[0036] FIG. 8 shows a reservoir transdermal drug delivery system.

[0037] FIG. 9 shows a transdermal drug delivery system with separated layers of antagonist and agonist.

[0038] FIG. 10 shows % naltrexone(NTX) Released relative to time for a variety of HP55 Nanoparticles.

[0039] FIG. 11 shows % NTX released relative to time for a variety of CAP Nanoparticles.

[0040] FIG. 12 shows % NTX released at specific times for HP55 Nanoparticles in a number of different solvents.

[0041] FIG. 13 shows % NTX released at specific times for CAP Nanoparticles in a number if different solvents.

[0042] FIG. 14 shows a transdermal drug delivery system with layers of antagonist and agonist separated by a membrane.

[0043] FIG. 15a shows an exemplary smart phone user interface.

[0044] FIG. 15b shows an exemplary desktop user interface.

[0045] FIG. 16 shows an exemplary method of using a transdermal drug delivery system with a sensor.

[0046] FIG. 17 shows another exemplary method of using a transdermal drug delivery system with a sensor.

[0047] FIG. 18 is a graph showing the agonist flux across the skin for exemplary gel formulations.

[0048] FIG. 19 is a graph showing the agonist flux across the skin for additional gel formulations.

[0049] FIG. 20 is a graph showing the amount of opioid agonist released over time in simulated saliva.

[0050] FIG. 21 is a graph showing the amount of opioid agonist released over time in solvent.

[0051] FIGS. 22A-22B show a PLGA-based gel clumping upon interaction with solvent.

[0052] FIG. 23 is a graph showing the agonist flux across the skin for exemplary patch formulations. [0053] FIG. 24 is a graph showing the antagonist flux across the skin for exemplary patch designs.

[0054] FIG. 25 is a graph showing the antagonist flux across the skin for exemplary patch designs where the antagonist is incorporated into nano-particles.

DETAILED DESCRIPTION

[0055] Described herein is a transdermal drug delivery system for delivering medications, such as opioids. The delivery system includes a smart abuse-deterrent transdermal drug delivery system containing opioid agonist and antagonist. The system is configured to selectively deliver opioid agonist transdermally while minimizing or preventing the delivery of opioid antagonist when the delivery system is used as intended/prescribed. If attempts to abuse or manipulate the transdermal drug delivery system are made, the opioid antagonist can be released and antagonize the effect of opioid agonist, eliminating or minimizing potential euphoric effects.

[0056] Figures 1-2 show an exemplary transdermal drug delivery device 100 that includes a dry powder formulation of mixed opioid agonist and antagonist during storage (Figure 1) that is dissolved by a solvent upon actuation (Figure 2). Thus, as shown in Figure 1, the transdermal drug delivery device 100 during storage includes a solvent reservoir 101 with a carrier solvent therein. A porous membrane scaffold 103 can include the dry powder formulation 110 of opioid agonist and modified opioid antagonist. A fluid path 105 can connect the solvent reservoir 101 and the porous membrane 103. The transdermal delivery device 100 can further include a mixing chamber 107 for mixing the solvent and dry powder formulation upon activation (the mixing chamber 107 can be empty during storage as shown in Figure 1). Further, the delivery device can include a delivery membrane 109, such as a rate controlling membrane with adhesive for attachment to the skin. A release liner 111 can further be included when system 100 is not in use (e.g. during storage). The dry formulation of opioid agonist and modified opioid antagonist can be a loose powder formulation or a compacted film/wafer. Further, in some embodiments, the dry formulation can be stored in the fluid path 105 connecting the solvent reservoir to the mixing chamber rather than within the porous membrane 103.

[0057] As shown in Figure 2, upon attachment to the skin 114 and actuation of the transdermal drug delivery device 100, the carrier solvent can be dispensed from the solvent reservoir 101 and travel towards the porous membrane 103 storing the dry powder formulation 110 of opioid agonist and modified opioid antagonist. The carrier solvent can dissolve the opioid agonist upon contacting the dry powder (and may dissolve or suspend the modified opioid antagonist), and the mixed solvent/antagonist/agonist solution 112 can fill the mixing chamber 107. The solution 112 including the opioid agonist (and optionally the modified opioid antagonist) can then be moved from the mixing chamber 107 such that it spreads on the transdermal delivery membrane 109, thus exposing the skin tissue in contact with the

transdermal delivery membrane 109 to the dissolved opioid agonist and optionally, to modified opioid antagonist.

