Methods of managing pain using dexmedetomidine transdermal delivery devices

Abstract

To provide methods of managing pain using dexmedetomidine.SOLUTION: Aspects of the invention include methods of managing pain in a subject by applying a transdermal delivery device containing a dexmedetomidine composition formulated to deliver a pain relieving effective amount of dexmedetomidine to the subject. In practicing methods according to certain embodiments, a transdermal delivery device having a dexmedetomidine composition is applied to a subject and is maintained in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective to manage pain in the subject. In some embodiments, methods include hydrating the subject, such as by administering a hydration fluid composition to the subject. Methods according to certain embodiments may also include co-administering an opioid to the subject.SELECTED DRAWING: Figure 24A

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to the filing dates of U.S. Provisional Patent Application No. 62 / 415,248, filed on October 31, 2016, and U.S. Provisional Patent Application No. 62 / 547,582, filed on August 18, 2017, the disclosures of which are incorporated herein by reference.

Background Art

[0002] In the United States, pain is the most common reason for a visit to a physician. Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue, bone, nerve, or cellular damage. Most pain resolves quickly once the painful stimulus is removed and the body is healing, but sometimes pain persists despite the removal of the stimulus and the apparent healing of the body (Foye’s Principles of Medicinal Chemistry (Seventh Edition, 2013), page 660).

[0003] In the United States, approximately 20 million surgical procedures are performed each year under general anesthesia. Pain that occurs after surgical pain or surgical or traumatic injury is severe and is often a refractory medical problem. Pain is usually localized within the area near the surgical site. Surgical pain can have two clinically important aspects: pain at rest, or pain that is active when the patient is not moving, and mechanical pain that is exacerbated by movement (coughing / sneezing, getting out of bed, physical therapy, etc.). The major problem with surgical pain management for major surgery is that currently used drugs have various significant side effects.

[0004] Dexmedetomidine is the S-enantiomer of medetomidine and is an agonist of the α2-adrenergic receptor used as a sedative in the intensive care unit and by anesthesiologists for intubated and non-intubated patients who require sedation for surgery or short-term procedures. The α2-adrenergic receptor is a G 2a , α 2b and α 2c -adrenergic receptor-containing G i protein-coupled receptor that associates with heterotrimeric G proteins. Agonists of the α2-adrenergic receptor are involved in sedation, muscle relaxation, and analgesia via effects on the central nervous system.

[0005] Since dexmedetomidine is used as a sedative in a clinical setting via intravenous administration, it requires careful monitoring by medical professionals in a hospital setting. Dexmedetomidine is currently employed for sedation of intubated subjects or subjects wearing a ventilator during treatment in the intensive care unit, as well as for sedation of non-intubated subjects prior to and / or during non-surgical procedures.

Summary of the Invention

[0006] Aspects of the invention include methods of managing pain in a subject by applying a transdermal delivery device containing a dexmedetomidine composition formulated to deliver an effective amount of dexmedetomidine for pain relief to the subject. In practicing the method according to certain embodiments, a transdermal delivery device having a dexmedetomidine composition is applied to the subject and maintained in contact with the subject in a manner sufficient to deliver an effective amount of dexmedetomidine to manage pain in the subject. In some embodiments, the method includes hydrating the subject. The method according to certain embodiments may also include co-administering an opioid to the subject. Also provided is a transdermal delivery device configured to deliver a sufficient amount of dexmedetomidine to practice the subject method, as well as a kit containing the transdermal delivery device.

Brief Description of the Drawings

[0007]

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Mode for Carrying Out the Invention

[0008] Aspects of the present invention include a method of managing pain in a subject by applying a transdermal delivery device containing a formulated dexmedetomidine composition that delivers an amount of dexmedetomidine effective for pain relief to the subject. In practicing the method according to certain embodiments, a transdermal delivery device having a dexmedetomidine composition is applied to the subject and maintained in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective to manage pain in the subject. In some embodiments, the method includes hydrating the subject. The method according to certain embodiments may also include co-administering an opioid to the subject. Also provided is a transdermal delivery device configured to deliver a sufficient amount of dexmedetomidine to practice the method of the subject, as well as a kit containing the transdermal delivery device.

[0009] Before the present invention is described in more detail, it should be understood that the present invention is not limited to the specific embodiments described and may, of course, vary. Since the scope of the present invention is limited only by the appended claims, it should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0010] ​When a range of values is provided, unless the context clearly dictates otherwise, each intervening value between the upper and lower limits of that range to one tenth of the unit of the lower limit, and any other recited or intervening value in the recited range, is understood to be included within the scope of the present invention. The upper and lower limits of these smaller ranges may independently be further limited to even smaller ranges, also included within the scope of the present invention, subject to any specifically excluded endpoints in the recited range. When the recited range includes one or both of the endpoints, ranges excluding either or both of those included endpoints are also included in the present invention.

[0011] Certain ranges are presented herein with numerical values preceded by the term "about." The term "about" is used herein to provide literal support for the exact number that it precedes, as well as literal support for numbers that are near to or approximately the number that the term precedes. In determining whether a number is near to or approximately the specifically recited number, a near or approximate recited number may be a number that provides substantial equivalence to the specifically recited number in the context in which it is presented.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, representative and illustrative methods and materials are described herein.

[0013] All publications and patents cited in this specification are hereby incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, and are incorporated herein by reference to disclose and describe the methods and / or substances so cited. The citation of a publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of the publications provided may be different from the actual filing dates which may need to be independently confirmed.

[0014] As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" are referred to as including plural referents. It is further referred to that the claims may be written to exclude any element. As such, this reference is intended to serve as a precursor for the use of exclusive terms such as "merely", "only", etc. in conjunction with the recitation of claim elements or the use of "negative" limitations.

[0015] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein may have separate calibration elements and features that can be readily separated from, or readily combined with, any of the features of some other embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of the recited events or in any other order that is theoretically possible.

[0016] In further describing various embodiments of the present invention, a method of maintaining a transdermal delivery device having a dexmedetomidine composition in contact with a subject in a manner sufficient to deliver a non-sedating amount of dexmedetomidine to the subject is first described in detail. Next, a transdermal delivery device suitable for practicing the subject method is described. A kit including the transdermal delivery device of interest is then described.

[0017] Method of managing pain with a transdermal delivery device for dexmedetomidine Aspects of the present invention include methods of managing pain by applying a transdermal delivery device containing a dexmedetomidine composition formulated to deliver an amount of dexmedetomidine effective for pain relief to a subject experiencing pain. In practicing the methods according to embodiments of the present invention, a transdermal delivery device having a dexmedetomidine composition is applied to a subject and maintained in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective for pain relief to the subject. The term "transdermal" is used in its conventional meaning to refer to a route of administration by which an active agent (i.e., a drug) is delivered across the skin (e.g., topical administration) or mucosa for systemic distribution. As such, transdermal dexmedetomidine compositions as described herein include compositions formulated to deliver dexmedetomidine to a subject through one or more of the subcutaneous tissue, dermis, and epidermis, including the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale. Accordingly, an extended transdermal delivery device containing a transdermal dexmedetomidine composition may be applied at conventional locations such as, for example, the arm, leg, buttock, abdomen, back, neck, scrotum, vagina, face, behind the ear, and inside the cheek, as well as sublingually. In describing the methods of the present invention, the term "subject" means a person or organism to which the transdermal delivery device is applied and maintained in contact. As such, subjects of the present invention may include, but are not limited to, mammals such as humans and other primates such as chimpanzees and other apes and monkey species, etc., and in certain embodiments, the subject is a human. The term subject is also intended to include persons or organisms of any age, weight, or other physical characteristic, where the subject may be an adult, child, infant, or neonate.

[0018] Transdermal administration of dexmedetomidine may be passive or active. "Passive" transport means that the dexmedetomidine composition is delivered across the skin or mucosa in the absence of applied energy (e.g., friction or heat), and depends primarily on the permeability of the barrier (e.g., skin or mucosa) and is due to the entropy of delivery. However, transdermal administration according to certain embodiments may also include active transport of the dexmedetomidine composition across the skin or mucosa. Active transport can be any conventional protocol sufficient to transport the composition through the skin or mucosa in conjunction with the applied energy, which may include, but is not limited to, among several protocols, micro-needle delivery, facilitated diffusion, electrochemically created gradients, iontophoresis systems.

[0019] In some embodiments, the method includes applying a transdermal delivery device having a dexmedetomidine composition to a subject experiencing pain and maintaining the transdermal delivery device in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective to relieve pain to the subject. By an amount effective to relieve pain is meant an amount that provides at least some, if not substantial, pain relief as experienced by the subject, and in some cases, the amount of pain relief is a complete cessation of the sensation or perception of pain. The amount of pain relief may be quantified or otherwise evaluated using conventional protocols.

[0020] In other embodiments, the method includes applying a transdermal delivery device having a dexmedetomidine composition to a subject not experiencing pain and maintaining contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective to reduce the amount of pain in the subject. "Reducing the amount of pain" means that when a transdermal delivery device is applied to a subject not experiencing pain and maintained in contact with the subject, the subject will experience at least less pain in response to a pain-inducing event (e.g., a physical trauma such as surgery) compared to a subject to whom a transdermal delivery device containing dexmedetomidine was not applied. For example, the transdermal delivery device containing dexmedetomidine is applied to the skin surface of a subject not experiencing pain and maintained in contact with the subject in a manner that reduces the amount of pain experienced by the subject in response to a pain-inducing event (e.g., surgery) by 5% or more, e.g., 10% or more, e.g., 15% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more, and 99% or more. In some cases, the transdermal delivery device of the subject is configured to deliver to a subject not experiencing pain an amount of dexmedetomidine sufficient to completely eliminate the pain experienced by the subject in response to a pain-inducing event (i.e., reduce the amount of pain by 100%). As described in more detail below, the amount of time the transdermal delivery device is applied to the subject prior to a pain-inducing event (e.g., surgery) may vary and may depend on a number of factors such as the amount of dexmedetomidine present in the transdermal delivery device and the type of pain-inducing event. In some cases, the transdermal delivery device may be applied to the skin surface of the subject 1 hour or more, e.g., 2 hours or more, e.g., 3 hours or more, e.g., 4 hours or more, e.g., 6 hours or more, e.g., 8 hours or more, e.g., 12 hours or more, e.g., 16 hours or more, and including 24 hours or more before a pain-inducing event (e.g., a surgical procedure).

[0021] In some cases, the amount of dexmedetomidine delivered to the subject is a non-sedating amount. "Non-sedating" means that the dexmedetomidine composition is formulated to deliver to the subject an amount of dexmedetomidine that does not cause complete sedation of the subject. In other words, the subject remains conscious and responsive throughout the time that dexmedetomidine is being administered transdermally to the subject. In some cases, throughout the administration of the dexmedetomidine transdermal composition, the subject is cooperative, retains orientation, and remains in a calm state. In other examples, throughout the administration of the dexmedetomidine transdermal composition, the subject remains awake and can respond to commands (e.g., verbal or written commands). In still other examples, throughout the administration of the dexmedetomidine transdermal composition, the subject is awake, cooperative, oriented, and calm and can respond to commands (e.g., verbal or written commands). As used herein, non-sedating includes cases where some sedation is present, as determined, for example, using a suitable sedation scale as described above. In some cases, the subject is not completely sedated. The term "not completely sedated" means that the subject experiences at least some level of sedation but can be aroused by mild physical stimulation or verbal commands. For example, if the subject is not completely sedated, the subject's eyes may be closed with a relaxed body but can be opened, for example, by one or more physical stimuli by a healthcare provider or by a command.

[0022] Protocols suitable for determining the level of sedation may include, but are not limited to, conventional protocols for determining the level of sedation, such as the Ramsay Sedation Scale, the Vancouver Sedation Recovery Scale, the Glasgow Coma Scale modified by Cook and Palma, the Comfort Scale, the New Sheffield Sedation Scale, the Sedation-Agitation Scale, and the Motor Activity Assessment Scale, the Wilson Sedation Score. No.

[0023] In some embodiments, the method may further include evaluating the level of sedation of the subject to determine whether a decrease in responsiveness or cognitive or motor activity has occurred from administration of a transdermal delivery device formulated to deliver a non-sedating amount of dexmedetomidine. The level of sedation may be evaluated by conventional protocols such as those mentioned above. In certain embodiments, the level of sedation is evaluated using the Wilson sedation scale, the details of which are available at the website resulting from placing "http: / / www." in front of "sedationsolutions.co.uk / training-series6.php" and below: Wilson sedation score (1) Fully awake and oriented (2) Drowsy (3) Eyes closed but can be aroused by command (4) Eyes closed but can be aroused by mild physical stimulation (pulling on earlobe) (5) Eyes closed and cannot be aroused by mild physical stimulation; and are available at

[0024] In some embodiments, during administration of the subject's dexmedetomidine transdermal composition, the level of sedation of the subject is evaluated and assigned a Wilson score of 3 or less, such as a Wilson score of 2 or less, including cases where the subject is assigned a Wilson score of 1. In these cases, throughout the administration of dexmedetomidine by the dexmedetomidine transdermal delivery device, the subject exhibits a brisk response to gentle tapping between the eyebrows or to an auditory stimulus of loud voice. In other examples, throughout the application of the dexmedetomidine transdermal device, the subject responds to verbal instructions. In still other examples, throughout the application of the dexmedetomidine transdermal device, the subject is cooperative, oriented, and calm. In still other examples, throughout the administration of dexmedetomidine by the transdermal delivery device, the subject is anxious, agitated, or restless. In other examples, during administration of the subject's dexmedetomidine by the transdermal device, the level of sedation of the subject is evaluated and the subject is assigned a Wilson score of 4. In these examples, the subject may be identified as not fully sedated.

[0025] The level of sedation of the subject may be evaluated at any time during the method. In some cases, at regular intervals, such as every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, or other intervals, the level of sedation is evaluated while maintaining contact with the subject and maintaining the transdermal delivery device for an extended period of time. For example, 15 minutes after applying the transdermal delivery device, 30 minutes after applying the transdermal delivery device, 1 hour after applying the transdermal delivery device, 2 hours after applying the transdermal delivery device, 4 hours after applying the transdermal delivery device, including 8 hours after applying the transdermal delivery device, the level of sedation may be evaluated while maintaining contact with the subject and maintaining the transdermal delivery device.

[0026] The level of sedation of the subject may be evaluated one or more times during the dosing interval, before, during, or after the dosing interval, including five or more times, for example, two or more times, for example, three or more times. The upper limit of the number of times the subject may be evaluated during the dosing interval may, in some cases, be ten or less, for example, seven or less, for example, five or less, for example, three or less, and including two or less. In certain embodiments, the number of times the subject may be evaluated during the dosing interval is, for example, from two to ten, for example, from three to nine, for example, from four to eight, and including from five to seven.

[0027] In certain embodiments, the sedation level may be monitored throughout the time the transdermal delivery device is in contact with the subject, for example, by a heart rate monitor, a respiratory monitor, or by visual observation with the aid of a video monitor.

[0028] In some embodiments, the subject being managed is in a non-sedated state, awake, alert, with orientation maintained, clear, and able to respond to verbal or written instructions, including questions or requests. For example, at the start of administration, the subject may be in a non-sedated state. In other embodiments, the subject is in a non-sedated state at the start of administration and remains in a non-sedated state throughout one or more dosing intervals (i.e., the time the dexmedetomidine transdermal delivery device being targeted is in contact with the subject). In yet other embodiments, the subject is in a non-sedated state at the start of administration and remains in a non-sedated state throughout the entire management protocol.

[0029] In yet other embodiments, the amount of dexmedetomidine delivered to the subject is a sedating amount. "Sedating" means that the dexmedetomidine composition is formulated to deliver to the subject an amount of dexmedetomidine that causes sedation of the subject. In such embodiments, the patient may have a Wilson score of four or more, including five, and in cases as described above, if the subject is assigned a score of four, the subject may be considered not fully sedated.

[0030] As summarized above, in practicing the method according to an embodiment of the present invention, a transdermal delivery device having a dexmedetomidine composition is applied to a subject and maintained in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective to manage pain in the subject. The term "pain" is used in its conventional sense to refer to an unpleasant sensory and emotional experience associated with actual or potential tissue damage and is described in terms of such damage (e.g., as defined by the International Association for the Study of Pain). In some cases, pain includes the sensory experience that causes suffering in the subject. In embodiments, pain may include, but is not limited to, among other types of pain, acute pain, chronic pain, neuropathic pain, cancer-related pain, postoperative pain, moderate to severe pain, labor pain, perioperative pain. In some embodiments, the subject methods and transdermal delivery devices containing dexmedetomidine are used to complement anesthesia for preoperative and postoperative analgesia as well as for obstetric analgesia during and after labor and delivery.

[0031] In some embodiments, the pain is surgical pain. Surgical pain (also interchangeably referred to as "post-operative", "post-incisional" or "post-traumatic pain") refers to pain that occurs or results from external trauma such as a cut, puncture, incision, laceration, or wound into an individual's tissue (including that which results from a surgical procedure whether invasive or non-invasive). Surgical pain that may be treated in accordance with embodiments of the present invention includes perioperative pain, e.g., pain experienced during and / or after a surgical procedure, as well as post-operative pain, e.g., pain experienced after a surgical procedure. As used herein, "surgical pain" does not include pain that occurs without external physical trauma. In some embodiments, the surgical pain is internal or external pain, and the wound, cut, trauma, laceration, or incision may occur accidentally (similar to a traumatic wound) or intentionally (similar to a surgical incision). As used herein, "pain" includes the sensation of pain and the feeling of pain, and pain can be objectively and subjectively evaluated using pain scores and other methods, e.g., by protocols well known in the art. Surgical pain, as used herein, includes allodynia (i.e., pain due to a stimulus that does not normally evoke pain) and hyperalgesia (i.e., a heightened response to a stimulus that normally elicits pain), which can similarly be, in practice, thermal or mechanical (tactile). In some embodiments, the pain is characterized by heat sensitivity, mechanical sensitivity, and / or resting pain (e.g., pain that persists in the absence of external stimuli). In some embodiments, surgical pain includes mechanically induced pain or resting pain. In other embodiments, surgical pain includes resting pain. The pain can be primary pain (e.g., directly resulting from the event causing the pain) or secondary pain (e.g., related to the event causing the pain but not directly resulting therefrom).

[0032] Aspects of the present invention include methods of treating a subject for pain. In some embodiments, the methods include methods of treating a subject for surgical pain such as one or more of allodynia, hyperalgesia, heat-induced pain, mechanically-induced pain, or resting pain. For example, surgical pain can include mechanically-induced pain and / or resting pain. In some cases, surgical pain can include resting pain. "Treating" or "treatment" means at least suppressing or ameliorating a symptom associated with a condition that afflicts a subject, where suppression and amelioration are used broadly to refer to at least a decrease in a parameter, such as the magnitude of a symptom associated with the condition being treated, such as pain. As such, treatment includes situations where the condition is completely suppressed, such as prevented from occurring, or completely stopped, such as terminated, so that the subject no longer experiences the condition. As such, treatment includes both preventing and managing the condition. In certain embodiments, allodynia is suppressed, ameliorated, and / or prevented, and in some embodiments, hyperalgesia is suppressed, ameliorated, and / or prevented. In some cases, the pain is chronic pain. In other cases, the pain is at or near one or more sites of external trauma, wound, or incision. Additional aspects of the subject methods include methods of ameliorating and / or preventing the occurrence or progression of surgical pain by administering the subject dexmedetomidine by a transdermal delivery device.

[0033] As discussed above, the method can include, in certain cases, applying a transdermal delivery device having a dexmedetomidine composition containing dexmedetomidine and a pressure-sensitive adhesive to the skin surface of a subject who may be in a non-sedated state, and maintaining contact with the subject in a manner sufficient to deliver an effective amount of dexmedetomidine over a time period for managing pain in the subject. As discussed above, the amount may or may not have a sedative effect as desired. A non-sedative amount may allow for patient response or arousal and may be related to a score of 3 or less, including 2 or less on the Wilson sedation score. "Managing pain" or "pain management" means at least suppressing or improving pain, where suppression and improvement refer to at least a reduction in the magnitude of pain.

[0034] In some embodiments, the method includes extended transdermal delivery to a subject. "Extended transdermal delivery" means that the transdermal administration is formulated to provide delivery of the dexmedetomidine composition over an extended period of time, including over a period of hours, days, and weeks, including, for example, 1 hour or more, for example 2 hours or more, for example 4 hours or more, for example 8 hours or more, for example 12 hours or more, for example 24 hours or more, for example 48 hours or more, for example 72 hours or more, for example 96 hours or more, for example 120 hours or more, for example 144 hours or more, and including 168 hours or more. For the above ranges, the upper limit of time is, in certain cases, 168 hours or less, for example 144 hours or less, for example 120 hours or less, for example 96 hours or less, for example 72 hours or less, for example 48 hours or less, and including 24 hours or less. In certain embodiments, the extended transdermal delivery ranges, for example, from 0.5 hours to 168 hours, for example from 1 hour to 144 hours, for example from 1.5 hours to 120 hours, for example from 2 hours to 96 hours, for example from 2.5 hours to 72 hours, for example from 3 hours to 72 hours.

[0035] In some embodiments, sustained release transdermal administration of a dexmedetomidine composition involves delivering a therapeutically effective amount of a dexmedetomidine active agent to the skin of a subject over multiple days. Delivery over multiple days means that the transdermal composition is formulated to provide a therapeutically effective amount to the subject when the transdermal delivery device is applied to the skin of the subject for a time of 1 day or more, such as 2 days or more, such as 4 days or more, such as 7 days or more, such as 14 days or more, and including up to 30 days. For delivery over multiple days, the upper limit of time is, in some cases, 30 days or less, such as 28 days or less, such as 21 days or less, such as 14 days or less, such as 7 days or less, and including up to 3 days. In certain embodiments, transdermal delivery over multiple days extends, for example, from 2 days to 30 days, from 2 days to 15 days, from 2 days to 7 days, from 2 days to 4 days, and including 2 days to 4 days, such as 3 days, or 4 days.

[0036] Depending on the particular protocol employed, one or more administration intervals may be included in the pain management according to embodiments of the present invention. The term "administration interval" is used herein in its conventional meaning to mean the duration of a single administration in which a transdermal delivery device is applied and maintained in contact with a subject. In other words, the administration interval begins by applying a transdermal dexmedetomidine composition to the skin or mucosa of the subject and ends by removing the transdermal dexmedetomidine composition from contact with the subject. As such, the administration interval is the time during which an amount of dexmedetomidine is in contact with the skin or mucosa of the subject and may continue for about 0.5 hours or more, such as 1 hour or more, such as 2 hours or more, such as 4 hours or more, such as 8 hours or more, such as 12 hours or more, such as 16 hours or more, such as 20 hours or more, such as 24 hours or more, such as 30 hours or more, such as 36 hours or more, such as 48 hours or more, such as 72 hours or more, such as 96 hours or more, such as 120 hours or more, such as 144 hours or more, and may continue including 168 hours or more. The upper limit of the duration for the administration interval is, in some cases, 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 72 hours or less, such as 48 hours or less, and includes 40 hours or less. In certain embodiments, the duration of the administration interval ranges from 0.5 hours to 168 hours, such as from 24 hours to 144 hours, such as from 30 hours to 120 hours, such as from 36 hours to 96 hours, such as from 48 hours to 84 hours, such as from 60 hours to 84 hours, such as from 66 hours to 78 hours, such as up to 72 hours.

[0037] As used herein, the term "administration protocol" refers to one or more sequential dosing intervals sufficient to produce the desired therapeutic effect of the dexmedetomidine transdermal delivery device. In certain embodiments, the protocol includes a single dosing interval, so that only one dose, which consists of one or more transdermal devices, is applied to the subject. In such an example, a single transdermal delivery device may be applied to the subject. In other examples of such embodiments, two or more separate transdermal delivery devices may be applied to the subject substantially simultaneously. In these examples, two or more, such as three or more, including four or more, are applied to the subject substantially simultaneously. In certain of these examples, the number of separate transdermal delivery devices applied to the subject is 10 or less, such as, including, 8 or less, 6 or less, such as, 5 or less. "Substantially simultaneously" means that multiple transdermal delivery devices are applied at the same time, i.e., simultaneously or sequentially with a minimum time interval between the administrations of each transdermal delivery device, where the minimum time interval may vary, but in some cases, the range includes 10 minutes or less, such as, including, 5 minutes or less, 2 minutes or less, such as, 1 minute or less, such as, 15 seconds or less, including 30 seconds or less. As such, if there is a time interval between the administrations of multiple transdermal delivery devices in these embodiments, even if there is an interval, it has little practical effect on the active agent delivery profile from the transdermal delivery device to the subject.

[0038] In certain embodiments, the protocol may include multiple dosing intervals. "Multiple dosing intervals" means that more than one transdermal delivery device is applied and maintained in contact with the subject in a sequential manner. As such, the transdermal delivery device is removed from contact with the subject and a new transdermal delivery device is reapplied to the subject. In practicing the methods of the present invention, the administration schedule may include two or more dosing intervals, such as three or more dosing intervals, such as four or more dosing intervals, such as five or more dosing intervals, including 10 or more dosing intervals.

[0039] The duration between dosing intervals in a dosing interval management protocol may vary according to the physiological function of the subject or according to a management protocol as determined by a medical professional. For example, the duration between dosing intervals in a dosing interval management protocol may be predetermined and follow at regular intervals. As such, the time between dosing intervals may vary and may be 1 day or more, including 30 days or more, for example 2 days or more, for example 3 days or more, for example 4 days or more, for example 5 days or more, for example 6 days or more, for example 7 days or more, for example 10 days or more. The upper limit period of the time between dosing intervals may in some cases be 30 days or less, for example 28 days or less, for example 21 days or less, for example 14 days or less, for example 7 days or less, and includes 3 days or less. In certain embodiments, the time between dosing intervals may range from, for example, 2 days to 30 days, for example 3 days to 28 days, for example 4 days to 21 days, for example 5 days to 14 days, and includes 6 days to 10 days.

[0040] In some cases, the duration between dosing intervals may depend on the plasma concentration of dexmedetomidine during the time when the transdermal delivery device is not in contact with the subject during the dosing interval. For example, when the plasma concentration of dexmedetomidine falls below a specific threshold, the next subsequent dosing interval may be initiated.

[0041] In certain embodiments, dexmedetomidine can be administered by a transdermal delivery device prior to an activity that may result in an incision, such as external trauma, a wound, or surgery. For example, it can be administered by a transdermal delivery device prior to an activity that may result in an incision, such as for 30 minutes or more, 1 hour or more, 2 hours or more, 5 hours or more, 10 hours or more, 15 hours or more, 24 hours or more, such as 1 day or more before, for example, surgery. In other embodiments, dexmedetomidine can be administered by a transdermal delivery device during and / or after a surgery or activity that has resulted in an external trauma, a wound, or an incision. In some cases, dexmedetomidine is administered by a transdermal delivery device 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, 6 hours or more, 8 hours or more, 12 hours or more, 18 hours or more, 24 hours or more, 30 hours or more, 36 hours or more after a surgery or activity that has resulted in an external trauma, a wound, or an incision.

[0042] In some cases, an active agent derived from the composition is administered to the subject during the perioperative period. The term "perioperative period," as used herein, means, for example, before, during, and after the surgery in which the surgical procedure is performed. As such, prior to the surgical procedure, a transdermal delivery device is applied to the subject and then maintained on the subject during and for some time after the surgical procedure. For example, dexmedetomidine can be administered by a transdermal delivery device more than 30 minutes, more than 1 hour, more than 2 hours, more than 5 hours, more than 8 hours, more than 9 hours, more than 10 hours, more than 11 hours, more than 12 hours, more than 15 hours, more than 18 hours, more than 24 hours, for example, 1 day or more before the surgical procedure and can be maintained on the subject during the surgical procedure. In some cases, the transdermal delivery device is applied somewhere between 0.50 to 30 hours before the surgery, for example, between 1 to 24 hours before the surgery. The subject composition is then maintained on the subject for the time following the surgical procedure, where the post-operative maintenance time may vary and in some cases is more than 1 hour, for example, more than 2 hours, for example, more than 4 hours, for example, more than 8 hours, for example, more than 12 hours, for example, more than 24 hours, for example, more than 48 hours, for example, more than 72 hours, for example, more than 96 hours, for example, more than 120 hours, for example, more than 144 hours, and includes more than 168 hours. For the above ranges, the upper limit time is in some cases 168 hours or less, for example, 144 hours or less, for example, 120 hours or less, for example, 96 hours or less, for example, 72 hours or less, for example, 48 hours or less, and includes 24 hours or less. In certain embodiments, the extended transdermal delivery extends, for example, from 0.5 hours to 168 hours, for example, from 1 hour to 144 hours, for example, from 1.5 hours to 120 hours, for example, from 2 hours to 96 hours, for example, from 2.5 hours to 72 hours, for example, from 3 hours to 72 hours. In certain embodiments, the perioperative delivery dosing schedule is a multi-day perioperative transdermal dosing schedule spanning from before to after the surgical procedure, where in some cases, this dosing schedule is from 2 days to 30 days, for example, from 2 days to 15 days, for example, from 2 days to 7 days, for example, from 2 days to 4 days and, and from 2 days to 4 days, for example, including 3 days.

[0043] In some embodiments, the transdermal delivery device is applied and maintained in contact with the subject for a total duration of 72 hours. In one example, the transdermal delivery device is applied 4 hours before the start of a surgical procedure, maintained in contact with the subject during the surgery, and removed after a total duration of 72 hours. In another example, the transdermal delivery device is applied 6 hours before the start of a surgical procedure, maintained in contact with the subject during the surgery, and removed after a total duration of 72 hours. In yet another example, the transdermal delivery device is applied 12 hours before the start of a surgical procedure, maintained in contact with the subject during the surgery, and removed after a total duration of 72 hours. In yet another example, the transdermal delivery device is applied 18 hours before the start of a surgical procedure, maintained in contact with the subject during the surgery, and removed after a total duration of 72 hours. In still another example, the transdermal delivery device is applied 24 hours before the start of a surgical procedure, maintained in contact with the subject during the surgery, and removed after a total duration of 72 hours. In still another example, the transdermal delivery device is applied 24 hours before the start of a surgical procedure, maintained in contact with the subject during the surgery, and removed after a total duration of 84 hours. In still another example, the transdermal delivery device is applied 24 hours before the start of a surgical procedure, maintained in contact with the subject during the surgery, and removed after a total duration of 96 hours.

[0044] In other embodiments, one or more of the transdermal delivery devices of the subject are applied to the subject at a predetermined time (e.g., 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc.) prior to the start of a surgical procedure and are maintained in contact with the subject for at least 72 hours after the completion of the surgery. As such, the total duration that the transdermal delivery device is maintained in contact with the subject may be 76 hours or more, such as 80 hours or more, such as 84 hours or more, such as 90 hours or more, and includes 96 hours or more. In one example, the transdermal delivery device is applied 4 hours prior to the start of the surgical procedure, is maintained in contact with the subject during the surgery, and is held in contact with the subject for at least 72 hours after the surgery. In another example, the transdermal delivery device is applied 6 hours prior to the start of the surgical procedure, is maintained in contact with the subject during the surgery, and is held in contact with the subject for at least 72 hours after the surgery. In yet another example, the transdermal delivery device is applied 12 hours prior to the start of the surgical procedure, is maintained in contact with the subject during the surgery, and is held in contact with the subject for at least 72 hours after the surgery. In yet another example, the transdermal delivery device is applied 18 hours prior to the start of the surgical procedure, is maintained in contact with the subject during the surgery, and is held in contact with the subject for at least 72 hours after the surgery. In still another example, the transdermal delivery device is applied 24 hours prior to the start of the surgical procedure, is maintained in contact with the subject during the surgery, and is held in contact with the subject for at least 72 hours after the surgery. In still another example, the transdermal delivery device is applied 24 hours prior to the start of the surgical procedure, is maintained in contact with the subject during the surgery, and is held in contact with the subject for at least 84 hours after the surgery. In still another example, the transdermal delivery device is applied 24 hours prior to the start of the surgical procedure, is maintained in contact with the subject during the surgery, and is held in contact with the subject for at least 96 hours after the surgery.

[0045] As described above, aspects of the invention include managing pain in a subject by applying to a transdermal delivery device containing a dexmedetomidine composition formulated to deliver an effective amount of dexmedetomidine. In some cases, aspects of the invention include managing perioperative pain, which in some cases results in the treatment of postoperative pain and in some cases results in the treatment of intraoperative pain, where perioperative pain includes postoperative pain and pain experienced during surgery. In some embodiments, the method comprises maintaining a transdermal delivery device in contact with the subject in a manner sufficient to deliver a target dose of dexmedetomidine to manage pain in the subject, e.g., delivering a target dose as determined by the total drug exposure that would manage pain, or by the average daily drug exposure. The term, target dose, means the desired amount of dexmedetomidine to be absorbed. Depending on the desired therapeutic effect of the transdermal dexmedetomidine composition, the target drug exposure to manage pain may vary according to the management protocol, the physiological state of the subject, and the level of sedation in the subject at the time of administration. In certain embodiments, the target drug exposure of dexmedetomidine is an amount within the non-sedating treatment window is.

[0046] The term "non - sedating treatment window" is used herein to refer to the dosage range of dexmedetomidine that is therapeutically effective in managing pain in subjects who produce little to no sedation, if any. In other words, the non - sedating treatment window of dexmedetomidine for a particular individual subject being managed for pain is the range of concentrations of dexmedetomidine that is defined as being below the amount considered to be "complete sedation" or "inducing complete sedation" and above the amount considered to be "ineffective" in managing pain in the subject. In certain embodiments of the present invention, the non - sedating and therapeutically effective amount provides a systemic amount of dexmedetomidine that enables the desired management while maintaining a Wilson score of 3 or less in the subject. For example, in managing pain in a subject, the targeted non - sedating dosage of dexmedetomidine can range from 50 μg / day to 350 μg / day over the course of the dosing interval, such as 100 μg / day to 340 μg / day, such as 145 μg / day to 330 μg / day, such as 155 μg / day to 320 μg / day, such as 165 μg / day to 310 μg / day, such as 175 μg / day to 300 μg / day, such as 185 μg / day to 290 μg / day, such as 195 μg / day to 280 μg / day, and can include 50 μg / day to 250 μg / day (e.g., for a 168 - hour dosing interval). In certain embodiments, the targeted dosage of dexmedetomidine ranges from 147 μg / day to 290 μg / day over the course of the dosing interval (e.g., for a dosing interval of 168 hours or more).

[0047] In some embodiments, the targeted dosage is an amount that provides a systemic amount of dexmedetomidine that results in a desired average plasma concentration of dexmedetomidine at a particular time during pain management when applied to the subject. In other embodiments, the targeted dosage is an amount that provides a steady - state average plasma concentration of dexmedetomidine over the entire dosing interval or management protocol when applied to the subject. In other embodiments, the targeted dosage is an amount that provides a particular rate of delivering dexmedetomidine to the subject in vivo when applied to the subject.

[0048] In some embodiments, applying and maintaining contact with a subject a transdermal delivery device containing a dexmedetomidine composition involves delivery of a target amount of dexmedetomidine, e.g., an average cumulative amount of dexmedetomidine delivered over the course of a dosing interval (e.g., 7 days or more). The term “target cumulative amount” means the total amount of dexmedetomidine delivered to the subject through the skin, which may vary depending on the permeability of the skin or mucosa and the metabolic activity of the site of application. In some embodiments, the average cumulative amount of dexmedetomidine is 5 μg / cm 2 or more, e.g., 25 μg / cm 2 or more, e.g., 50 μg / cm 2 or more, over a dosing interval, e.g., 75 μg / cm 2 or more, e.g., 100 μg / cm 2 or more, e.g., 125 μg / cm 2 or more, and may include 200 μg / cm 2 or more. For the average cumulative amount of dexmedetomidine delivery over a dosing interval, the upper limit may in some cases be 500 μg / cm 2 or less, e.g., 400 μg / cm 2 or less, e.g., 300 μg / cm 2 or less, e.g., 200 μg / cm 2 or less, e.g., 100 μg / cm 2 or less, and may include 50 μg / cm 2 or less. In certain embodiments, the average cumulative amount of dexmedetomidine delivery over a dosing interval is, e.g., 5 μg / cm 2 to 500 μg / cm 2 , e.g., 25 μg / cm 2 to 400 μg / cm 2 , and may include 50 μg / cm 2 to 300 μg / cm 2 .