[0058] Because the device 100 includes separate solvent and agonist/antagonist, chemical degradation of the agonist and/or modified antagonist in solution during storage can be prevented. Similarly, physical separation/sedimentation of modified antagonist under gravity during storage (which could enable an abuser to gain access to a formulation containing opioid agonist with minimal modified opioid antagonist) can be avoided.

[0059] In some embodiments, the device 100 can include more than one solvent reservoir. The plurality of fluid reservoirs can include the same type of solvent or different types of solvents. In some embodiments, the device 100 can include more than one chamber for dry powder formulation. The plurality of chambers can include the same type of dry powder formulation or different types of dry powder formulation. Similarly, the device 100 can include more than one fluid path connecting the fluid reservoir(s) to the chamber(s).

[0060] Referring to Figure 3, exemplary device 300 includes a drug reservoir 331 and a transdermal delivery membrane 309 that is configured to be placed on the skin 314. The reservoir 331 holds a gel formulation 333, which includes the opioid agonist dissolved and optionally an antagonist (or modified antagonist) dispersed therein. For example, the antagonist can be encapsulated in nano-particles or micro-particles. In some embodiments, the reservoir 331 can be made of polypropylene OR glass-filled polypropylene. The gel formulation can, for example, increase the flux of opioid across the skin. In some embodiments, the higher flux of gel formulations across the skin may be the result of having the salt form or opioid agonist (which is less lipophilic and enables shorter lag time relative to opioid base) and the higher thermodynamic activity of gel.

[0061] In some embodiments, the gel formulation can be a hydro-alcoholic gel. For example, the gel formulation can include carbopol, polyvinylpyrrolidone (PVP), or

hydroxylpropyl cellulose (HPC). In addition, the gel formulation can include propylene glycol (PG), lauryl alcohol (LAL), levulinic acid (LEV), or propylene glycol monolaurate (PGML). An opioid agonist, such as the salt form of buprenorphine, can be present in the gel formulation at 1- 10% w/w, such as 2-6% w/w. Further, an opioid antagonist can be dispersed within the hydro- alcoholic gel. Exemplary hydro-alcoholic gel formulations are shown in Figures 4 and 18. As shown in Figures 4 and 18, dissolved opioid agonist in a hydro-alcoholic gel formulation can advantageously result in higher flux of agonist across the skin relative to patch designs and/or available commercial products. For example, referring to Figure 4, gel formulations A and B can have 3-7 times higher flux across the skin relative to Butrans® (or a patch that includes an acrylic adhesive, buprenorphine, levulinic acid, and oleyl oleate). Similarly, gel formulations A and B can have 2-3 times lower drug content (w/w) relative to Butrans®. As another example, referring to Figure 18, formulations C and D can have a 6-9 times higher flux across the skin relative to Butrans®, and can have a 3-4 times lower drug content relative to Butrans®. In some embodiments, the drug delivery area of a hydro-alcoholic gel formulation, such as formulations A, B, C, or D, can be less than 25cm ² , such as less than 20cm ² , such as less than 15 cm ² , such as approximately 10 cm ² (which is lower than the 25cm ² of Butrans®).

[0062] In some embodiments, the gel formulation can be a poly(lactic-co-glycolic acid) (PLGA) - based gel. An opioid agonist, such as the salt form of buprenorphine, can be present in the gel formulation at 1-10%, such as 2-6% w/v. In some embodiments, the gel formulation can include PLGA and propylene glycol (PG) or n-methylpyrrolidone. In other embodiments, the PLGA-based formulation can include dimethylsulfoxide or polyethylene glycol. Exemplary PLGA-based gel formulations are shown in Figure 19. As shown in Figure 19, dissolved opioid agonist in a PLGA-based hydrogel formulation can advantageously result in higher flux of agonist across the skin relative to available products. For example, gel formulations E and F can have a 2-3 times higher flux relative to Butrans®. Similarly, gel formulations E and F can have 2-3 times lower drug content (w/w) relative to Butrans®. In some embodiments, the drug delivery area of a PLGA-based gel formulation, such as formulations E and F can be less than 25cm ² , such as less than 20cm ² , such as less than 15 cm ² , such as approximately 10 cm ² (which is lower than the 25cm ² of Butrans®).