[0049] The method according to a particular embodiment involves applying to one or more transdermal delivery devices containing a dexmedetomidine composition, for example, 2 to 4, for example, 3 transdermal delivery devices, and contacting the subject in a manner sufficient to provide an average plasma concentration ranging from 0.05 ng / mL to 0.5 ng / mL, for example, from 0.1 ng / mL to 0.45 ng / mL, for example, from 0.15 ng / mL to 0.4 ng / mL, for example, from 0.2 ng / mL to 0.35 ng / mL, and including 0.25 ng / mL to 0.3 ng / mL over the course of the dosing interval to maintain the transdermal dex medetomidine composition. For example, the transdermal delivery device may be maintained in contact with the subject in a manner sufficient to provide an average plasma concentration ranging from 0.16 ng / mL to 0.36 ng / mL over the course of the dosing interval (for example, a dosing interval of 168 hours or more). In other embodiments, the method involves maintaining the dexmedetomidine composition by contacting the subject in a manner sufficient to provide an average plasma concentration ranging from 0.05 ng / mL to 0.5 ng / mL over the course of the entire administration protocol (i.e., over one or more dosing intervals), for example, from 0.1 ng / mL to 0.45 ng / mL over the course of the entire administration protocol, for example, from 0.15 ng / mL to 0.4 ng / mL, for example, from 0.2 ng / mL to 0.35 ng / mL, and including 0.25 ng / mL to 0.3 ng / mL. For example, the transdermal delivery device may be maintained in contact with the subject in a manner sufficient to provide an average plasma concentration ranging from 0.16 ng / mL to 0.36 ng / mL over the course of the entire administration protocol.

[0050] As discussed above, the method includes delivering dexmedetomidine to a subject to manage surgical pain in the subject over an extended period of time, such as over 6 hours, such as over 12 hours, such as over 24 hours, such as over 48 hours, such as over 72 hours, such as over 96 hours, such as over 120 hours, such as over 144 hours, and over 168 hours. In certain embodiments, the method includes maintaining a transdermal dexmedetomidine composition in contact with the skin surface of the subject sufficient to provide a target average amount of absorbed dexmedetomidine over 72 hours. Depending on the surface area of the transdermal delivery device (e.g., 6 cm 2 , 4 cm 2 , 2 cm 2 , etc.), the average amount of dexmedetomidine absorbed over 72 hours may vary, such as, for example, 150 mcg to 600 mcg, such as 175 mcg to 575 mcg, such as 100 mcg to 400 mcg, such as 125 mcg to 375 mcg, such as 50 mcg to 200 mcg, and including 60 mcg to 190 mcg. In some cases, the transdermal delivery device has a surface area of 6 cm 2 , and the transdermal dexmedetomidine composition is maintained in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 192.7 mcg to 551.7 mcg over 72 hours, such as 224 mcg to 437 mcg, such as 278 mcg to 384 mcg, such as 304 mcg to 357 mcg, and including 320 mcg to 341 mcg. In other examples, the transdermal delivery device has a surface area of 4 cm 2 , and the transdermal dexmedetomidine composition is maintained in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 100 mcg to 400 mcg over 72 hours, such as 125 mcg to 375 mcg, such as 128.5 mcg to 367.8 mcg, such as 150 mcg to 292 mcg, such as 185 mcg to 256 mcg, such as 203 mcg to 238 mcg, and including 213 mcg to 228 mcg. In yet other examples, the transdermal delivery device has a surface area of 2 cm 2Having a surface area, the transdermal dexmedetomidine composition is maintained in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine with an average absorption amount of 50 mcg to 200 mcg over 72 hours, such as 60 mcg to 190 mcg, such as 64 mcg to 184 mcg, such as 75 mcg to 146 mcg, such as 93 mcg to 128 mcg, such as 101 mcg to 119 mcg, and including 107 mcg to 114 mcg.

[0051] In other embodiments, the method may include maintaining the transdermal dexmedetomidine composition in contact with the skin surface of the subject sufficient to provide average dexmedetomidine absorption over 72 hours. The surface area of the transdermal delivery device (e.g., 6 cm 2 , 4 cm 2 , 2 cm 2 , etc.), depending on the surface area of the transdermal delivery device, the average dexmedetomidine absorption over 72 hours may range from 1 mcg / hour to 10 mcg / hour, 2 mcg / hour to 8 mcg / hour, 0.5 mcg / hour to 6 mcg / hour, 1 mcg / hour to 5.5 mcg / hour, 0.1 mcg / hour to 5 mcg / hour, and may vary to include 0.5 mcg / hour to 3 mcg / hour. In some cases, the transdermal delivery device has a surface area of 6 cm 2 , and the transdermal dexmedetomidine composition is maintained in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 1 mcg / hour to 10 mcg / hour over 72 hours, such as 2 mcg / hour to 8 mcg / hour, such as 3.1 mcg / hour to 6.1 mcg / hour, such as 3.9 mcg / hour to 5.3 mcg / hour, such as 4.2 mcg / hour to 5.0 mcg / hour, and including 4.4 mcg / hour to 4.7 mcg / hour. In other examples, the transdermal delivery device is 4 cm 2has a surface area, and the transdermal dexmedetomidine composition is maintained in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of from 0.5 mcg / hour to 6 mcg / hour over 72 hours, such as from 1 mcg / hour to 5.5 mcg / hour, such as from 1.8 mcg / hour to 5.1 mcg / hour, such as from 2.1 mcg / hour to 4.1 mcg / hour, such as from 2.6 mcg / hour to 3.6 mcg / hour, such as from 2.8 mcg / hour to 3.3 mcg / hour, and including from 3.0 mcg / hour to 3.2 mcg / hour. In yet other examples, the transdermal delivery device is 2 cm 2 has a surface area, and the transdermal dexmedetomidine composition is maintained in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of from 0.1 mcg / hour to 5 mcg / hour over 72 hours, such as from 0.5 mcg / hour to 3 mcg / hour, such as from 0.9 mcg / hour to 2.6 mcg / hour, such as from 1.0 mcg / hour to 2.0 mcg / hour, such as from 1.3 mcg / hour to 1.8 mcg / hour, such as from 1.4 mcg / hour to 1.7 mcg / hour, and including from 1.5 mcg / hour to 1.6 mcg / hour.

[0052] In other embodiments, the method may include maintaining a transdermal dexmedetomidine composition in contact with the skin surface of the subject sufficient to provide an average maximum plasma concentration of dexmedetomidine over 72 hours. Depending on the surface area of the transdermal delivery device (e.g., 6 cm 2 , 4 cm 2 , 2 cm 2 , etc.), the average maximum plasma concentration of dexmedetomidine absorption over 72 hours may range from 50 pg / mL to 250 pg / mL, from 70 pg / mL to 225 pg / mL, from 25 pg / mL to 150 pg / mL, from 40 pg / mL to 140 pg / mL, from 10 pg / mL to 80 pg / mL, and including from 20 pg / mL to 70 pg / mL. In certain cases, the transdermal delivery device is 6 cm 2has a surface area, and the transdermal dexmedetomidine composition is maintained in contact with the subject's skin surface in a manner sufficient to provide a mean maximum plasma concentration of dexmedetomidine of 50 pg / mL to 250 pg / mL over 72 hours, such as 70 pg / mL to 225 pg / mL, such as 70.1 pg / mL to 205 pg / mL, such as 77 pg / mL to 153 pg / mL, such as 96 pg / mL to 134 pg / mL, such as 106 pg / mL to 125 pg / mL, and including 111 pg / mL to 119 pg / mL. In other examples, the transdermal delivery device is 4 cm 2 has a surface area, and the transdermal dexmedetomidine composition is maintained in contact with the subject's skin surface in a manner sufficient to provide a mean maximum plasma concentration of dexmedetomidine of 25 pg / mL to 150 pg / mL over 72 hours, such as 40 pg / mL to 140 pg / mL, such as 47 pg / mL to 137 pg / mL, such as 51 pg / mL to 102 pg / mL, such as 64 pg / mL to 90 pg / mL, such as 70 pg / mL to 83 pg / mL, and including 74 pg / mL to 79 pg / mL. In yet other examples, the transdermal delivery device is 2 cm 2 has a surface area, and the transdermal dexmedetomidine composition is maintained in contact with the subject's skin surface in a manner sufficient to provide a mean maximum plasma concentration of dexmedetomidine of 10 pg / mL to 80 pg / mL over 72 hours, such as 20 pg / mL to 70 pg / mL, such as 23.4 pg / mL to 68.3 pg / mL, such as 26 pg / mL to 51 pg / mL, such as 32 pg / mL to 45 pg / mL, and including 35 pg / mL to 42 pg / mL.

[0053] In other embodiments, the method may include maintaining the transdermal dexmedetomidine composition in contact with the subject's skin surface sufficient to provide an area under the curve of the plasma dexmedetomidine concentration from the time of application to infinity. The surface area of the transdermal delivery device (e.g., 6 cm 2 , 4 cm 2 , 2 cm 2 , etc.) depends on the concentration of plasma dexmedetomidine over 72 hours The average area under the curve may vary over 3000 hours × pg / mL to 10000 hours × pg / mL, 3500 hours × pg / mL to 9000 hours × pg / mL, 2000 hours × pg / mL to 7500 hours × pg / mL, 2250 hours × pg / mL to 6000 hours × pg / mL, 1000 hours × pg / mL to 3500 hours × pg / mL, and may include 1100 hours × pg / mL to 3000 hours × pg / mL. In some cases, the transdermal delivery device is 6 cm 2 in surface area, and the transdermal dexmedetomidine composition is maintained in contact with the subject's skin surface in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 3517 hours × pg / mL to 8954 hours × pg / mL over 72 hours, such as 4548 hours × pg / mL to 7712 hours × pg / mL, such as 5339 hours × pg / mL to 6921 hours × pg / mL, such as 5735 hours × pg / mL to 6525 hours × pg / mL, and including 5972 hours × pg / mL to 6288 hours × pg / mL. In other examples, the transdermal delivery device is 4 cm 2 in surface area, and the transdermal dexmedetomidine composition is maintained in contact with the subject's skin surface in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 2345 hours × pg / mL to 5969 hours × pg / mL over 72 hours, such as 3032 hours × pg / mL to 5141 hours × pg / mL, such as 3559 hours × pg / mL to 4614 hours × pg / mL, such as 3823 hours × pg / mL to 4350 hours × pg / mL, and including 3981 hours × pg / mL to 4192 hours × pg / mL. In yet other embodiments, the transdermal delivery device is 2 cm 2 in surface area, and the transdermal dexmedetomidine composition is maintained in contact with the subject's skin surface in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 1172 hours × pg / mL to 2985 hours × pg / mL over 72 hours, such as 1516 hours × pg / mL to 2571 hours × pg / mL, such as 1780 hours × pg / mL to 2307 hours × pg / mL, such as 1912 hours × pg / mL to 2175 hours × pg / mL, and including 1991 hours × pg / mL to 2096 hours × pg / mL.

[0054] In certain embodiments, the method may also include determining the plasma concentration of dexmedetomidine in the subject during pain management in the subject. The concentration of plasma dexmedetomidine may be determined using any conventional protocol, for example, by liquid chromatography - mass spectrometry (LCMS). The plasma concentration of dexmedetomidine may be determined at a desired time. In some embodiments, the plasma concentration of dexmedetomidine may be monitored, for example, by real - time data collection, throughout the entire time the transdermal delivery device is maintained in contact with the subject. In other examples, the plasma concentration of dexmedetomidine is monitored by collecting data at regular intervals while maintaining the transdermal delivery device in contact with the subject, for example, every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours, every 72 hours, or at some other interval. In yet other examples, the plasma concentration of dexmedetomidine is monitored by collecting data according to a specific time schedule after applying the transdermal delivery device to the subject while maintaining the transdermal delivery device in contact with the subject. For example, the plasma concentration of dexmedetomidine may be determined 15 minutes after applying the transdermal delivery device to the subject, 30 minutes after applying the transdermal delivery device to the subject, 1 hour after applying the transdermal delivery device to the subject, 2 hours after applying the transdermal delivery device to the subject, 4 hours after applying the transdermal delivery device to the subject, 8 hours after applying the transdermal delivery device to the subject, 12 hours after applying the transdermal delivery device to the subject, 24 hours after applying the transdermal delivery device to the subject, 48 hours after applying the transdermal delivery device to the subject, 72 hours after applying the transdermal delivery device to the subject, 76 hours after applying the transdermal delivery device to the subject, 80 hours after applying the transdermal delivery device to the subject, 84 hours after applying the transdermal delivery device to the subject, 96 hours after applying the transdermal delivery device to the subject, 120 hours after applying the transdermal delivery device to the subject, and 168 hours after applying the transdermal delivery device to the subject.

[0055] In certain embodiments, the plasma concentration of dexmedetomidine is determined before the transdermal delivery device is applied to the subject, e.g., to determine the baseline plasma concentration of dexmedetomidine. For example, the plasma concentration may be determined 5 minutes before applying the transdermal delivery device, e.g., 10 minutes before applying the transdermal delivery device, e.g., 30 minutes before, e.g., 60 minutes before, e.g., 120 minutes before, e.g., 240 minutes before, and including 480 minutes before applying the transdermal delivery device. As described in detail below, the method may include multiple dosing intervals that may be repeated, including applying the transdermal delivery device and maintaining contact with the subject. In these embodiments, the plasma concentration may be determined after the first transdermal delivery device is removed and before the second transdermal delivery device is applied. The plasma concentration of dexmedetomidine may be determined one or more times during any given measurement period, including five or more times during each measurement period, e.g., two or more times, e.g., three or more times. The upper limit on the number of times the plasma concentration of dexmedetomidine is determined during any given measurement period may, in some cases, be ten or less, e.g., seven or less, e.g., five or less, e.g., three or less, and including two or less. In certain embodiments, the number of times the plasma concentration of dexmedetomidine is determined during any given measurement period ranges, e.g., from two to ten times, e.g., from three to nine times, e.g., from four to eight times, and including from five to seven times.

[0056] The plasma concentration of dexmedetomidine may be determined one or more times during any given measurement period, including five or more times during each measurement period, e.g., two or more times, e.g., three or more times. The upper limit on the number of times the plasma concentration of dexmedetomidine is determined during any given measurement period may, in some cases, be ten or less, e.g., seven or less, e.g., five or less, e.g., three or less, and including two or less. In certain embodiments, the number of times the plasma concentration of dexmedetomidine is determined during any given measurement period ranges, e.g., from two to ten times, e.g., from three to nine times, e.g., from four to eight times, and including from five to seven times.

[0057] A method of managing pain according to certain embodiments comprises applying a transdermal delivery device containing a dexmedetomidine composition to a subject and maintaining the transdermal dexmedetomidine composition in contact with the subject in a manner sufficient to maintain a transdermal dexmedetomidine flux within a range of at least 30% of the peak transdermal flux after reaching the peak transdermal flux. As such, once the transdermal delivery device targeted reaches the peak transdermal dexmedetomidine flux, the transdermal delivery device is configured to maintain a flux of dexmedetomidine to the subject that is at least 30% of the peak flux, for example at least 35%, for example at least 40%, and including at least 50% during the course of any given dosing interval. In other words, once the peak flux is achieved by the transdermal delivery device according to these particular embodiments, the transdermal flux of dexmedetomidine to the subject does not fall below 30% of the peak flux at any time during the dosing interval.

[0058] For example, the transdermal dexmedetomidine delivery device may be maintained in contact with the subject in a manner sufficient to maintain a transdermal dexmedetomidine flux within a range of at least 50% of the peak transdermal dexmedetomidine flux, for example at least 55%, for example at least 60%, for example at least 65%, for example at least 70%, for example at least 75%, for example at least 80%, for example at least 85%, for example at least 90%, for example at least 95%, and including within a range of 99% after reaching the peak transdermal flux. In certain embodiments, the transdermal dexmedetomidine flux does not decrease at all after reaching the peak flux and maintains a ratio of 100% of the peak dexmedetomidine flux from the moment the peak flux is reached until the end of a given dosing interval.

[0059] The flux of the active agent by transdermal administration is the rate of penetration of the active agent through the skin or mucosa of the subject. In some cases, the flux of dexmedetomidine is given by the equation: (1) J 皮膚の流量 = P × C It can be determined by the formula, where J is the skin flux, C is the concentration gradient across the skin or mucosa, and P is the permeability coefficient. The skin flux is the change in the cumulative amount of the drug entering the body across the skin or mucosa with respect to time.

[0060] In some cases, the transdermal dexmedetomidine delivery device is 0.05 μg / cm 2 / hour or more, for example 0.1 μg / cm 2 / hour or more, for example 0.5 μg / cm 2 / hour or more, for example 1 μg / cm 2 / hour, for example 2 μg / cm 2 / hour, for example 3 μg / c m 2 / hour or more, for example 5 μg / cm 2 / hour or more, for example 7.5 μg / cm 2 It is maintained in contact with the subject in a manner sufficient to provide a peak flux of 10 μg / cm 2 / hour or more and is maintained including maintaining the transdermal dexmedetomidine delivery device in contact with the subject in a manner sufficient to provide a peak flux of 10 μg / cm 2 / hour or less, for example 9 μg / cm 2 / hour or less, for example 8 μg / cm 2 / hour or less, for example 7 μg / cm 2 / hour or less, 6 μg / cm 2 / hour or less, for example 5 μg / cm 2 / hour or less and includes 2 μg / cm 2 / hour or less. In certain embodiments, the peak flux of transdermal dexmedetomidine delivery is, for example, 0.05 μg / cm 2 / hour to 10 μg / cm 2 / hour, for example 1 μg / cm 2 / hour to 9 μg / cm 2 / hour and extends to and includes 2 μg / cm 2 / hour to 8 μg / cm 2 / hour.