[0063] No antagonist need to be included in the PLGA-based gel. That is, the PLGA-based gel formulations can solidify or clump together upon exposure to solvents such as water, saliva, blood, or other body fluids. This solidification can trap the opioid and prevent its immediate release, thereby providing slow-release of the opioid in the bloodstream and/or saliva, which can help prevent abuse. Such clumping is shown in Figures 22A-22B. There, a PLGA-based gel formulation with opioid agonist was injected into a solvent (Figure 22A). The PLGA solidifies or clumps together in the solvent, thereby preventing abuse (Figure 22B). For example, as shown in Figure 20, if gel formulation E or F is extracted from the device and then chewed by the user (a common form of opioid abuse of patches), the percent of opioid released can be lower relative to Butrans®. That is, for the simulated saliva results (of Figure 20), 9% of the drug was released from formulation F, 16% from formulation E, and 16% from Butrans® at 120 minutes. Similarly, as shown in Figure 21, if gel formulation F is extracted from the device and then injected (another common form of opioid abuse of patches), the percent of opioid released can be lower relative to Butrans®. That is, for the 95% ethanol results (simulating solvent for drug extraction) (of Figure 21), 7% of the drug was released from Formulation F, and approximately

100% was released from Butrans® at 60-120 minutes.

[0064] Advantageously, the devices 100, 300 can provide therapeutic delivery of opioid agonist with negligible or no delivery of opioid antagonist (for embodiments where antagonist is present). However, upon attempted formulation abuse, such as extraction of the drug formulation via needle/syringe, both species i.e. opioid agonist and opioid antagonist, can become bioavailable, causing deactivation of the opioid agonist. The device 300 with a PLGA- based gel formulation can also help prevent abuse due to the solidification or clumping of the formulation, as described above. As a result, the devices 100, 300 are less prone to abuse than other transdermal drug delivery systems.

[0065] The delivery devices 100 and 300 can be simple devices that include only the elements shown in Figures 1-3 or they can be part of a more complex transdermal drug delivery system. For example, delivery devices 100, 300 can be used as part of any of the delivery systems described in U.S. Application No. 15/009,683, filed January 28, 2016, International Application No. PCT/US2017/064765, filed December 5, 2017, International Application No. PCT/US2017/054093, filed September 28, 2017, and International Application No.

PCT/US2015/015469, filed January 28, 2016 the entireties of which are incorporated by reference herein.

[0066] In some embodiments, the reservoir 331 of the delivery device 300 can be a sealed reservoir, and a breaking element can cut or slice the reservoir 331 to release the gel formulation upon activation.

[0067] In some embodiments, the devices 100, 300 can be implemented in a two-part system design. FIGS 5A-5B illustrate an exemplary two-part transdermal drug delivery device 200. The device 200 includes a reusable part 202 and a disposable part 204. The reusable part can include the electronics and controller while the disposable part 204 can include a drug reservoir 224, transdermal membrane, adhesive, etc. Further, the disposable part 204 include a magnetic sensor 220 on an opioid reservoir piston 222 and in the opioid reservoir 224. The magnetic sensors 220 can communicate with the reusable part 202 to provide information about the piston positioning and opioid delivery. A piston spring 232 can provide a force to the opioid reservoir piston 222 to expel a controlled amount of the opioid source. The opioid source can travel from the opioid reservoir 224 through a valve 230 through a transdermal membrane and then into contact with the skin. The linear travel of the piston 222 can be correlated to the volume of the opioid source expelled from the opioid reservoir 224. The linear motion of the opioid reservoir piston 222 can be controlled to deliver a variable amount of the opioid source. [0068] In some embodiments, the device 200 can include a matrix barcode 206 (e.g., QR code) or other scanned code on the disposable part 204 for the user to scan with a hand-held computer device as part of the authentication process. After the authentication is performed, the controller for the reusable part 202 can be activated to proceed with the drug delivery protocol. The device 200 can also include an impedance sensor 208 to detect contact with the skin of the user. The disposable part 204 can include a monitoring sensor 210 on the drug reservoir to detect tampering with the chamber that can occur with physical tampering.

[0069] In some embodiments, a transdermal drug delivery device as described herein can be a transdermal patch. For example, referring to Figure 6, a smart abuse-deterrent transdermal drug delivery system 500 can be a patch that includes an adhesive polymer matrix 551 having an agonist (or partial agonist) dissolved therein. Additionally, the matrix 551 can include an antagonist 553 (e.g., a modified antagonist) dispersed therein. The agonist and/or antagonist can be uniformly distributed throughout the polymer matrix 551. Further, the adhesive polymer matrix 551 can be supported on or covered by a polymer or fabric backing film 552.