[0061] As such, when a transdermal dexmedetomidine delivery device is maintained in contact with a subject in a manner sufficient to provide a transdermal dexmedetomidine flux that is at least within 30% of the peak transdermal dexmedetomidine flux, the transdermal delivery device reaches a peak transdermal flux of 0.5 μg / cm 2 / hour and then is at least 0.15 μg / cm 2 / hour, reaches a peak transdermal flux of 0.6 μg / cm 2 / hour and then is for example at least 0.18 μg / cm 2 / hour, reaches a peak transdermal flux of 0.75 μg / cm 2 / hour and then is for example at least 0.225 μg / cm 2 / hour, reaches a peak transdermal flux of 0.9 μg / cm 2 / hour and then is for example at least 0.27 μg / cm 2 / hour, reaches a peak flux of 1.0 μg / cm 2 / hour and then is for example at least 0.3 μg / cm 2 / hour, reaches a peak flux of 5 μg / cm 2 / hour and then is for example at least 1.5 μg / cm 2 / hour, and may be maintained in contact with the subject in a manner sufficient to provide a flux that is at least 3.0 μg / cm 2 / hour after reaching a peak flux of 10.0 μg / cm 2 / hour. This includes maintaining the transdermal dexmedetomidine delivery device in contact with the subject in a manner sufficient to provide such fluxes.

[0062] Depending on the amount of dexmedetomidine present in the dexmedetomidine composition of the transdermal delivery device, the physiological state of the subject, the target site of application, and the time required to reach the peak dexmedetomidine flux may vary. In some cases, the peak dexmedetomidine flux is reached after 2 hours or more after applying the transdermal delivery device to the subject, for example, after 4 hours or more, for example, after 6 hours or more, for example, after 12 hours or more, for example, after 18 hours or more, and including after 24 hours or more. In other examples, the peak dexmedetomidine flux is reached 168 hours or earlier, for example, 144 hours or earlier, for example, 120 hours or earlier, for example, 96 hours or earlier, for example, 72 hours or earlier, for example, 48 hours or earlier, for example, 24 hours or earlier, for example, 12 hours or earlier, for example, 8 hours or earlier, for example, 4 hours or earlier, and including 2 hours or earlier after applying the transdermal delivery device to the subject. In some embodiments, the peak dexmedetomidine flux is reached 24 hours after applying the transdermal delivery device to the subject.

[0063] In certain embodiments, during the management of pain in a subject, the transdermal composition is maintained in contact with the subject for a sufficient time to provide the subject with a steady-state average flux of dexmedetomidine. The term "steady state" is used in its conventional meaning to mean that the amount of dexmedetomidine released from the transdermal delivery device maintains a substantially constant average flux of dexmedetomidine. As such, the flux of dexmedetomidine from the transdermal delivery device being targeted varies by 50% or less, for example, 45% or less, for example, 40% or less, for example, 35% or less, for example, 30% or less, for example, 25% or less, for example, 20% or less, for example, 15% or less, for example, 12% or less, for example, 10% or less, for example, 6% or less, for example, 5% or less, for example, 4% or less at any time while the transdermal delivery device is maintained in contact with the subject, and varies by 1% or less, including at any time while the transdermal delivery device is maintained in contact with the subject.

[0064] When the dexmedetomidine transdermal delivery device is maintained in contact with a subject sufficient to provide a steady state average flow rate of dexmedetomidine, the steady state average dexmedetomidine flow rate may be maintained for 0.5 hours or more, such as 1 hour or more, such as 2 hours or more, such as 3 hours or more, such as 4 hours or more, such as 8 hours or more, 12 hours or more, such as 24 hours or more, such as 36 hours or more, such as 48 hours or more, such as 72 hours or more, such as 96 hours or more, such as 120 hours or more, such as 144 hours or more, and may be maintained including 168 hours or more. For maintaining the steady state average dexmedetomidine flow rate, the upper limit is, in some cases, 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 72 hours or less, such as 48 hours or less, such as 24 hours or less, such as 12 hours or less, such as 8 hours or less, such as 4 hours or less, and includes 2 hours or less.

[0065] In these embodiments, the transdermal delivery device is configured to provide a constant flow rate by introducing a concentration gradient across the skin or mucosa or by providing an excess in the dosage of dexmedetomidine. For example, the targeted dexmedetomidine transdermal composition may include a dosage of dexmedetomidine that exceeds the normal dosage by more than 5%, for example by more than 10%, for example by more than 15%, for example by more than 20%, and including more than 25%. For the amount of excess dexmedetomidine present in the transdermal delivery device to provide a constant flow rate, the upper limit is, in some cases, an excess of 50% or less of the normal dosage, for example an excess of 45% or less, for example an excess of 25% or less, for example an excess of 20% or less, and including an excess of 10% or less. While the targeted dexmedetomidine transdermal composition may include an excess to provide a constant flow rate, the excess dosage is not absorbed as part of the dosing interval and is not sufficient to produce a fully sedating dosage (i.e., the dosage of dexmedetomidine delivered to the subject remains a non-sedating amount). As such, in some embodiments where the transdermal dexmedetomidine delivery device is maintained in a manner sufficient to provide a constant flow rate, 25% or less of the available dexmedetomidine in the transdermal composition may not be utilized, for example 20% or less, for example 15% or less, for example 10% or less, for example 5% or less, and including 1% or less of the available dexmedetomidine in the transdermal composition may not be utilized during the dosing interval.

[0066] A method for managing pain (e.g., surgical pain) in a subject according to certain embodiments includes applying to the subject a transdermal delivery device containing a dexmedetomidine composition configured to deliver a non-sedating amount of dexmedetomidine, and at any time after applying the transdermal delivery device, from about 0.005 to about 5 μg / cm 2 ·hour, for example from about 0.01 to about 4 μg / cm 2 ·hour, for example from about 0.02 to about 3 μg / cm 2 ·hour, for example from about 0.05 to about 2.5 μg / cm 2 ·hour, for example from about 0.1 to about 2 μg / cm2 · per unit time and about 0.1 to about 1 μg / cm 2 · maintaining a transdermal dexmedetomidine composition by contacting a subject in a manner sufficient to provide an average flux of dexmedetomidine in vivo that includes time. In some embodiments, the method comprises applying a transdermal dexmedetomidine composition to a subject and, about 24 hours after application, about 0.005 to about 2 μg / cm 2 · per unit time, for example about 0.01 to about 1.75 μg / cm, about 24 hours after application 2 · per unit time, for example about 0.02 to about 1.5 μg / cm 2 · per unit time, for example about 0.05 to about 1.25 μg / cm 2 · per unit time and, for example, about 0.1 to about 1 μg / cm 2 · maintaining a transdermal delivery device by contacting a subject in a manner sufficient to provide an average flux of dexmedetomidine in vivo that includes time. In still other embodiments, the method comprises applying a transdermal dexmedetomidine delivery device to a subject and, about 168 hours after application, 0.005 to about 2.0 μg / cm 2 · per unit time, for example about 0.01 to about 1.75 μg / cm, about 168 hours after application 2 · per unit time, for example about 0.02 to about 1.5 μg / cm 2 · per unit time, for example about 0.05 to about 1.25 μg / cm 2 · per unit time and about 0.1 to about 1 μg / cm 2 · maintaining a transdermal delivery device by contacting a subject in a manner sufficient to provide an average flux of dexmedetomidine in vivo that includes time.

[0067] In certain embodiments, the method includes determining the flux of transdermal dexmedetomidine. The flux of transdermal dexmedetomidine may be determined using any conventional protocol, for example, by a protocol using human cadaver skin including the epidermal layer (stratum corneum and epidermis) in a Franz cell having a fixed donor side and receptor side together with a receptor solution containing phosphate buffer. The amount of dexmedetomidine permeated can be further characterized by liquid chromatography. The flux of transdermal dexmedetomidine may be determined at any time during the method of the present invention. In some embodiments, the flux of transdermal dexmedetomidine may be monitored throughout the time that the transdermal dexmedetomidine delivery device is maintained in contact with the permeation barrier (e.g., human cadaver skin), for example, by real-time data collection. In other examples, the flux of transdermal dexmedetomidine is monitored by collecting data at regular intervals, including, for example, every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours, every 72 hours, or by collecting data at other regular or irregular intervals. In still other examples, the flux of transdermal dexmedetomidine is monitored by collecting data according to a specific time schedule. For example, the flux of transdermal dexmedetomidine may be determined 15 minutes after application of the transdermal delivery device, 30 minutes after application of the transdermal delivery device, 1 hour after application of the transdermal delivery device, 2 hours after application of the transdermal delivery device, 4 hours after application of the transdermal delivery device, 8 hours after application of the transdermal delivery device, 12 hours after application of the transdermal delivery device, 24 hours after application of the transdermal delivery device, 48 hours after application of the transdermal delivery device, 72 hours after application of the transdermal delivery device, 76 hours after application of the transdermal delivery device, 80 hours after application of the transdermal delivery device, 84 hours after application of the transdermal delivery device, 96 hours after application of the transdermal delivery device, 120 hours after application of the transdermal delivery device, and 168 hours after application of the transdermal delivery device.

[0068] The flow rate of transdermal dexmedetomidine may be determined one or more times, such as two or more times, such as three or more times, including five or more times, in any given measurement period. The upper limit of the number of times the flow rate of transdermal dexmedetomidine is determined is, in some cases, 10 or less, such as 7 or less, such as 5 or less, such as 3 or less, and includes 2 or less. In certain embodiments, the number of times the flow rate of transdermal dexmedetomidine is determined ranges from, for example, 2 to 10, such as 3 to 9, such as 4 to 8, and includes 5 to 7.

[0069] In some embodiments, in maintaining the dexmedetomidine transdermal delivery device in contact with the subject, the average cumulative amount of dexmedetomidine that has permeated increases at a substantially linear rate over the course of the dosing interval (e.g., 2 days or more, such as 3 days or more). "Substantially linear" means that the cumulative amount of dexmedetomidine released from the transdermal composition increases at a substantially constant rate (i.e., defined by zero-order kinetics). As such, the change in the ratio of the cumulative permeated dexmedetomidine increases or decreases by 10% or less, such as 8% or less, such as 7% or less, such as 6% or less, such as 5% or less, such as 3% or less, such as 2.5% or less, such as 2% or less, at any time during the maintenance of the transdermal composition in contact with the subject, and increases or decreases by including 1% or less at any time during the maintenance of the dexmedetomidine transdermal delivery device in contact with the subject.

[0070] As described above, aspects of the present invention include applying a transdermal delivery device containing a dexmedetomidine composition and maintaining the dexmedetomidine delivery device in contact with the subject for a time sufficient to deliver an amount of dexmedetomidine effective to relieve pain to the subject over a period of time to manage pain in the subject. In some embodiments, pain management The method of treatment may include maintaining a dexmedetomidine transdermal delivery device in contact with a subject in a manner sufficient to deliver a predetermined amount of dexmedetomidine to the subject. Where the protocol includes delivering a predetermined amount of dexmedetomidine to the subject, the amount of dexmedetomidine in the dexmedetomidine transdermal composition to be targeted may range from 0.001 mg to 50 mg, such as from 0.005 to 40 mg, such as from 0.01 mg to 30 mg, such as from 0.05 to 20 mg, such as from 0.1 mg to 15 mg, such as from 0.5 mg to 12.5 mg, and may include from 0.5 mg to 10 mg, such as from 0.5 mg to 2 mg or from 0.7 mg to 1.5 mg, including 4 to 9 mg, such as 6 to 8 mg, 2 to 10 mg.

[0071] In certain embodiments, the predetermined amount of dexmedetomidine delivered to a subject may be a ratio of the total amount of dexmedetomidine present in the dexmedetomidine transdermal composition of the transdermal delivery device. For example, the predetermined amount of dexmedetomidine delivered to a subject may be 1% or more, such as 2% or more, such as 5% or more, such as 10% or more, such as 25% or more of the total amount of dexmedetomidine present in the dexmedetomidine transdermal composition, and includes 50% or more of the total amount of dexmedetomidine present in the dexmedetomidine transdermal composition. In other words, the method of managing pain may include maintaining contact with the subject in a manner sufficient to deliver 5% or more of the dexmedetomidine in the dexmedetomidine transdermal composition to the subject over the course of a single dosing interval. In these embodiments, the utilization ratio of dexmedetomidine is 5% or more during the time the transdermal delivery device is maintained in contact with the subject. As such, 95% or less of the original amount of dexmedetomidine remains in the dexmedetomidine transdermal composition after the dosing interval. As described in more detail below, the subject transdermal delivery device enables a high utilization ratio. In other words, the subject transdermal delivery device can deliver dexmedetomidine to the subject with little residual dexmedetomidine remaining in the transdermal delivery device after a given dosing interval. The utilization ratio may be 5% or more, such as 10% or more, such as 25% or more, such as 40% or more, such as 45% or more over the course of the dosing interval, and includes 50% or more of the dexmedetomidine over the course of the dosing interval. For the utilization ratio, the upper limit over the course of the dosing interval may, in some cases, be 90% or less, such as 50% or less, such as 25% or less, and includes 5% or less over the course of the dosing interval.

[0072] For example, when the dexmedetomidine transdermal composition of the subject contains 1 mg of dexmedetomidine, the method of managing pain is to deliver over the course of the dosing interval (e.g., 2 to 3 days or more) 0.05 mg or more of dexmedetomidine in the dexmedetomidine transdermal composition, such as 0.1 mg or more, such as 0.25 mg or more, such as 0.4 mg or more, such as 0.45 mg or more, and may include maintaining the transdermal delivery device in contact with the subject in a manner sufficient to deliver 0.5 mg or more of dexmedetomidine in the dexmedetomidine composition. As such, after 2 to 3 days or more, 0.95 mg or more of dexmedetom idine remains in the dexmedetomidine transdermal composition, and dexmedetomidine including 0.9 mg or less, such as 0.75 mg or less, such as 0.6 mg or less, and 0.5 mg or less remains in the dexmedetomidine transdermal composition after the dosing interval.

[0073] As described above, the method according to certain embodiments includes applying one or more of the transdermal delivery devices of the subject having the dexmedetomidine composition to a subject not experiencing pain and maintaining the transdermal delivery device in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective to prevent a certain amount of pain in the subject. In embodiments, the transdermal delivery device is applied to the skin surface of the subject before the subject experiences (or is expected to experience) pain, such as 1 hour or more before, such as 2 hours or more, such as 3 hours or more, such as 4 hours or more, such as 6 hours or more, such as 8 hours or more, such as 1 2 hours or more, such as 16 hours or more, such as 20 hours or more before, and including more than 24 hours before the pain-inducing event.

[0074] Applying a transdermal delivery device containing dexmedetomidine according to embodiments of the present invention before the subject experiences pain, in certain embodiments, reduces the amount of pain experienced by the subject by 5% or more, such as 10% or more, such as 15% or more, such as 25% or more, such as 50% or more, such as 75% or more, such as 90% or more, such as 95% or more, and including 99% or more, compared to a subject to whom a transdermal delivery device of the subject containing dexmedetomidine was not applied. In some cases, the method includes applying a transdermal delivery device containing dexmedetomidine to a subject who is not experiencing pain and maintaining the transdermal delivery device in contact with the subject in a manner sufficient to completely eliminate (i.e., reduce the amount of pain by 100%) the pain experienced by the subject in response to a pain-inducing event. For example, if the transdermal delivery device is applied before the start of surgery, such as 1 hour or more before the start of surgery, such as 2 hours or more, such as 3 hours or more, such as 4 hours or more, such as 6 hours or more, such as 8 hours or more, such as 12 hours or more, such as 16 hours or more, such as 20 hours or more before, and including 24 hours or more before the start of surgery, the subject may experience a reduction in the amount of pain in response to the surgical procedure.

[0075] As described in further detail below, in certain embodiments, the transdermal delivery device may include a single-layer matrix dexmedetomidine composition configured to deliver a non-sedating amount of dexmedetomidine to the subject. As such, a method according to certain examples includes applying a transdermal delivery device having a single-layer matrix dexmedetomidine composition to the subject and maintaining the single-layer dexmedetomidine composition in contact with the subject for a time sufficient to deliver an effective amount of dexmedetomidine to the subject.

[0076] In certain embodiments, each of the methods of the subject matter described in further detail below may further include the step of removing the transdermal delivery device(s) from contact with the subject at the end of the dosing interval. For example, after maintaining for 0.5 hours or more, such as 1 hour or more, such as 2 hours or more, such as 4 hours or more, such as 8 hours or more, such as 12 hours or more, such as 24 hours or more, such as 36 hours or more, such as 48 hours or more, such as 60 hours or more, such as 72 hours or more, such as 96 hours or more, such as 120 hours or more, including 144 hours or more and including 168 hours or more, the transdermal delivery device may be removed from contact with the subject. The upper limit of the amount of time the transdermal delivery device is maintained in contact with the subject prior to removal may, in some cases, be 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 84 hours or less, such as 78 hours or less, such as 72 hours or less.

[0077] "Removing" the transdermal delivery device from contact with the subject means that the transdermal delivery device is not in contact with the subject any longer. In other words, once the transdermal delivery device is removed, it is no longer in contact with the surface of the skin or mucosa at the application site.

[0078] As described above, the dosing interval begins by applying a transdermal dexmedetomidine composition(s) to the skin or mucosa of the subject and ends by removing the transdermal delivery device(s) from contact with the subject, and is a single administration where one or more, such as two, transdermal delivery devices are applied and maintained in contact with the subject. As outlined above, in some embodiments, the protocol includes a single dosing interval. Alternatively, in certain embodiments, the protocol may include multiple dosing intervals. "Multiple dosing intervals" means that one or more transdermal delivery devices are applied and maintained in contact with the subject in a sequential manner. As such, the transdermal delivery device is removed from contact with the subject and a new transdermal delivery device is reapplied to the subject. In practicing the methods of the present invention, the controlled dosing regimen Two or more dosing intervals, such as three or more dosing intervals, such as four or more dosing intervals, such as five or more dosing intervals, may be included, including dosing intervals of 10 or more.

[0079] In certain embodiments, the method further comprises hydrating the subject. The term "hydrating" is used herein in its conventional meaning to provide hydration to a subject, for example, by administering a hydrating fluid composition (e.g., an aqueous fluid) to the subject. The hydrating fluid composition may be provided to the subject by a suitable protocol including, but not limited to, oral administration or intravenous administration. In certain embodiments, an amount of fluid is administered intravenously to the subject. The hydrating fluid administered to the subject may include, but is not limited to, an aqueous saline solution, an electrolyte replacement fluid, a buffer fluid, a nutrient fluid, etc., and may be any suitable composition that provides an increase in hydration to the subject as determined by a qualified medical professional. In some cases, a hydrating fluid such as an isotonic, hypertonic, and hypotonic electrolyte solution, including a balanced salt / electrolyte solution, is administered intravenously. Exemplary hydrating fluids according to certain embodiments may be, among other hydrating fluids, lactated Ringer's solution, saline, D5 lactated Ringer's dextrose solution, D5 saline dextrose solution, D5,45 saline dextrose solution, D5,25 saline dextrose solution, 7.5% saline solution, D5 anhydrous dextrose solution, 6% hydroxyethyl starting solution.

[0080] The subject may be hydrated at a convenient time during the method of the present invention. An amount of a hydration fluid composition may be administered to the subject before, during, after, or a combination thereof, of a surgical procedure. In some embodiments, the hydration fluid composition is administered to the subject in conjunction with applying a transdermal delivery device to the subject and may continue as long as the transdermal delivery device remains in contact with the subject. Optionally, the hydration fluid composition is administered to the subject at a time prior to applying a transdermal delivery device to the subject, such as 1 minute or more prior, such as 2 minutes or more prior, such as 5 minutes or more prior, such as 10 minutes or more prior, such as 15 minutes or more prior, such as 30 minutes or more prior, such as 1 hour or more prior, such as 2 hours or more prior, such as 3 hours or more prior, such as 6 hours or more prior to applying a transdermal delivery device to the subject, and including 12 hours or more prior to applying a transdermal delivery device to the subject. In some embodiments, the hydration fluid composition is continuously administered to the subject while the transdermal delivery device remains in contact with the subject. After removing the transdermal delivery device from the subject, hydration may continue for, for example, 1 minute or more, for example, 2 minutes or more, for example, 5 minutes or more, for example, 10 minutes or more, for example, 15 minutes or more, for example, 30 minutes or more, for example, 1 hour or more, for example, 2 hours or more, for example, 3 hours or more, for example, 6 hours or more, and may continue including 12 hours or more after removing the transdermal delivery device from the subject.

[0081] In other examples, the rehydration fluid composition is administered to the subject prior to the start of a surgical procedure, for example, 1 or more minutes before the start of the surgical procedure in the subject, for example, 2 or more minutes before, for example, 5 or more minutes before, for example, 10 or more minutes before, for example, 15 or more minutes before, for example, 30 or more minutes before, for example, 1 hour or more before, for example, 2 hours or more before, for example, 3 hours or more before, for example, 6 hours or more before, and is administered including 12 hours or more before the start of the surgical procedure in the subject. In some embodiments, the rehydration fluid composition is continuously administered to the subject while the transdermal delivery device is in contact with and maintained on the subject and during the surgical procedure. Rehydration may continue for example for 1 minute or more, for example for 2 minutes or more, for example for 5 minutes or more, for example for 10 minutes or more, for example for 15 minutes or more, for example for 30 minutes or more, for example for 1 hour or more, for example for 2 hours or more, for example for 3 hours or more, for example for 6 hours or more after the surgical procedure is completed in the subject, and may continue including 12 hours or more after the surgical procedure is completed in the subject.

[0082] In some embodiments, the method includes administering a rehydration fluid composition to the subject at a first rate for a first predetermined time and administering a rehydration fluid composition to the subject at a second rate for a second predetermined time.

[0083] In one example, the method includes orally administering a rehydration fluid composition to the subject at a first rate for a first predetermined time and orally administering a rehydration fluid composition to the subject at a second rate for a second predetermined time. For example, the method may include orally administering a rehydration fluid composition to the subject at a rate of 450 mL / hour to 550 mL / hour for 2 hours; and orally administering a rehydration fluid composition to the subject at a rate of 100 mL / hour to 150 mL / hour for 12 hours after the first 2 hours. In some cases, the method of rehydrating the subject includes orally administering a rehydration fluid composition to the subject at a rate of 500 mL / hour for 2 hours; and orally administering a rehydration fluid composition to the subject at a rate of 125 mL / hour for 12 hours after the first 2 hours.

[0084] ​In another example, the method includes intravenously administering a rehydration fluid composition to a subject at a first drip rate for a first predetermined time and intravenously administering the rehydration fluid composition to the subject at a second drip rate for a second predetermined time. For example, the method may include intravenously administering the rehydration fluid composition to the subject at a rate of 450 mL / hour to 550 mL / hour for 2 hours and intravenously administering the rehydration fluid composition to the subject at 100 mL / hour to 150 mL / hour for 12 hours after the first 2 hours. In some cases, the method of rehydrating a subject includes intravenously administering the rehydration fluid composition to the subject at a rate of 500 mL / hour for 2 hours and intravenously administering the rehydration fluid composition to the subject at 125 mL / hour for 12 hours after the first 2 hours.

[0085] In certain embodiments, the dexmedetomidine transdermal delivery device can be administered prior to, simultaneously with, or after other therapeutic agents for treating or managing pain. If provided simultaneously with another therapeutic agent, the subject dexmedetomidine may be administered by the transdermal delivery device in the same composition or in a different composition. Accordingly, the subject dexmedetomidine delivery device and other therapeutic agents can be administered to a subject by combination therapy. "Combination therapy" is intended to be administered to a subject such that the therapeutic effect of the combination of substances is elicited in the subject being treated.For example, the combination therapy may be achieved by administering dexmedetomidine by the transdermal delivery device of the present invention and administering a pharmaceutical composition having at least one other active substance, for example, an anesthetic agent, for example, a non-opioid intravenous general anesthetic agent (for example, propofol, etomidate, ketamine, barbiturates (for example, amobarbital, methohexital, thiopental, and thiamylal), benzodiazepines (for example, diazepam, lorazepam, and midazolam), but not limited thereto), an opioid intravenous general anesthetic agent (for example, alfentanil, fentanyl, remifentanil, sufentanil, buprenorphine, butorphanol, diacetylmorphine, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, but not limited thereto), an intravenous active substance containing an inhaled general anesthetic agent (for example, desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, and xenon), a local anesthetic agent (for example, procaine, amethocaine, lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, and dibucaine, but not limited thereto), NSAIDs and COX2 inhibitors (aspirin, ibuprofen, naproxen, celecoxib, acetaminophen), for example, an opioid such as codeine, oxycodone, morphine, methadone, buprenorphine, and fentanyl, an antidepressant, an anticonvulsant, a dexmedetomidine agent, a cannabinoid, N-methyl-D-aspartic acid, and a pain treatment composition including, but not limited to, a neuromodulator to create a therapeutically effective dose in combination according to a specific dosing schedule. As long as the therapeutic effect of the combination of these substances occurs in the subject undergoing treatment, the administration of the separate pharmaceutical compositions can be carried out simultaneously or at different times (i.e., sequentially on the same day or on different days, in either order). is.

[0086] Depending on the second therapeutic agent administered and the indicated condition, co - administration with dexmedetomidine may reduce the required dosage of the second therapeutic agent. For example, co - administration with dexmedetomidine may reduce the amount of opioid or other analgesic required to effectively treat or manage pain such as, for example, postoperative pain, pain induced by chemotherapy, or pain induced by radiotherapy. Co - administration with dexmedetomidine may reduce the required dosage of the second therapeutic agent by 10% or more, for example 25% or more, for example 35% or more, and may include reducing the required dosage of the second therapeutic agent by 50% or more.

[0087] In certain embodiments, the method includes co - administering one or more opioids to the subject. The term "opioid" is used herein in its conventional meaning to refer to a naturally occurring or synthetic chemical substance that exerts a pharmacological effect by interaction at opioid receptors (i.e., μ, κ, and δ opioid receptors). In certain embodiments, the opioid is a biosynthetic benzylisoquinoline alkaloid and may be an agonist, antagonist, or inverse agonist of an opioid receptor. The opioid may be administered to the subject, for example, at any time during the subject method, for example, before applying a dexmedetomidine transdermal delivery device to the subject's skin surface or after applying a dexmedetomidine transdermal delivery device to the subject's skin surface. Any convenient protocol including, but not limited to, oral, intravenous injection, transdermal, or other delivery protocols may be employed to deliver the opioid to the subject. In some embodiments, the method includes administering the opioid intravenously. In some embodiments, the opioid is administered perioperatively.

[0088] Among the numerous opioids administered simultaneously to a subject by the methods according to these embodiments, in particular, codeine, morphine, oripavine, thebaine, 14-dihydromorphine, 2,4-dinitrophenylmorphine, 6-methyldihydromorphine, 6-methylenedihydodesoxymorphine, 6-acetyl-dihydromorphine, azidomorphine, chloronaltrexamine, chlorooxymorphamine, desomorphine (dihydodesoxymorphine), dihydromorphine, ethyldihydromorphine, hydromorphinol, methyldesorphine, N-phenethylnormorphine, RAM-378, 6-nicotinoyldihydromorphine, acetylpropionylmorphine, diacetyldihydromorphine (dihydroheroin, acetylmorphinol), dibutyrylmorphine, dibenzoylmorphine, diformylmorphine, dipropanoylmorphine, heroin (diacetylmorphine), nicomorphine, 6-monoacetylcodeine, benzylmorphine, methylcodeine bromide, desocodeine, dimethylmorphine (6-O-methylcodeine), ethyldihydromorphine, methyldihydromorphine (dihydroheterocodeine), ethylmorphine (dionin), heterocodeine, isocodeine, pholcodine (morpholinylethylmorphine), myrophine, nalodeine (N-allyl-norcodeine), transisocodeine, 14-cinnamoyloxycodeinone, 14-ethoxymethopon, 14-methoxymethopon, 14-phenylpropoxymethopon, 7-spiroindanyloxymorphone, 8,14-Dihydroxy-dihydromorphinone, acetylcodeine, acetylmorphine, α-hydrocodol, bromoisopropyl-dihydromorphinone, codeinone, codolphine, codol, codoxime, IBNtxA, acetyldihydrocodeinone, dihydrocodeinone enol acetate, hydrocodone, hydromorphine, hydroxycodeine, methyldihydromorphinone, morphinol, morphinone, morphol, N-phenethyl-14-ethoxymethopon, oxycodone, oxymorphol, oxymorphinone, pentamorphinone, semorphinone, α-chlorocodide, β-chlorocodide, α-chloromorphide, bromocodide, bromomorphide, chlorodihydrocodide, chloromorphide, codide, 14-hydroxy-dihydrocodeine, acetyldihydrocodeine, dihydrocodeine, dihydrodesoxycodeine, dihydroisocodeine, nicocodeine, nicodicodide, 1-nitrocodide, codeine-N, -oxide, morphine-N-oxide, oxymorphone, 1-bromocodeine, 1-chlorocodeine, 1-iodomorphine, codeine-N-oxide, heroin-7,8-oxide, morphine-6-glucuronide, 6-monoacetylmorphine, morphine-N-oxide, naltrexol, norcodeine, normorphine, 4-chlorophenylpyridomorphinan, cyclorphane, dextrorolphan, levallorphan, levorphanol, levophenacylmorphan, levorphanol, norlevorphanol, N-methylmorphinan, oxylorophan, phenomorphan, metorphan, morphanol, Ro4-1539, stefadeline, xylorphanol, 1-nitroacronycine, 14-episinomenine, 5,6-dihydronorsalsolidine, 6-ketonalbufen, acronycine, butorphanol, cefazolin, cefathiamidine, ciprocin, drotebanol, fenfangine G, nalbuphine, sinococuline, sinomenine, tannagin, 5,9α-Diethyl-2-hydroxybenzomorphan (5,9-DEHB), 8-carboxamidosympathomimetic (8-CAC), terazosin, anazosin, bremazosin, butanazosin, carbazosin, cogramostim, cyclazosin, desozin, eptazosin, etazosin, ethylketocyclazosin, fedotozin, fluorophen, gemazosin, ibazosin, ketazosin, metazosin, moxazosin, pentazosin, phenazosin, quanadazosin, thiazosin, tamsulosin, borazosin, zenazosin, 4-fluoromeperidine, allylnorpethidine, anileridine, benzetidine, carpethidine, diphenoxylate, difenoxin, ethoxeridine, carbetidine, fretidine, hydroxypethidine, bemidone, morpheridine, meperidine-N-oxide, oxypheneridine, carbamethylidine, pethidine, meperidine, norpethidine, pethidinic acid, pheneridine, phenoperidine, piminodine, propethidine, ipropepethidine, sameridine, allylprodine, (α / β)-meprodine, desmethylprodine (MPPP), PEPAP, (α / β)-prodine, prosidol, trimethidine (promedol), acetoxyketobemidone, droxypropine, ketobemidone, methylketobemidone, propylketobemidone, alvimopan, loperamide, picenadol, dextromethorphan, dipipanone, isomethadone, levoisomethadone, levomethadone, methadone, normethadone, norpipanone, phenadoxone (heptazone), pipidone (6-piperidin-4,4-Diphenyl-5-methyl-hexanone-3 hydrochloride), alpha-acetylmethadol, dimepheptanol (racemethadol), levoacetylmethadol, noracetylmethadol, desmethylmoramide, dextromoramide, levomoramide, moramide intermediate, racemoramide, diethylthiambutene, dimethylthiambutene, ethylmethylthiambutene, piperidylthiambutene, pyrrolidinylthiambutene, thiambutene, tipepidine, dextropropoxyphene (propoxyphene), dimenoxadol, dioxaphetyl butyrate, levopropoxyphene, norpropoxyphene, diamidone, phenamidone, propiram, IC-26, isoaminile, levetamine, R-4066, 3-allylfentanyl, 3-methylfentanyl, 3-methylthiofentanyl, 4-phenylfentanyl, alfentanyl, alpha-methylacetylfentanyl, alpha-methylfentanyl, alpha-methylthiofentanyl, benzylfentanyl, beta-hydroxyfentanyl, beta-hydroxythiofentanyl, beta-methylfentanyl, brifentanyl, carfentanyl, fentanyl, lofentanyl, mirfentanyl, ocfentanyl, oramfentanyl, parafluorofentanyl, pheneridine, remifentanyl, sufentanyl, tenilfentanyl, thiofentanyl, treflentanyl, 7-PET, acetorphine, aretorphine (N-allyl-noretorphine), BU-48, dexmedetomidine, ciproxenorphine, dihydroetorphine, etorphine, homoproxenorphine, 18,19-didehydrodexmedetomidine, N-cyclopropylmethylnoretorphine, nepentone, nordexmedetomidine, tebipenone, thienorphine, etoheptazine, meptazinol, metheptazine, metethoheptazine, proheptazine, vedotramide, pyrtramide, cronitazene, etonitazene, nitazene, 18-methoxycoronaridine, 7-acetoxymitragynine, 7-hydroxymitragynine, aquamidine, aquami, eseroline, , Hodgkin's, mitragynine, pericine, pseudoaquamidine, BW373U86, DPI-221, DPI-287, DPI-3290, SNC-80, dinorphin A, dinorphin B, β-endorphin, α-endorphin, γ-endorphin, α-neo-endorphin, β-neo-endorphin, DADLE, DAMGO, dermenkephalin, met-enkephalin, leu-enkephalin, adrenorphin, amidorphin, casomorphin, DALDA (Tyr-D-Arg-Phe-Lys-NH2), deltorphin, dermorphin, DPDPE, endomorphin, gliadorphin, morphiceptin, nociceptin, octreotide, opioiorphin, rubiscorin, TRIMU5, 3-(3-methoxyphenyl)-3-ethoxycarbonyltropane, AD-1211, AH-7921, azaproscine, BDPC, bisnorcytisine, BRL-52537, bromadoline, C-8813, silamadol, doxpicomine, enadoline, faxeladol, GR-89696, helquinoline, ICI-199,441, ICI-204,448, J-113,397, JTC-801, ketamine, KNT-42, LPK-26, methotrexate, MT-45, desmethylclozapine, NNC63-0532, norcytisine, O-desmethyltramadol, phenadon, fencyclidine, projiridine, profadol, Ro64-6198, salvianoline A, SB-612,111, SC-17599, RWJ-394,674, TAN-67, tapentadol, oxycodone, tifluadom, cytisine, tramadol, trimebutine, U-50,488, U-69,593, biminol, 1-(4-nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide (W-18), 5'-guanidinonaltrexamine, β-funaltrexamine, 6β-naltrexol, alvimopan, binaltorphimine, chlornaltrexamine, crocinamox, cyclazosin, ciprozin, diacetylnalorphine, diphenamidol, diprenorphine, fedotozine, JDTic, levallorphan, metocinamox, methylnaltrexon, nalflafine, nalmeffene, nalmezone, naloxazone, naloxonazine, naloxone, naloxone benzoylhydrazone, nalorphine, naltrexone, naltriben, naltrindole, norbinaltorphimine, oxycodone, S-allyl-3-hydroxy-17-thionomorphinan, alimadol, anilopam HCl, asimadoline, FE200665, fedotozine, MCOPPB, nalflafine, nalorphine, dinicotinic acid nalorphine, SoRI-9409, etc., and the types of opioids may vary, not limited to these.,

[0089] In certain embodiments, the dexmedetomidine transdermal delivery device as described herein, when co-administered with an opioid, may reduce the amount of opioid required to effectively treat or manage pain (e.g., postoperative pain). In some cases, applying the dexmedetomidine transdermal delivery device according to the methods described above reduces the amount of co-administered opioid required to manage pain by at least 1 wt%, such as at least 2 wt%, such as at least 3 wt%, such as at least 5 wt%, such as at least 10 wt%, such as at least 15 wt%, such as at least 25 wt%, and includes reducing the amount of co-administered opioid required to manage pain by at least 50 wt%. In other words, the amount of opioid required to manage pain is reduced by at least 1 wt%, such as at least 2 wt%, such as at least 3 wt%, such as at least 5 wt%, such as at least 10 wt%, such as at least 15 wt%, such as at least 25 wt% compared to the amount of opioid alone required to manage pain, and includes cases where the amount of opioid required to manage pain is reduced by at least 50 wt% compared to the amount of opioid alone required to manage pain.