Additionally, the drug delivery system 500 patch can include a protective release lining 554 on the side of the system 500 intended to interact with the skin. The release lining can be configured to be removed prior to application.

[0070] Another exemplary patch transdermal drug delivery system 600 is shown in Figure 7. The system 600 is similar to system 500 except that it includes a rate controlling membrane 661 configured to control the rate of delivery of the opioid agonist. The rate controlling membrane 661 can be positioned between the release liner and the matrix with the opioid

agonist/antagonist.

[0071] Another exemplary patch transdermal drug delivery system 700 is shown in Figure 8. The system 700 includes a reservoir 771 thereon. The reservoir 771 can include, for example, a gel formulation with opioid agonist as described above with respect to delivery device 300. In some embodiments, the gel formulation can include opioid antagonist 773 dispersed therein. The reservoir 771 can be located between a polymer or fabric backing film 752 and a rate controlling membrane 761. The rate controlling membrane can further include a layer of adhesive contacting the skin. The adhesive can be protected by a release liner 754 prior to use.

[0072] In some embodiments, the transdermal drug delivery system can be a patch with separate agonist and antagonist layers. For example, patch drug delivery system 800 can include a backing film 852, an antagonist layer 882 that includes a polymer matrix with opioid antagonist distributed therein, an agonist layer 884 that includes an adhesive polymer matrix with opioid agonist dissolved therein, and a release liner 854. The opioid agonist and antagonist can thus be in separate layers. Further, in some embodiments, the polymer used for the agonist layer 884 can be a different polymer than that used for the antagonist layer 882, which can help prevent mixing or migration of the antagonist into the layer with the agonist. In some embodiments, the antagonist layer 882 can be made with a polymer that is relatively more susceptible to solvents commonly used to manipulate the formulation to extract the opioid than the polymer (e.g., adhesive) used for the agonist layer 884.

[0073] Figure 14 shows a patch transdermal drug delivery system 1400 that is similar to system 800 in that it can be a patch including a backing film 1452, an antagonist layer 1482 of polymer matrix with opioid antagonist distributed therein, an agonist layer 1484 of adhesive polymer matrix with opioid agonist dissolved therein, and a release liner 1454. However, system 1400 includes a membrane 1414 separating the antagonist layer 1482 from the agonist layer 1484. Additionally, in some embodiments, the backing film 1452 can include an additional antagonist or aversive therein (e.g., with different antagonist release characteristics, or unpleasant effects such as bitterness on abuse) to help deter or prevent abuse. In some embodiments, the membrane 1414 can be inseparable from the agonist layer 1484 or the antagonist layer 1482 so as to help prevent abuse. Further, the membrane 1414 can be impermeable to the antagonist and/or the agonist. The membrane 1414 can be selected so as to not significantly impact moisture vapor transmission. In some embodiments, the membrane 1414 can be used in conjunction with a backing layer to control moisture vapor transmission rate and skin hydration, which in turn can affect the flux of opioid across the skin. The membrane 1414 can be made, for example, of polyester, ethylene vinyl acetate (EVA). In some

embodiments, the membrane 1414 can be impregnated with antagonist and may be used to hold the antagonist in place. In such an embodiment, a back layer may be useful to separate the agonist and antagonist layer.

[0074] In some embodiments, the agonist layer of patches 800 and 400 can include acrylate adhesive with levulinic acid and lauryl alcohol (see Figure 4). In other embodiments, the agonist layer of patches 800 and 400 can include both acrylate adhesive (e.g., DT 387-2510 and/or GELVA GMS 788) and silicone adhesive (BioPSA 7-4202). The layer can further include levulinic acid, dimethylisosorbide (DMI), and/or glycerol monooleate (GMO). An opioid agonist can be incorporated in the layers 800, 400 at 3-15% w/w, such as 5-12% w/w.

Exemplary formulations are shown in Figure 23. As shown in Figure 23, the agonist layers with acrylate and silicone adhesive can have similar or better flux relative to Butrans® (e.g., due to the combination of adhesives and permeation enhancers used).