[0090] In some embodiments, the opioid is administered before the transdermal delivery device is applied to the subject, such as at least 1 minute before the transdermal delivery device is applied to the subject, such as at least 2 minutes before, such as at least 5 minutes before, such as at least 10 minutes before, such as at least 15 minutes before, such as at least 30 minutes before, such as at least 1 hour before, such as at least 2 hours before, such as at least 3 hours before, such as at least 6 hours before, and including administration up to 12 hours before the transdermal delivery device is applied to the subject. In other embodiments, the opioid is administered to the subject after the transdermal delivery device is applied to the subject, such as at least 1 minute after the transdermal delivery device is applied to the subject, such as at least 2 minutes after, such as at least 5 minutes after, such as at least 10 minutes after, such as at least 15 minutes after, such as at least 30 minutes after, such as at least 1 hour after, such as at least 2 hours after, such as at least 3 hours after, such as at least 6 hours after, and including administration up to 12 hours after the transdermal delivery device is applied to the subject. ​

[0091] In other embodiments, the opioid is administered before the start of a surgical procedure in a subject, for example, at least 1 minute before the start of the surgical procedure in the subject, for example, at least 2 minutes before, for example, at least 5 minutes before, for example, at least 10 minutes before, for example, at least 15 minutes before, for example, at least 30 minutes before, for example, at least 1 hour before, for example, at least 2 hours before, for example, at least 3 hours before, for example, at least 6 hours before, and including at least 12 hours before the start of the surgical procedure in the subject. In other embodiments, the opioid is administered after the start of the surgical procedure, for example, at least 1 minute after the start of the surgical procedure in the subject, for example, at least 2 minutes after, for example, at least 5 minutes after, for example, at least 10 minutes after, for example, at least 15 minutes after, for example, at least 30 minutes after, for example, at least 1 hour after, for example, at least 2 hours after, for example, at least 3 hours after, for example, at least 6 hours after, and including at least 12 hours after the start of the surgical procedure in the subject.

[0092] In certain embodiments, the method comprises replacing one or more doses of an opioid (e.g., an opioid agonist) administered in an opioid pain management dosing regimen with a transdermal delivery device containing dexmedetomidine as described herein. The term “opioid pain management dosing regimen” refers to a pain management protocol having a planned dosage administration of an opioid for managing pain in a subject (e.g., by a healthcare professional at a healthcare facility under supervision, or at the subject's home under the direction / prescription of a healthcare professional). For example, a subject opioid pain management dosing regimen may include a pain management protocol that employs multiple planned administrations of opioid dosages to manage, reduce or eliminate, among several pains known to be managed by opioids, particularly acute pain, chronic pain, neuropathic pain, cancer-related pain, postoperative pain, moderate to severe pain, labor pain, perioperative pain. In certain embodiments, the opioid pain management dosing regimen that is replaced or supplemented by applying a transdermal delivery device containing dexmedetomidine as described herein is moderate to severe pain that typically requires an opioid and for which alternative pain relief protocols have been found to be inadequate.

[0093] The methods according to these embodiments involve applying a transdermal delivery device containing dexmedetomidine as described herein to replace one or more, such as two or more, such as three or more, such as four or more, such as five or more, such as six or more, such as seven or more, such as eight or more, such as nine or more, such as ten or more, such as fifteen or more, such as twenty-five or more, such as fifty or more, such as seventy-five or more, planned opioid administrations and including replacing one hundred or more planned opioid administrations for pain management. As such, applying and maintaining a transdermal delivery device containing dexmedetomidine as described herein may be sufficient to reduce the number of planned opioid administrations in an opioid pain management dosing regimen by 5% or more, such as 10% or more, such as 15% or more, such as 20% or more, such as 25% or more, such as 50% or more, such as 75% or more, such as 90% or more, such as 95% or more, and may be sufficient including reducing the number of planned opioid administrations in an opioid pain management dosing regimen by 99% or more. In certain embodiments, the subject method completely (i.e., 100% of the opioid dosage administered) replaces the opioid in an opioid pain management dosing regimen as described herein It is suitable for replacement with a transdermal delivery device containing dexmedetomidine as described above. In certain embodiments, the method includes applying and maintaining one or more transdermal delivery devices of the subject containing dexmedetomidine in conjunction with the administration of an opioid in an opioid pain management dosing regimen. In some cases, when the dexmedetomidine transdermal delivery device is in contact with the subject, for example, the dose of each planned administration of an opioid in an opioid pain management dosing regimen is reduced by 5% or more, such as 10% or more, such as 15% or more, such as 20% or more, such as 25% or more, such as 50% or more, and including 75% or more, the opioid at the reduced dose may be administered to the subject in an opioid pain management dosing regimen. In some cases, one or more of the planned doses of opioid administration, for example, every other planned dose of opioid administration, every two planned doses, every three planned doses, every four planned doses, or some other interval is excluded (i.e., skipped). In some cases, applying one or more of the subject's dexmedetomidine transdermal delivery devices is sufficient to exclude sequential planned doses of opioid administration in an opioid pain management dosing regimen, such as two or more sequential planned doses, such as three or more sequential planned doses, and is sufficient to exclude including four or more sequential planned doses of opioid administration in an opioid pain management dosing regimen.

[0094] In certain embodiments, the method includes applying one or more of the subject dexmedetomidine transdermal delivery devices to manage obstetric pain associated with childbirth (e.g., labor and delivery). In these embodiments, the transdermal delivery device is applied to the subject after the onset of labor (e.g., after the first onset of labor contractions) or prior to the onset of labor and then maintained on the subject throughout labor and delivery as well as for an amount of time after delivery. For example, dexmedetomidine can be administered by the transdermal delivery device 30 minutes or more, 1 hour or more, 2 hours or more, 5 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, 11 hours or more, 12 hours or more, 15 hours or more, 18 hours or more, 24 hours or more, e.g., 1 day or more prior to the onset of labor and maintained on the subject throughout labor and delivery. In some cases, the transdermal delivery device is applied anywhere from 0.50 to 30 hours prior to the onset of labor, e.g., 1 to 24 hours prior to surgery. The subject composition is then maintained on the subject for a time after delivery, where the post-delivery maintenance time can vary and in some cases is 1 hour or more, e.g., 2 hours or more, e.g., 4 hours or more, e.g., 8 hours or more, e.g., 12 hours or more, e.g., 24 hours or more, e.g., 48 hours or more, e.g., 72 hours or more, e.g., 96 hours or more, e.g., 120 hours or more, e.g., 144 hours or more, and includes 168 hours or more. For the above ranges, the upper limit time is in some cases 168 hours or less, e.g., 144 hours or less, e.g., 120 hours or less, e.g., 96 hours or less, e.g., 72 hours or less, e.g., 48 hours or less, and includes 24 hours or less. In certain specific embodiments, the extended transdermal delivery ranges from, e.g., 0.5 hours to 168 hours, e.g., 1 hour to 144 hours, e.g., 1.5 hours to 120 hours, e.g., 2 hours to 96 hours, e.g., 2.5 hours to 72 hours, e.g., 3 hours to 72 hours. In certain specific embodiments, the dosing schedule for labor and delivery is a multi-day transdermal dexmedetomidine delivery dosing schedule that spans from the time prior to the treatment of labor and delivery to subsequent times and in some cases this dosing schedule ranges from 2 days to 30 days, e.g., 2 days to 15 days, e.g., 2 days to 7 days, e.g., 2 days to 4 days, and includes 2 days to 4 days, e.g., 3 days.

[0095] In some embodiments, the transdermal delivery device is applied in contact with the subject and maintained for a total duration of 72 hours. In one example, the transdermal delivery device is applied 4 hours before the onset of labor, maintained in contact with the subject during labor, and removed after the full 72-hour duration. In another example, the transdermal delivery device is applied 6 hours before the onset of labor, maintained in contact with the subject during labor, and removed after the full 72-hour duration. In yet another example, the transdermal delivery device is applied 12 hours before the onset of labor, maintained in contact with the subject during labor, and removed after the full 72-hour duration. In yet another example, the transdermal delivery device is applied 18 hours before the onset of labor applied, maintained in contact with the subject during labor, and removed after the full 72-hour duration. In still another example, the transdermal delivery device is applied 24 hours before the onset of labor, maintained in contact with the subject during labor, and removed after the full 72-hour duration. In still another example, the transdermal delivery device is applied 24 hours before the onset of labor, maintained in contact with the subject during labor, and removed after the full 84-hour duration. In still another example, the transdermal delivery device is applied 24 hours before the onset of labor, maintained in contact with the subject during labor, and removed after the full 96-hour duration.

[0096] In other embodiments, one or more of the transdermal delivery devices of the subject are applied to the subject for a predetermined time (e.g., 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc.) prior to the onset of labor and maintained in contact with the subject for 72 hours or more after delivery. As such, the total duration that the transdermal delivery device is maintained in contact with the subject may be 76 hours or more, such as 80 hours or more, such as 84 hours or more, such as 90 hours or more, and includes 96 hours or more. In one example, the transdermal delivery device is applied 4 hours before the onset of labor, maintained in contact with the subject during delivery, and held in contact with the subject for 72 hours or more after surgery. In another example, the transdermal delivery device is applied 6 hours before the onset of labor, maintained in contact with the subject during delivery, and held in contact with the subject for 72 hours or more after delivery. In yet another example, the transdermal delivery device is applied 12 hours before the onset of labor, maintained in contact with the subject during delivery, and held in contact with the subject for 72 hours or more after delivery. In yet another example, the transdermal delivery device is applied 18 hours before the onset of labor, maintained in contact with the subject during delivery, and held in contact with the subject for 72 hours or more after delivery. In still another example, the transdermal delivery device is applied 24 hours before the onset of labor, maintained in contact with the subject during delivery, and held in contact with the subject for 72 hours or more after delivery. In still another example, the transdermal delivery device is applied 24 hours before the onset of labor, maintained in contact with the subject during delivery, and held in contact with the subject for 84 hours or more after delivery. In still another example, the transdermal delivery device is applied 24 hours before the onset of labor, maintained in contact with the subject during delivery, and held in contact with the subject for 96 hours or more after delivery.

[0097] Dexmedetomidine transdermal delivery device containing a dexmedetomidine composition for managing surgical pain in a subject Aspects of the invention also include a dexmedetomidine transdermal delivery device for delivering to a subject an effective amount (e.g., a sedative or non-sedative amount) of dexmedetomidine suitable for practicing the methods of the subject. The transdermal delivery device for the subject includes a composition having dexmedetomidine and a pressure-sensitive adhesive. Dexmedetomidine has the formula:

Chemical formula

[0098] Dexmedetomidine according to an embodiment of the present invention may be in the form of a free base, a salt, a solvate, a hydrate or a complex. For example, dexmedetomidine may be in the form of a pharmaceutically acceptable salt including, but not limited to, mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide, esylate, p - toluenesulfonate, benzoate, acetate, phosphate and sulfate. Dexmedetomidine according to some embodiments may be a free base. In other examples, dexmedetomidine may form a complex.

[0099] Depending on the site of application, the type of pain being managed and the physiological state of the subject (e.g., body weight), the amount of dexmedetomidine in the composition for the subject may vary. In some cases, the amount of dexmedetomidine ranges from 0.001 mg to 50 mg, such as 0.005 mg to 40 mg, such as 0.01 to 30 mg, such as 0.05 to 20 mg, and includes 0.1 mg to 10 mg. In some embodiments, the amount of dexmedetomidine in the transdermal composition ranges from 0.1% to 20% w / w, such as 0.5% to 18% w / w, such as 1% to 15%, such as 2% to 12.5% w / w, and includes 3% to 10% w / w. In other embodiments, the amount of dexmedetomidine in the transdermal composition of the subject is 10% by weight or less of the total weight of the transdermal composition, such as 9% by weight or less, such as 8% by weight or less, such as 7% by weight or less, such as 6% by weight or less, such as 5% by weight or less, and includes 3% by weight or less of the total weight of the transdermal composition. In certain embodiments, the dexmedetomidine composition contains an amount of dexmedetomidine below the saturation point. In other embodiments, the dexmedetomidine composition contains a saturated amount of dexmedetomidine. In still other embodiments, the dexmedetomidine composition contains a supersaturated amount of dexmedetomidine.

[0100] In some embodiments of the present invention, the dexmedetomidine compositions described herein are formulated to deliver a non-sedating amount of dexmedetomidine. As described above, non-sedating means that the dexmedetomidine composition is formulated to deliver to a subject an amount of dexmedetomidine that does not cause complete sedation of the subject. In other words, the subject remains conscious and responsive throughout the entire time the dexmedetomidine composition is administered transdermally to the subject. In some cases, the subject remains cooperative, oriented, and calm throughout the entire administration of the dexmedetomidine transdermal composition. In other examples, the subject remains awake throughout the entire administration of the dexmedetomidine transdermal composition and is able to respond to commands (verbal or written). In yet other examples, the subject is awake, cooperative, oriented, and calm throughout the entire administration of the dexmedetomidine transdermal composition and is able to respond to commands (verbal or written).

[0101] As described in further detail below, in some embodiments, the dexmedetomidine transdermal composition to be administered to a subject is formulated such that the subject is evaluated according to the Wilson sedation score system throughout the entire transdermal administration and may be assigned a Wilson score of 3 or less, such as 2 or less, including cases where the subject is assigned a Wilson score of 1. In some cases, the subject exhibits a mild tap on the glabella or an active response to a loud auditory stimulus throughout the entire administration of the dexmedetomidine transdermal composition. In other examples, the subject responds to verbal commands throughout the entire administration of the dexmedetomidine transdermal composition. In yet other examples, the subject is cooperative, oriented, and calm throughout the entire administration of the dexmedetomidine transdermal composition. In yet other examples, the subject is anxious, excited, or restless throughout the entire administration of the dexmedetomidine transdermal composition.

[0102] In an embodiment of the present invention, the transdermal dexmedetomidine composition also includes a pressure-sensitive adhesive. Examples of the pressure-sensitive adhesive may include, but are not limited to, poly-isobutene adhesives, poly-isobutylene adhesives, poly-isobutene / polyisobutylene adhesive mixtures, carboxylated polymers, acrylic or acrylate copolymers, such as carboxylated acrylate copolymers.

[0103] When the pressure-sensitive adhesive contains polybutene, the polybutene may be saturated polybutene. Alternatively, the polybutene may be unsaturated polybutene. Furthermore, the polybutene may be a mixture or combination of saturated polybutene and unsaturated polybutene. In some embodiments, the pressure-sensitive adhesive includes Indopol (registered trademark) L-2, Indopol (registered trademark) L-3, Indopol (registered trademark) L-6, Indopol (registered trademark) L-8, Indopol (registered trademark) L-14, Indopol (registered trademark) H-7, Indopol (registered trademark) H-8, Indopol (registered trademark) H-15, Indopol (registered trademark) H-25, Indopol (registered trademark) H-35, Indopol (registered trademark) H-50, Indopol (registered trademark) H-100, Indopol (registered trademark) H-300, Indopol (registered trademark) H-1200, Indopol (registered trademark) H-1500, Indopol (registered trademark) H-1900, Indopol (registered trademark) H-2100, Indopol (registered trademark) H-6000, Indopol (registered trademark) H-18000, Panalan (registered trademark) L-14E, Panalan (registered trademark) H-300E, and compositions that are the same as or substantially the same as combinations thereof. In certain embodiments, the polybutene pressure-sensitive adhesive is Indopol (registered trademark) H-1900. In other embodiments, the polybutene pressure-sensitive adhesive is Panalan (registered trademark) H-300E.

[0104] The acrylate copolymers targeted include, for example, copolymers of various monomers such as “soft” monomers, “hard” monomers or “functional” monomers. The acrylate copolymer can be composed of a copolymer including a bipolymer (i.e., made of two monomers), a terpolymer (i.e., made of three monomers), or a tetrapolymer (i.e., made of four monomers), or a copolymer having an even larger number of monomers. The acrylate copolymer may or may not be crosslinked. The polymer can be crosslinked by known methods to provide the desired polymer. The monomer form of the acrylate copolymer may include at least two exemplary components selected from the group including acrylic acid, alkyl acrylate, methacrylate, copolymerizable secondary monomers, or monomers with functional groups. The monomers (“soft” and “hard” monomers) may be, for example, methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, acrylonitrile, methoxyethyl acrylate, methoxyethyl methacrylate, etc. Additional examples of acrylic adhesive monomers are described in Satas, “Acrylic Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989), the disclosure of which is incorporated herein by reference. In some embodiments, the pressure-sensitive adhesive is an acrylate-vinyl acetate copolymer.In some embodiments, the pressure-sensitive adhesive may be a composition of Duro-Tak® 87-9301, Duro-Tak® 87-200A, Duro-Tak® 87-2353, Duro-Tak® 87-2100, Duro-Tak® 87-2051, Duro-Tak® 87-2052, Duro-Tak® 87-2194, Duro-Tak® 87-2677, Duro-Tak® 87-201A, Duro-Tak® 87-2979, Duro-Tak® 87-2510, Duro-Tak® 87-2516, Duro-Tak® 87-387, Duro-Tak® 87-4287, Duro-Tak® 87-2287, and Duro-Tak® 87-2074 and combinations thereof, or a composition that is substantially the same as it. The term "substantially the same" when used in this context refers to a composition that is an acrylate-vinyl acetate copolymer in an organic solvent solution. In certain embodiments, the acrylic pressure-sensitive adhesive is Duro-Tak® 87-2054.

[0105] For example, the acrylate copolymer of interest may be of the formula

Chemical formula

[0106] The amount of the pressure-sensitive adhesive in the transdermal dexmedetomidine composition to be targeted may vary, and the amount of the pressure-sensitive adhesive ranges from 0.1 mg to 2000 mg, for example, from 0.5 mg to 1500 mg, for example, from 1 to 1000 mg, for example, from 10 to 750 mg, and includes 10 mg to 500 mg. As such, the amount of the pressure-sensitive adhesive in the transdermal composition ranges from 1% to 99% w / w, for example, from 5% to 95% w / w, for example, from 10% to 95%, for example, from 15% to 90% w / w, and includes 20% to 85% w / w. In other embodiments, the amount of the pressure-sensitive adhesive in the transdermal composition of the subject is 70% by weight or more of the total weight of the transdermal composition, for example, 75% by weight or more, for example, 80% by weight or more, for example, 85% by weight or more, for example, 90% by weight or more, for example, 95% by weight or more, and includes 97% by weight or more of the total weight of the transdermal composition.