[0075] In some embodiments, the antagonist layer of patches 800 and 400 can include silicone or acrylic adhesive with antagonist (e.g., Naltexone (NTX)). The percent antagonist in the layers of patches 800, 400 can, for example, be between 2-3% w/w. In some embodiments, the ratio of agonist to antagonist can be between 3: 1 and 5: 1, such as approximately 4: 1. Figure

24 shows exemplary formulations for the antagonist layer as well as the percent of antagonist released over time. In some embodiments of the antagonist layer of patches 800 and 400, the antagonist can be encapsulated in micro-particles or nano-particles. Figure 25 shows exemplary formulations for the antagonist layer as well as the percent of antagonist released over time.

[0076] The opioid agonist described herein can be fentanyl, buprenorphine, sufentanil, other opioid agonist or partial agonist molecules, or their respective salts. The opioid antagonist described herein can be naloxone, naltrexone, other opioid antagonist molecules, or their respective salts. The opioid antagonist may be present in a modified form. For example, the antagonist may be an encapsulated opioid antagonist in the form of nano/microparticles or in the form of an opioid antagonist prodrug. The modified form can minimize delivery of opioid antagonist into the skin, but make opioid antagonist bioavailable in case of abuse of transdermal drug delivery system.

[0077] In some embodiments, the modified form of opioid antagonist can be an encapsulated opioid antagonist in the form of nano/microparticles. The nano/microparticles can be in the size range of nanometer to micrometer and can be large enough to not permeate the skin passively. In some embodiments, the particles are sufficiently small to be incorporated into a standard transdermal patch (< 250 μιη). In another embodiment, the particles are sufficiently small to be not filterable by standard clinical syringe filters (<220 nm). Further, the nano/microparticles can be of different shapes, such as spherical or cylindrical. In one embodiment, the opioid antagonist can be uniformly distributed in the polymer matrix of the nano/microparticles. In another embodiment, the opioid antagonist can form a core within the nano/microparticle with a layer or layers of polymer and sugar forming an outer casing or shell (which can be called "drug core- shell particles"). The nano/microparticles can further have a coating or coatings of lipid.

Examples of lipids are stearic acid, myristic acid, soybean lecithin, l,2-dipalmitoyl-sn-glycero-3- phosphocholine, l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[succinyl( polyethylene glycolO-2000, etc. Examples of polymers used for encapsulating opioid antagonist can include cellulose-based polymers such as cellulose acetate phthalate, cellulose acetate butyrate, hydroxylpropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, etc. and/or acrylate-based polymers such as methacrylate, methyl acrylate, ethyl acrylate, etc. or a combination of cellulose and acrylate-based polymers. The polymer selected for encapsulating opioid antagonist in the form of nano/microparticles can be pH-sensitive and can dissolve at pH greater than 5.5, such as greater than 6, such as at physiological pH of 7. As a result of the pH-sensitive nature of the polymers, the nano/microparticles can dissolve at physiological pH to release the antagonist in case of misuse/abuse of the formulation by injecting, chewing or snorting. Further, the antagonist can be released from the nano/microparticles in the event of manipulation of formulation to extract the opioid using common household solvents such as water, alcohol, etc. due to change in pH. However, the nano/microparticles containing opioid antagonist can advantageously remain stable (and not release opioid antagonist) during transdermal application and during storage.

[0078] Solvents that are commonly used for opioid extraction and abuse from opioid dosage forms include water, vodka, vinegar, 0.2% baking soda solution, ethanol, isopropanol (IPA), acetone (e.g. as used in nail polish remover), 0.1 N hydrogen chloride (HC1), 0.1 N sodium hydroxide (NaOH), simulated saliva, carbonated drink, or oil. In one specific example, the abuse deterrence of two different polymeric nanoparticles, synthesized using

Hydroxypropylmethylcellulose Phthalate (HP-55) and Cellulose Acetate Phthalate (CAP) was tested through in vitro extraction studies per FDA abuse-deterrence guidance category 1 studies (under the General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products, Guidance for Industry, Nov 2017). To do so, nanoparticles synthesized using HP-55 and CAP polymers were placed in different solvents while stirring at room temperature (N=3 for each solvent). Samples were then withdrawn at 5 minutes, 15 minutes, 30 minutes 1, hour, and 2 hours. An additional test was run for an overnight stretch (i.e., about 12 hours). Fresh solvent was replenished after samples were taken. Samples were filtered to remove undissolved nanoparticles, and the naltrexone (NTX) release in extraction solvents was determined. The release of naltrexone was expressed as percent (%) of total amount of naltrexone loaded in nanoparticle sample. The graphs of %NTX release versus time is shown in Figure 10 (nanoparticles synthesized using HP-55 polymer) and Figure 11 (nanoparticles synthesized using CAP polymer) for a variety of different solvents. Additionally, the naltrexone released in the overnight test for a variety of different solvents is shown in Figure 12