[0107] The weight ratio of the pressure-sensitive adhesive to dexmedetomidine in the composition of the subject may range from 1:2 to 1:2.5; 1:2.5 to 1:3; 1:3 to 1:3.5; 1:3.5 to 1:4; 1:4 to 1:4.5; 1:4.5 to 1:5; 1:5 to 1:10; 1:10 to 1:25; 1:25 to 1:50; 1:50 to 1:75; and 1:75 to 1:99 or fall within that range. For example, the weight ratio of the pressure-sensitive adhesive to dexmedetomidine in the composition to be targeted may range between 1:1 to 1:5; 1:5 to 1:10; 1:10 to 1:15; 1:15 to 1:25; 1:25 to 1:50; 1:50 to 1:75 or 1:75 to 1:99. Alternatively, the weight ratio of dexmedetomidine to the pressure-sensitive adhesive in the composition of the subject may range between 2:1 to 2.5:1; 2.5:1 to 3:1; 3:1 to 3.5:1; 3.5:1 to 4:1; 4:1 to 4.5:1; 4.5:1 to 5:1; 5:1 to 10:1; 10:1 to 25:1; 25:1 to 50:1; 50:1 to 75:1; and 75:1 to 99:1 and fall within that range. For example, the ratio of dexmedetomidine to the pressure-sensitive adhesive in the composition to be targeted may range between 1:1 to 5:1; 5:1 to 10:1; 10:1 to 15:1; 15:1 to 25:1; 25:1 to 50:1; 50:1 to 75:1; or 75:1 to 99:1.

[0108] In some embodiments, the transdermal dexmedetomidine composition may further comprise one or more cross-linked hydrophilic polymers. For example, the cross-linked polymer may be an amine-containing hydrophilic polymer. Amine-containing polymers may include, but are not limited to, polyethyleneimine, amine-terminated oxidized polyethylene, amine-terminated oxidized polyethylene / polypropylene, polymers of dimethylaminoethyl methacrylate, and copolymers of dimethylaminoethyl methacrylate and vinyl pyrrolidone. In certain embodiments, the cross-linked polymer is cross-linked polyvinyl pyrrolidone, for example, PVP-CLM.

[0109] The matrix may contain other additives depending on the adhesive used. Substances that inhibit crystallization of the drug, for example, PVP-CLM, PVP K17, PVP K30, PVP K90, have hygroscopicity that improves the duration of abrasion and the physical properties of the adhesive, such as cold flow, viscosity, and adhesiveness.

[0110] The amount of the cross-linked polymer in the targeted dexmedetomidine composition may vary, and the amount of the cross-linked polymer ranges from 0.1 mg to 500 mg, for example 0.5 mg to 400 mg, for example 1 to 300 mg, for example 10 to 200 mg, and includes 10 mg to 100 mg. As such, the amount of the cross-linked polymer in the transdermal composition ranges from 2% to 30% w / w, for example 4% to 30% w / w, for example 5% to 25%, for example 6% to 22.5% w / w, and includes 10% to 20% w / w. In other embodiments, the amount of the cross-linked polymer in the transdermal composition of the subject is 8% by weight or more of the total weight of the transdermal composition, for example 10% by weight or more, for example 12% by weight or more, for example 15% by weight or more, for example 20% by weight or more, for example 25% by weight or more, and contains 30% by weight or more of the cross-linked polymer of the total weight of the transdermal composition.

[0111] In certain embodiments, the transdermal dexmedetomidine composition of the subject further comprises a dexmedetomidine solubility enhancer. A "solubility enhancer" means a compound or composition that increases the solubility of dexmedetomidine in the composition of the subject, for example, preventing unwanted crystallization of dexmedetomidine in the composition. The dexmedetomidine solubilization enhancer may be incorporated into the dexmedetomidine composition in an amount ranging from 0.01% to 20% (w / w), for example, from 0.05% to 15% (w / w), for example, from 0.1% to 10% (w / w), for example, from 0.5% to 8% (w / w), and including 1% to 5% (w / w).

[0112] Exemplary solubility enhancers include linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid, levulinic acid, palmitic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid (i.e., stearic acid), N-lauroyl sarcosine, L-pyroglutamic acid, lauric acid, succinic acid, pyruvic acid, glutaric acid, sebacic acid, cyclopentanecarboxylic acid; acids including acylated amino acids, but not limited to these. Other solubility enhancers of interest include aliphatic alcohols, such as saturated or unsaturated higher alcohols having 12 to 22 carbon atoms (e.g., oleyl alcohol or lauryl alcohol); fatty acid esters, such as isopropyl myristate, diisopropyl adipate, lauryl lactate, propyl laurate, ethyl oleate, and isopropyl palmitate; alcohol amines, such as triethanolamine, triethanolamine hydrochloride, and diisopropanolamine; polyhydric alcohol alkyl ethers, such as polyhydric alcohols, such as glycerol, ethylene glycol, propylene glycol, 1,3-butylene glycol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, polypropylene glycol monolaurate, sorbitan, sorb etc. Alkyl ethers of vitol, isosorbide, methyl glucoside, oligosaccharides, and reducing oligosaccharides, wherein the number of carbon atoms in the alkyl group portion of the polyhydric alcohol alkyl ether is preferably 6 to 20; polyoxyethylene alkyl ethers, for example, the number of carbon atoms in the alkyl group portion is 6 to 20, and the number of repeating units (for example, -O-CH2CH2-) of the polyoxyethylene chain is 1 to 9, for example, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyoxyethylene oleyl ether, but not limited to these polyoxyethylene alkyl ethers; glycerides (that is, fatty acid esters of glycerol), for example, glycerol esters of fatty acids having 6 to 18 carbon atoms, wherein the glycerides may be monoglycerides (that is, glycerol molecules covalently bonded to one fatty acid chain via an ester bond), diglycerides (that is, glycerol molecules covalently bonded to two fatty acid chains via an ester bond), triglycerides (that is, glycerol molecules covalently bonded to three fatty acid chains via an ester bond), or combinations thereof, and the fatty acid components forming the glycerides include octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid (that is, stearic acid), and oleic acid; medium-chain fatty acid esters of polyhydric alcohols; alkyl lactates; alkyl dibasic acid esters; acylated amino acids; pyrrolidone; pyrrolidone derivatives, and combinations thereof may be mentioned, but are not limited thereto. Additional types of solubility improvers include lactic acid, tartaric acid, 1,2,6-hexanetriol, benzyl alcohol, lanolin, potassium hydroxide (KOH), tris(hydroxymethyl)aminomethane, glycerol monooleate (GMO), sorbitan monolaurate (SML), sorbitan monooleate (SMO), laureth-4 (LTH), and combinations thereof may be mentioned. In certain embodiments, the solubility absorption improver is levulinic acid, lauryl lactate, or propylene glycol monolaurate.

[0113] The formulation of the transdermal dexmedetomidine composition of the subject matter may vary. For example, the composition of the present invention may be in the form of a liquid solution or suspension, syrup, gel, foam, or a combination thereof for application by a transdermal delivery device.

[0114] In some embodiments, the transdermal delivery device is configured to include a single-layer matrix of dexmedetomidine composition. By "single-layer", it means that the transdermal delivery device includes only a single layer of dexmedetomidine composition disposed on the surface of the substrate of the transdermal delivery device, and does not include a pressure-sensitive adhesive, a transdermal dexmedetomidine composition, or another different layer for a solubility enhancer if present. Similarly, the single-layer transdermal delivery device of the present invention does not further include a separate reservoir of dexmedetomidine (i.e., an active agent reservoir) separated from the pressure-sensitive adhesive. As such, the single-layer transdermal delivery device of the present invention may include the respective amounts of the components of the transdermal dexmedetomidine composition necessary to practice the subject method in a single matrix, as described in more detail below. For example, in some embodiments, the single-layer transdermal delivery device of interest includes a single-layer matrix of dexmedetomidine and a pressure-sensitive adhesive configured to deliver a non-sedating amount of dexmedetomidine to the subject. In another embodiment, the single-layer transdermal delivery device of interest includes a single-layer matrix of dexmedetomidine, a pressure-sensitive adhesive, and a solubility enhancer configured to deliver a non-sedating amount of dexmedetomidine to the subject. In another embodiment, the single-layer transdermal delivery device of interest includes a single-layer matrix of dexmedetomidine, a pressure-sensitive adhesive, and a fatty acid ester configured to deliver a non-sedating amount of dexmedetomidine to the subject. In certain embodiments, the single-layer transdermal delivery device of interest includes a single-layer matrix having only dexmedetomidine and a pressure-sensitive adhesive. Depending on the length of the dosing interval and the desired target dose, the thickness of the single-layer matrix of interest may vary, in some cases, ranging from 10 to 260 microns in thickness, such as 15 to 250 microns, such as 25 to 225 microns, such as 50 to 200 microns, such as 75 to 175 microns, and including 20 to 130 microns, such as 35 to 110 microns.

[0115] The size of the transdermal delivery device of the subject may vary, and in some cases, it may be sized to cover the entire application site on the subject. As such, the transdermal delivery device may have a length ranging from 1 to 100 cm, for example 1 to 60 cm, and a width ranging from 1 to 100 cm, for example 1 to 60 cm. As such, the area of the transdermal delivery device is 4 cm 2 ~10,000 cm 2 , for example 5 cm 2 ~1000 cm 2 , for example 10 cm 2 ~100 cm 2 , for example 15 cm 2 ~50 cm 2 and extends to, and includes 20 cm 2 ~40 cm 2 . In certain embodiments, the transdermal delivery device is sized to have an area of 30 cm 2 . In certain embodiments, the transdermal delivery device is water-insoluble. By water-insoluble is meant that the transdermal delivery device may be immersed in water for one day or more, including one month or more, for example one week or more, and show little or no dissolution, for example, show no observable dissolution.

[0116] In certain embodiments, the transdermal delivery device as described above further includes a multilayer backing layer. The multilayer backing may be flexible, so that, for example, it can closely contact the desired application site on the subject. The multilayer backing may be manufactured from a material that does not adsorb dexmedetomidine and prevents dexmedetomidine from exuding from the matrix. The target multilayer backing layer may include, but is not limited to, non-woven fabrics, woven fabrics, films (including sheets), porous bodies, foams, papers, composites obtained by laminating a film on a non-woven fabric or cloth, and combinations thereof.

[0117] The nonwoven fabric may include, for example, polyolefin resins such as polyethylene and polypropylene; polyester resins such as polyethylene terephthalate, polybutylene terephthalate and polyethylene naphthalate; rayon, polyamide, poly(ester ether), polyurethane, polyacrylic resins, polyvinyl alcohol, styrene-isoprene-styrene copolymer and styrene-ethylene-propylene-styrene copolymer, and combinations thereof. The fabric may include cotton, rayon, polyacrylic resins, polyester resins, polyvinyl alcohol, and combinations thereof. The film may include, for example, polyolefin resins such as polyethylene and polypropylene; polyacrylic resins such as polymethyl methacrylate and polyethyl methacrylate; polyester resins such as polyethylene terephthalate, polybutylene terephthalate and polyethylene naphthalate; and further, cellophane, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluororesin, styrene-isoprene-styrene copolymer, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymer, polyamide, and polysulfone; and combinations thereof. The paper may include impregnated paper, coated paper, fine paper, kraft paper, Japanese paper, glassine paper, synthetic paper, and combinations thereof.

[0118] Depending on the dosing interval and the desired target dose, the size of the multilayer backing may vary, and in some cases, it may be sized to cover the entire application site on the subject. As such, the backing layer may have a length ranging from 2 to 100 cm, for example 4 to 60 cm, and a width ranging from 2 to 100 cm, for example 4 to 60 cm. In some cases, the multilayer backing layer may be water-insoluble. Water-insoluble means that the backing layer may be immersed in water for a period of one day or more, including one month or more, for example one week or more, and shows little or no dissolution, for example, no observable dissolution.

[0119] The transdermal delivery device having the dexmedetomidine composition according to the embodiment of the present invention is not irritating to the skin of the subject at the application site. Skin irritation refers in its general sense to adverse effects, stinging or damage to the skin, such as erythema, pain, swelling, or dryness, as referred to in this specification. As such, in practicing the method with the subject transdermal delivery device, the quality of the skin remains normal and the transdermal delivery is consistent throughout the dosing interval.

[0120] In some embodiments, skin irritation is evaluated to determine the nature and color of the skin at the application site and to determine whether any damage, pain, swelling or dryness has occurred from maintaining contact with the subject and the transdermal composition. The skin may be evaluated using the Draize scale as disclosed, for example, in Draize, J.H., Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, pp. 46 - 49, The Association of Food and Drug Officials of the United States: Austin, Texas, the disclosure of which is incorporated herein by reference. In particular, the skin may be evaluated for erythema or edema at the transdermal application site. For example, the grades of erythema and edema may be assigned based on visual observation or palpation. Erythema: 0 = no visible erythema; 1 = very mild erythema (barely perceptible); 2 = mild but limited erythema; 3 = moderately strong erythema; 4 = severe erythema (dark red staining of the skin); 5 = eschar formation Edema: 0 = no visible reaction or swelling; 1 = very mild edema (barely perceptible); 2 = mild edema (the corners of the area are distinct due to swelling); 3 = moderate edema (swelling up to 1 mm); 4 = severe edema (swelling exceeding 1 mm)

[0121] At any time during the method of the subject, the site of application may be evaluated for skin irritation. In some cases, at regular intervals, such as every 72 hours, or including any interval, every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours, the skin is observed or palpated while maintaining contact with the subject and the transdermal delivery device, and the skin is evaluated for irritation. For example, including after 168 hours of application of the transdermal delivery device, for example, 15 minutes after application of the transdermal delivery device to the subject, 30 minutes after application of the transdermal delivery device, 1 hour after application of the transdermal delivery device, 2 hours after application of the transdermal delivery device, 4 hours after application of the transdermal delivery device, 8 hours after application of the transdermal delivery device, 12 hours after application of the transdermal delivery device, 24 hours after application of the transdermal delivery device, 48 hours after application of the transdermal delivery device, 72 hours after application of the transdermal delivery device, 76 hours after application of the transdermal delivery device, 80 hours after application of the transdermal delivery device, 84 hours after application of the transdermal delivery device, 96 hours after application of the transdermal delivery device, 120 hours after application of the transdermal delivery device, while maintaining contact with the subject and the transdermal delivery device, the site of application may be evaluated for skin irritation.

[0122] In other embodiments, the site of transdermal application is evaluated for skin irritation after the transdermal delivery device has been removed from contact with the subject. For example, including after 72 hours of removal of the transdermal delivery device, 30 minutes after removal of the transdermal delivery device, for example 1 hour after removal of the transdermal delivery device, for example 2 hours after removal of the transdermal delivery device, for example 4 hours after removal of the transdermal delivery device, for example 8 hours after removal of the transdermal delivery device, for example 12 hours after removal of the transdermal delivery device, for example 24 hours after removal of the transdermal delivery device, for example 48 hours after removal of the transdermal delivery device, the site of application may be evaluated for skin irritation.

[0123] In some embodiments, for example, to record the color and texture of the skin before starting the dosing interval, the site of transdermal application is evaluated for skin irritation before the transdermal delivery device is applied to the subject. For example, the site of application may be evaluated for skin irritation 5 minutes before applying the transdermal delivery device, for example 10 minutes, for example 30 minutes, for example 60 minutes, for example 120 minutes, for example 240 minutes, and including 480 minutes before applying the transdermal delivery device. If the method includes a plurality of dosing intervals in which sequential applications are made, the site of application may be evaluated for skin irritation after each transdermal delivery device is removed and before the next transdermal delivery device is applied. For example, when the first transdermal delivery device is removed, the site of application may be evaluated for skin irritation 2 hours, 24 hours, and 48 hours after removal and before application of the second transdermal delivery device. The next transdermal delivery device may be applied immediately after evaluating the skin for irritation, at the previous site of application before application, or at a predetermined time after evaluating the skin for irritation, for example 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, or 168 hours after evaluating the skin for irritation.

[0124] The site of application may be evaluated for skin irritation one or more times, including five or more times, for example two or more times, for example three or more times, before, during, or after the dosing interval. The upper limit of the number of times the site of application may be evaluated for skin irritation before, during, or after the dosing interval is, in some cases, 10 or less, for example 7 or less, for example 5 or less, for example 3 or less, and 2 or less. In certain embodiments, the number of times the site of application may be evaluated for skin irritation before, during, or after the dosing interval ranges from, for example, 2 to 10, for example 3 to 9, for example 4 to 8, and includes 5 to 7. In certain embodiments, skin irritation may be monitored, for example, by video monitoring throughout the entire time the transdermal delivery device is in contact with and maintained on the subject.

[0125] A further aspect of the subject method includes a method of increasing a pain threshold. As used herein, "increasing a pain threshold" refers to the reduction, decrease and / or minimization of pain associated with surgery, incision, trauma or wound (including the reduced, decreased and / or minimized subjective perception of pain). In yet another aspect, the subject method provides for enhancing recovery from surgery, as well as enhancing recovery from trauma, injury, and / or incision.

[0126] In certain embodiments, the subject method includes a diagnostic step. An individual may be diagnosed as in need of the subject method using any conventional protocol. Additionally, an individual may be known to be in need of the subject method, for example, prior to practicing the subject method, an individual has been determined to suffer from, or be at risk of suffering from, a target disease state. Diagnosis or assessment of pain is well established in the art. The assessment may be performed based on objective measures, such as observation of behavior, such as response to a stimulus, facial expression, etc. The assessment may also be based on subjective measures, such as characterization of pain by the patient using various pain scales. See, for example, Katz, et al, Surg. Clin. North Am. (1999) 79(2):231-52; Caraceni, et al, J. Pain Symptom Manage (2002) 23(3):239-55.

[0127] Pain relief may be characterized by a time course of relief. Thus, in some embodiments, pain relief is subjectively or objectively observed after 1 hour, 2 hours or several hours (and in some embodiments, a peak at about 12-18 hours). In other embodiments, pain relief is subjectively or objectively observed more than 24, 36, 48, 60, 72 hours after surgery (or an activity related to a wound or trauma).