(nanoparticles synthesized using HP-55 polymer) and Figure 13 (nanoparticles synthesized using CAP polymer). As shown, overnight extraction with some solvents (e.g. vodka and IPA) resulted in additional release of naltrexone. For several other solvents, the data indicated that naltrexone release was maximized within 2 hrs from the start of extraction. Conducting the extraction studies at elevated temperature of 60 °C for solvents that showed low naltrexone release at room temperature resulted in increased naltrexone release for both polymers (Figure 12 and Figure 13).

[0079] In one embodiment, in the event of abuse, misuse, or manipulation of the formulation using common household solvent, the antagonist can be released from the micro/nanoparticles in a controlled fashion in a ratio of 1:4 or greater to the agonist. This ratio of antagonist to agonist, when reached systemically, can advantageously negate the effects of the opioid agonist, thereby preventing abuse. Additionally, for solvents in which the release of the antagonist is minimal or less than the desired amount as defined by the antagonist amount required to achieve a ratio of 1:4 or greater to the agonist, the formulation can still be abuse-deterrent for other reasons. For example, some solvents, such as vinegar, can be painful upon injection into the body. Hence, the formulation described herein can be abuse-deterrent even without achieving a release of antagonist at a ratio of 1:4 or greater.

[0080] In some embodiments, the modified form of opioid antagonist can be an inactivated form of antagonist that converts into an active form in vivo (e.g., the "prodrug" form). The prodrug form of antagonist can have a molecular weight greater than 500 Daltons and will not permeate skin passively in therapeutic amounts during use of the transdermal delivery device. The prodrug form of antagonist can have a biodegradable and biocompatible polymer linked to the antagonist by means of breakable linkages. The breakable linkage can be any linkage that breaks sufficiently rapidly during misuse/abuse so as to release the antagonist in vivo, thereby minimizing or eliminating the euphoric effects of the agonist drug. Examples of breakable linkages for use in the prodrug form include ester, and carbonate linkages. Examples of biodegradable polymer for use in the prodrug form include polyethylene glycol, poly(lactic-co- glycolic acid), poly lactic acid, and poly glycolic acid. The prodrug form of opioid antagonist can be solubilized or uniformly dispersed in the formulation and can remain stable in the formulation during storage as well as during intended use i.e. transdermal application. The prodrug form, however, can undergo hydrolytic cleavage in vivo, thereby releasing the antagonist if the formulation is abused by injecting or chewing the formulation.

[0081] In embodiments where an antagonist is described, the antagonist can be substituted with other abuse deterrent elements. For example, an aversive (e.g., Capsaicin) or bitterant (e.g., Denatonium or Sucrose octaacetate) agent can be used. Additionally, in some embodiments, an adversive or bitterant can be incorporated into other layers or elements on the drug delivery system so as to help prevent abuse.

[0082] While the drug delivery systems described herein are described as being used with an opioid agonist-antagonist, the systems can similarly be used with other compounds that have a high risk of abuse. For example, the delivery systems can be used with a stimulant (e.g., amphetamine, methylphenidate) co-formulated with an antidopaminergic (e.g., haloperidol), such as for the treatment of attention deficit disorder. The systems can also be used with a central nervous system depressants (e.g., a benzodiazepine) co-formulated with a benzodiazepine antagonist (e.g., flumazenil), such as for the treatment of anxiety and sleep disorders. [0083] In some embodiments, an agonist stabilizer can be included in the transdermal delivery systems described herein. For example, polyvinyl pyrrolidone (e.g. PVP K30) can be used as a stabilizer.

[0084] In some embodiments, the adhesive used with the transdermal delivery systems described herein can be a pressure-sensitive adhesive. Adhesives can include acrylate-based, silicone-based, polyisobutylene -based, styrene block copolymer-based (e.g. Styrene-Isoprene- Styrene or SIS), or hydrogel-based adhesives, or a combination thereof. In some embodiments, the adhesive layer can include a permeation enhancer to help provide therapeutic delivery of agonist to the skin. For example, the permeation enhancer can include oleyl alcohol, lauryl alcohol, oleyl oleate, levulinic acid, lauric acid, oleic acid, polysorbate 20, polysorbate 80, or diethylene glycol monoethyl ether.

[0085] In some embodiments, an antioxidant can be included in the transdermal delivery systems described herein. For example, Butylated hydroxytoluene can be used as an antioxidant.

[0086] In some embodiments, the transdermal delivery systems described herein may include backings such as woven and non- woven polyester fabric or woven and non-woven poly-ethylene films.

[0087] In some embodiments, the rate controlling membranes used with the delivery systems described herein can be ethylene vinyl acetate-based or polyester-based membranes.

[0088] In some embodiments, the release liners used with the transdermal delivery systems described herein can include polymer films manufactured from fluoropolymers or coated with fluoropolymers.

[0089] In some embodiments, the transdermal drug delivery devices described herein can include a sensor element that includes one or more sensors. The sensor element can be built into the drug delivery system or can be a separate removable/detachable element. Further, the one or more sensors can be used, for example, to authenticate the patient, monitor compliance, detect safety or emergency conditions, and/or detect disposal. In one embodiment, the sensor element can be activated (i.e., so as to start collecting data) when a release liner is removed from the transdermal drug delivery device.

[0090] The one or more sensors can be, for example, an ECG sensor, a heart rate sensor, a respiration rate sensor, a GPS sensor (e.g., for locating the transdermal drug delivery system), a temperature sensor, an impedance sensor, an accelerometer, an inertial measurement unit (IMU), a capacitive sensor, a PH sensor, an IR sensor, an RF sensor, a reflectance pulse oximetry sensor, a motion sensor, a pulse oximeter, a fingerprint scanner, a heart rate sensor, a skin sensor, a blood flow sensor, a retina scanner, a voice recognition sensor, a gait sensor, or a facial recognition sensor. [0091] In one embodiment, a temperature sensor (e.g., a silicon bandgap sensor or an IC temperature sensor) can be used to infer skin wear (e.g., for compliance) using the temperature profile of the applied surface. Such temperature data can further be used to identify not only skin wear, but also whether the patient is asleep or awake, exercising, and/or can aid in the diagnosis or evaluation of certain diseases. In another embodiment, a motion or gait sensor (inertial measurement unit), such as an accelerometer or gyroscope, can be used to infer skin wear based upon the user's movements. In another embodiment, the transdermal drug delivery device can include both a motion/gait sensor and a temperature sensor. The combined data can be used to more effectively detect wear and/or compliance. In another embodiment, an impedance sensor (measuring impedance at frequencies ranging from 1 Hz to 1 Mhz) can be used to detect skin wear. In another embodiment, an electrocardiography (ECG) sensor can be used to measure heart activity to detect compliance and/or to gather safety/health data. In another embodiment, a reflectance pulse oximeter that measures heart rate using light emitted from 2 LEDs that has reflected off of bone or other dense tissue and is measured with a photodiode can be used to detect compliance and/or to gather safety/health data. In another embodiment, the transdermal drug delivery device can include both an impedance sensor and a motion/gait sensor. The combined data can be used to more effectively detect wear and/or compliance.

[0092] In some embodiments, the sensor data can be used to detect wear and/or compliance, and the device can activate (e.g., begin drug delivery) based upon the sensor data. For example, the sensor (e.g., temperature sensor) can be used to determine that the transdermal drug delivery device has been applied to the skin, which can then trigger delivery of the drug (e.g., opioid).

[0093] The transdermal drug delivery device can further have wireless connectivity (e.g., via Bluetooth or writable NFC) to communicate data obtained from the one or more sensors to electronic devices, such as phones or computers (e.g., electronic devices including an associated application). The data can further be available at backend/cloud for use by clinicians to monitor use, misuse, and compliance with the prescribed regimen. An exemplary phone display 1515 is shown in Figure 15a. The display 1515 can show data gathered from the sensors while also allowing input from the user (e.g., regarding pain or withdrawal symptoms). An exemplary clinician interface 1517 is shown in Figure 15b. The display can show data gathered from the sensors and can display, for example, when the transdermal drug delivery system was worn by the user.

[0094] Figure 16 shows an exemplary method 1616 of using a transdermal delivery device with one or more sensors and NFC Communication as described herein. At step 1662, the release liner can be removed from the device such that biometric data starts and is collected in the memory. At step 1664, the device can be applied to the skin, and time stamped biometric data can be stored on chip memory to show when the patch is applied. At step 1666, the time stamped data stored on the chip memory can show wear duration. At step 1668, the transdermal device can be removed and disposed of, and the time of removal and disposal can be stored on chip memory. At step 1670, the transdermal device can be scanned, and data stored on the chip memory can be uploaded (e.g., to a phone) and transmitted to a database.

[0095] Figure 17 shows an exemplary method 1717 of using a transdermal delivery device with one or more sensors and Bluetooth Communication as described herein. At step 1772, the release liner can be removed from the patch such that biometric data starts and is collected in the memory. At step 1774, the patch can be applied to the skin, and time stamped biometric data can be stored on chip memory to show when the patch is applied. At step 1776, the device can be paired with a device (e.g., a phone) so as to upload stored data to the phone for transmission to a data base. At step 1778, the time stamped data can be stored in chip memory, automatically uploaded to the device (e.g., phone), and transmitted to the database at discrete intervals. At step 1780, the device can be removed, and the time of removal and disposal can be broadcast to the device (e.g., phone).

[0096] In an exemplary embodiment, when used for compliance purposes, the one or more sensors of the transdermal drug delivery device can be used to confirm application to the skin, wear, and/or removal from the skin. The sensor can gather such compliance information for 3 or more days of wear. A controller on the device can then report the event to a back-end data base (e.g., via wireless connectivity) for compliance monitoring.

[0097] In some embodiments, the sensor element can be rechargeable. In some

embodiments, the battery for the sensor element can be carbon zinc, power paper, or coin cell.

[0098] In some embodiments, the one or more sensors can be used to detect disposal of all or a part of the transdermal drug delivery device. Typically, transdermal patches containing controlled substances are disposed by folding the patch onto itself, sticking the patch onto an adhesive paper, or disposing the patch in a disposal pouch containing activated charcoal to adsorb the drug. For example, the sensor can detect folding, application of a disposal line, or insertion into a smart disposal pouch.

[0099] Additionally, in some embodiments, the transdermal delivery systems described herein can include sensors such as Near Field Communication (NFC) or Radiofrequency identification (RFID) on the packaging to help protect against diversion and/or to monitor compliance. For example, patients can be instructed to read the NFC tags on the packaging prior to opening the package in order to monitor compliance. The NFC tag can additionally provide information regarding the state of the tag, the device used to read the tag and/or the location where it was read, linking information to patient. Failure to comply with the instructions can be assumed to mean product diversion and/or abuse.

[0100] In some embodiments, a passive sensor can be integrated into the transdermal systems described herein, e.g., as part of the lining such as the backing layer. For example, a passive NFC thin film sensor can be layered on the system and can be read by an electronic device (e.g., a smartphone or computer application). The data acquired by the smartphone can be used to confirm that the patient is using the transdermal delivery system and can be relayed to a cloud-based database for the physician to monitor proper patient compliance. In some embodiments, the transdermal delivery system can also use this information to provide psychosocial behavioral support (e.g., via the transdermal delivery system or the electronic device such as the smartphone app or computer application). The behavioral support can be provided, for example, through automated messages or a user interface or through

communication with human coaches or therapists.

[0101] The sensor(s) of the transdermal drug delivery devices described herein can be positioned therein so as to not interfere with the drug and/or the moisture vapor transmission rate through the device.

[0102] In some embodiments, the transdermal drug delivery devices described herein can have a thickness of 2mm or less. In some embodiments, the drug delivery portion of the transdermal drug delivery devices can have an area of approximately 30-50cm ² , such as 40cm ² , and a thickness of 0.3mm- lmm, such as 0.5mm.

[0103] The transdermal drug delivery devices described herein can be disposable, can be reusable, or can be part of a two-part design that includes a disposable portion and a reusable portion.

[0104] It should be understood that any element described herein with respect to one embodiment can be combined with or substituted for any element described herein with respect to another embodiment.

[0105] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0106] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as "/".

[0107] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under" or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0108] Although the terms "first" and "second" may be used herein to describe various features/elements, these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.

[0109] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or "approximately," even if the term does not expressly appear. The phrase "about" or

"approximately" may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/- 0.1% of the stated value (or range of values), +/- 1% of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc. Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[0110] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative

embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others.

Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0111] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term "invention" merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.