[0128] Utility The subject dexmedetomidine transdermal delivery device and method are used in a variety of applications, including preventing or treating surgical pain. Thus, the subject dexmedetomidine trans The transdermal delivery device and method are useful for treating surgical pain, delaying its onset, and / or preventing it in subjects including all mammals, including carnivores (e.g., dogs and cats), rodents (e.g., mice, guinea pigs, and rats), lagomorphs (e.g., rabbits), and primates (e.g., humans, chimpanzees, and monkeys), both human and non-human. In certain embodiments, the subject, e.g., the patient, is human. Further, the subject dexmedetomidine transdermal delivery device and method are useful in individuals having incisional wounds in tissue, whether internal or external, whether by incision, puncture, or laceration. Such incisional wounds may occur incidentally, like trauma, or may occur intentionally, like surgery.

[0129] In some embodiments, for example, the methods and transdermal delivery devices of the invention as described above are used in the treatment of surgical pain resulting from a surgical procedure involving, for example, making an incision in a patient. The surgical pain may be perioperative pain and / or postoperative pain. The surgical procedures in which the transdermal delivery device and method may be used may vary, where the surgical procedures include, among numerous surgeries, in particular, median sternotomy, laparoscopy, mastectomy, arthroplasty, osteotomy, cancer surgery, knee surgery, shoulder surgery, including but not limited to bone model surgery or soft tissue surgery. In an embodiment, the surgery is aponeurotoma resection, total knee arthroplasty, hernia repair, open cholecystectomy, hip arthroplasty, or arthroscopic examination of the shoulder and knee in a patient. In some embodiments, the surgical procedure is a dental surgical procedure, e.g., surgical extraction of a molar (e.g., the first, second, or third adult molar).

[0130] In some cases, the methods and transdermal delivery devices of the present invention are used in the treatment of surgical pain associated with aponeurotic fibroma resection. An aponeurotic fibroma or hallux valgus is an inflammation or hypertrophy of the joint capsule of the big toe of the foot. This inflammation causes damage and deformation to the joint due to abnormal bone growth. The big toe of the foot is forced towards the other toes, causing the head of the first metatarsal bone to protrude against the side of the shoe and rub; the underlying tissue becomes inflamed and the pain is increased. As this bone growth occurs, the big toe grows at an increased angle towards the other toes, resulting in the formation of an aponeurotic fibroma. Aponeurotic fibromas can also occur in the fifth metatarsal bone, in which case it is known as a bunionette or tailor's bunion. Aponeurotic fibromas often result from wearing narrow, high-heel shoes with pointed tips that place great pressure on the front of the foot and force the foot and toes into unnatural angles. Damage to the joint can also cause aponeurotic fibromas over time. Heredity accounts for 10% - 15% of all cases of aponeurotic fibroma problems; hallux valgus, one of the genetic deformities, shifts and grows the bone and joint of the big toe inward, causing the second toe of the foot to cross over it. Flat feet, gout, and arthritis increase the risk of aponeurotic fibroma. Surgery for aponeurotic fibroma is usually called aponeurotomy and is almost always performed as an outpatient procedure. The procedure itself varies depending on the type and severity of the deformity. Although the procedure varies, the recovery is the same for all. Some of the aponeurotomy procedures are named Akin, Austin Akin, Keller, Silver, Silver Akin, and Kalish, depending on the area of bone to be cut and the type of cut to be made. Once the subject enters the operating room and anesthesia is initiated, a tourniquet is applied either to the thigh or ankle, depending on the type of anesthesia, to prevent bleeding during the surgery. A tourniquet is used to prevent bleeding during the surgery. After the tourniquet is applied, the foot and lower leg are aseptically washed to help prevent infection. The surgeon then makes an incision into the joint capsule at the tip of the big toe.

[0131] Once the bone is exposed, the surgeon makes cuts in the bone to correct the deformity. This is called "osteotomy." As defined herein, osteotomy is a surgical procedure that cuts the bone to shorten, lengthen, or change its placement. It is used, for example, to straighten a bone that has healed in a bent position after a fracture. Bone is defined herein as a connective tissue consisting of osteoblasts, resting osteocytes, and osteoclasts that break down bone, which form bone embedded in a mineralized matrix fused with spaces and canals. In the case of hallux valgus, bone fragments are removed and the bone is readjusted to correct the deformity. Correction of the tendon and other soft tissues may also be necessary to ensure complete correction.

[0132] Depending on the type of aponeurotomy, fixation may be required. Fixation may be internal, percutaneous, or by external means such as, for example, a Gibbs or splint, surgical shoe, adhesive form, or bandage. Fixation is often internal in aponeurotomy. This is usually done with screws or wires. Once the bone is readjusted, the wound is irrigated with warm sterile saline, then sutured closed and a bandage is applied. Recovery varies according to the extent of the surgical procedure and the rate of healing of each individual.

[0133] Ordinary postoperative care consists of rest, elevation, and ice for the first 3 to 5 days. Depending on the procedure performed, some walking in special shoes may be done during this time. Examinations are done in the clinic and the dressing is changed. Depending on work requirements, the subject often returns to work 3 to 7 days later. The skin usually heals in 2 weeks, at which time the sutures are removed. The bone takes 6 to 8 weeks to heal. The rate of bone healing can be evaluated by taking X-rays at regular intervals. The aponeurotic fibroma surgery causes some stiffness. Physical therapy is started in the second or third week to minimize this stiffness, and usually home exercises are sufficient. If these exercises are not done, insufficient results may occur due to excessive stiffness. The swelling gradually subsides, and if sufficient bone healing occurs in 2 months, regular shoes may be worn. It is often possible to resume normal activities in 2 to 3 months as tolerated. Some swelling may be present for more than 6 months. The recovery period varies according to the procedure and the individual's rate of healing. For example, some factors such as circulation, smoking, bone mass, and overall health may have an impact.

[0134] As outlined above, the method and transdermal delivery device of the present invention are used for the treatment of pain after aponeurotic fibroma resection surgery and are effective in providing immediate relief of moderate to severe acute pain to patients following postoperative procedures, particularly outpatient postoperative procedures such as aponeurotic fibroma resection, and thus can delay, reduce, or completely eliminate the need for alternative pain relievers such as NSAIDS, opioids, etc.

[0135] As used herein, the term "acute pain" means pain that has a sudden onset, generally decreases within a short period (days, hours, minutes), follows physical injury, and gradually disappears as the physical injury heals. The intensity of acute pain following aponeurotic fibroma resection can be mild to moderate, moderate to slightly severe, or moderate to severe. The intensity of pain is measured using a pain rating scale in daily clinical practice. Commonly used measurement scales include the Visual Analogue Scale (VAS), Graphic Rating Scale (GRS), Simple Descriptor Scale (SDS), Numerical Rating Scale (NRS), and Facial Rating Scale (FRS). All of these scales are documented as valid measurements of pain intensity. The three most commonly used scales in the United States are the numerical, word, and facial scales. The Visual Analogue Scale (VAS) is a 10 cm vertical or horizontal line with extreme and word anchors such as "no pain" at one end and "the worst possible pain" at the other end. The patient is asked to mark along the line to indicate the intensity of the pain. The Graphic Rating Scale (GRS) is a variation of the visual scale that adds words or numbers between the extremes. Phrases that may be added include "no pain", "mild", "severe". The Descriptor Scale (SDS) is a list of adjectives that describe various levels of pain intensity. For example, the intensity of pain may be described as "no pain", "mild", "moderate", or "severe". The Numerical Pain Rating Scale (NPRS) refers to a numerical rating of 0 - 10 or 0 - 5, or a visual scale with words and numbers. The patient is asked to rate the pain on a scale of 0 for no pain and 10 for the worst possible pain. The facial scale was developed for use with children. This scale exists in several variations and relies on a series of facial expressions to convey the intensity of pain.

[0136] Grouping patients' ratings of pain intensity, measured on a numerical scale ranging from 0 to 10, into mild, moderate, and severe pain is useful for informing treatment decisions and interpreting study results. In 1995, Serlin and co-workers (Pain, 1995, 277-84) developed a technique for establishing cut-points for mild, moderate, and severe pain by grading pain intensity and making functional inferences. Since then, numerous studies have been conducted associating numerical scales, such as the NPRS, with cut-points for levels of pain intensity. Common severity cut-points are (1-4) for mild pain, (5-6) for moderate pain, and (7-10) for severe pain.

[0137] As used herein, the term "patient" refers to a warm-blooded animal such as a mammal that is the subject of a surgical trauma. It is understood that at least dogs, cats, mice, and humans are within the meaning of the term. As used herein, the term "treatment" or its derivatives contemplate partial or complete suppression of acute pain when the transdermal delivery device of the present invention is administered following the onset of acute pain. In one embodiment, a method is provided for the treatment of acute pain following postoperative treatment, particularly following osteotomy such as aponeurotomy.

[0138] Kit Also provided is a kit for use in practicing certain methods described herein. In certain embodiments, the kit includes one or more transdermal delivery devices containing a dexmedetomidine composition having an amount of dexmedetomidine and a pressure-sensitive adhesive as described above. In certain embodiments, the kit includes an adhesive laminate as described above. In a given kit containing more than two of the subject transdermal delivery devices, the compositions may be individually packaged or present in a common container.

[0139] In certain embodiments, the kit further includes instructions for practicing the subject method or means for obtaining them (e.g., a website URL that directs the user to a web page providing the instructions), where these instructions may be printed on a substrate, which may be one or more of an accompanying document, packaging, reagent container, etc. In the subject kit, one or more components may be present in the same or different containers, as convenient or desired.

[0140] The following examples are provided for illustrative purposes and not for purposes of limitation. Specifically, the following examples are of specific embodiments for practicing the present invention. The examples are for illustrative purposes only and are in no way intended to limit the scope of the present invention. Although efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), some experimental error and deviation are to be expected.

Examples

[0141] I. Materials and Methods Preparation of an Exemplary Dexmedetomidine Transdermal Formulation The formulation was prepared by mixing dexmedetomidine with a pressure-sensitive adhesive in an organic solvent (e.g., 30 - 60 wt% solids in ethyl acetate, isopropyl alcohol, hexane, or heptane), followed by subsequent mixing. Once a homogeneous mixture was formed, the solution was poured onto a release liner (a 2 - 3 mil polyester sheet coated with silicon-treated polyester or fluoropolymer) and dried at 60 °C - 80 °C for 10 - 90 minutes. The single-layer adhesive film was then laminated onto a PET backing, cut to the desired size, and placed in a bag. In some cases, cross-linked polyvinylpyrrolidone (PVP-CLM), polyvinylpyrrolidone K90 (PVP K90), levulinic acid (LA), oleic acid (OA), lauryl lactate (LL), or propylene glycol monolaurate (PGML) was added to the adhesive composition.

[0142] Transdermal Flux Test Using human cadaver skin, the epidermal layer (stratum corneum and viable epidermis) was separated from the full-thickness skin as a skin membrane. The sample was punched and cut with a bow punch to a final diameter of about 2.0 cm 2 The release liner was removed, and the system was placed on the epidermis / stratum corneum with the dexmedetomidine adhesive layer facing the outer surface of the stratum corneum. Gentle pressure was applied to achieve good contact between the adhesive layer and the stratum corneum. The donor side and the receptor side of the Franz cell were fixed together, and a receptor solution containing phosphate buffer at pH 6.5 and 0.01% gentamicin was added to the Franz cell. During the experiment, the cell was maintained at 32 °C to 35 °C. Samples of the receptor solution were taken at regular intervals, and the concentration of the active agent was measured by HPLC. The removed solution was replaced with a fresh solution to maintain a sink state. The flux was calculated from the slope of the cumulative amount of the drug permeated into the receiving compartment compared to the time plot.

[0143] II. Examples Example 1 In vitro flux obtained from a dexmedetomidine transdermal composition formulation with a PIB / PB polymer The pressure-sensitive adhesive used in this example is a polyisobutylene / polybutene (PIB / PB) adhesive. The PIB / PB adhesive is a mixture of high molecular weight PIB (5% Oppanol B100), low molecular weight PIB (25% Oppanol B12), and a polybutene tackifier, such as Indopol H1900 or Panalan H-300e (20%) in an organic solvent, such as heptane (50%). The combination was mixed for about 3 days until homogeneous. Exemplary dexmedetomidine transdermal composition formulations are shown in Tables 1 and 2.

[0144] An in vitro skin flux test was conducted as described above with a transdermal delivery device having various concentrations of dexmedetomidine as shown in Table 1. The in vitro skin flux of dexmedetomidine related to time is illustrated in Figure 1. As shown in Figure 1, the in vitro skin flux of dexmedetomidine was higher in the first few hours for the 1% formulation (Formulation 1) compared to the high drug load (Formulations 2 and 3). Formulations 2 and 3 were found to have needle-like crystals of dexmedetomidine, so the flux profile was constant and did not vary with drug load. However, crystals were not observed in Formulation 1. Formulation 1 contains a saturated or supersaturated amount of dexmedetomidine.

[0145] Dexmedetomidine transdermal formulations were also prepared using PIB made from Indopol H1900 as shown in Table 2. The results of in vitro permeation of dexmedetomidine from a 1% dexmedetomidine formulation made with 20% PVP-CLM in a PIB / PB adhesive through skin with various skin permeabilities are illustrated in Figure 2. Figure 2(A) shows the cumulative dexmedetomidine delivery over time. The in vitro permeation of dexmedetomidine was displaced according to the skin permeability. The amount of dexmedetomidine delivered in vitro could vary from 4 - 35 μg / cm 2 at 8 hours and 15 - 67 μg / cm 2 up to 24 hours. Figure 2(B) shows the flux or derivative of the cumulative drug delivery with respect to time. The delivery rate of dexmedetomidine from Formulation 2 reached a maximum at about 5 - 7 hours and then remained constant for at least 24 hours. In the case of highly permeable skin (Skin #14), the flux may decrease due to depletion. Figure 2(C) shows the % drug remaining in the patch over time. As shown in Figure 2(C), the utilization of dexmedetomidine obtained from Formulation 4 was 20 - 70% after applying the patch for 24 hours.

Table 1

Table 2

[0146] Example 2 In vitro flux obtained from a transdermal composition formulation of dexmedetomidine with a non-functionalized acrylate polymer The in vitro flux of dexmedetomidine was measured using a non-functionalized acrylate adhesive. Examples of non-functionalized acrylate adhesives experimentally used include the non-functionalized acrylate polymer Duro-Tak 87-9301. In vitro skin flux tests were performed as described above with transdermal delivery devices having various concentrations of dexmedetomidine with non-functionalized Duro-Tak 87-9301. The transdermal composition formulations of dexmedetomidine are shown in Table 3. The average in vitro flux of dexmedetomidine over time is illustrated in Figure 3. As shown in Figure 3, a high dexmedetomidine loading gave an increased in vitro skin flux.

Table 3

[0147] Example 3 In vitro flux obtained from a transdermal composition formulation of dexmedetomidine with a hydroxyl (-OH)-functionalized acrylate polymer The in vitro flux of dexmedetomidine was measured using a hydroxyl (-OH)-functionalized acrylate adhesive. Examples of hydroxyl-functionalized acrylate adhesives experimentally used include hydroxyl-functionalized acrylate polymers such as Duro-Tak 87-428 7, Duro-Tak 387 / 87-2510, Duro-Tak 387 / 87-2287, and Duro-Tak 387 / 87-2516. In vitro skin flux tests were performed as described above with transdermal delivery devices having various concentrations of dexmedetomidine with various hydroxyl-functionalized acrylate adhesives.

[0148] Tables 4 and 5 show dexmedetomidine transdermal composition formulations containing various concentrations of dexmedetomidine in Duro-Tak 87-4287 (acrylate-vinyl acetate polymer) or Duro-Tak 387 / 87-2510 (acrylate polymer). The average in vitro flux of dexmedetomidine is illustrated in FIGS. 4 and 5. As shown in FIGS. 4 and 5, the in vitro flux of dexmedetomidine increased with the dexmedetomidine loading in the formulation.

Table 4

Table 5

[0149] Table 6 shows dexmedetomidine transdermal composition formulations containing 1% dexmedetomidine in another hydroxyl-functionalized acrylate polymer containing vinyl acetate, such as Duro-Tak 87-2287 (a polymer without added crosslinker) and Duro-Tak 87-2516 (a polymer with added crosslinker). The average in vitro flux of dexmedetomidine is illustrated in FIG. 6. As shown in FIG. 6, the in vitro flux obtained from Duro-Tak 387 / 87-2287 was slightly higher than that from Duro-Tak 387 / 87-2516, probably due to the higher adhesiveness of Duro-Tak 387 / 87-2287 compared to Duro-Tak 387 / 87-2516.

Table 6

[0150] Example 4 In vitro flux obtained from transdermal composition formulations of 1% dexmedetomidine with non-functionalized or hydroxyl (-OH)-functionalized acrylate polymers Another series of examples of dexmedetomidine transdermal formulations are transdermal compositions containing 1% w / w dexmedetomidine with a non-functionalized acrylate polymer (Duro-Tak 87-9301, formulation 5), a hydroxyl-functionalized acrylate polymer (Duro-Tak 387 / 87-2510, formulation 11), and a hydroxyl-functionalized acrylate polymer containing vinyl acetate (Duro-Tak 87-4287, formulation 8). In vitro flux experiments were conducted for 3 days and 1 day, and the results are shown in Figures 7A and 7B, respectively. As shown in Figures 7A and 7B, the in vitro flux of dexmedetomidine was less with the non-functionalized adhesive compared to the hydroxyl-functionalized adhesive at the same drug loading.

[0151] Example 5 In Vitro Flux Obtained from Dexmedetomidine Transdermal Composition Formulations with Acid (-COOH)-Functionalized or Acid / Hydroxyl (-COOH / OH)-Functionalized Acrylate Polymers The in vitro flux of dexmedetomidine was measured using acid (-COOH)-functionalized or acid / hydroxyl (-COOH / OH)-functionalized acrylate adhesives. An example of an acid (-COOH)-functionalized acrylate adhesive used in this study is Duro-Tak 387 / 87-2353 (acrylate polymer without added crosslinker). The acid / hydroxyl (-COOH / OH)-functionalized acrylate adhesive used in this study is Duro-Tak 87-2979 (acrylate-vinyl acetate polymer with added crosslinker).

[0152] Tables 7 and 8 show dexmedetomidine transdermal composition formulations containing different acid (-COOH) - functionalized or acid / hydroxyl (-COOH / OH) - functionalized acrylate polymers. The concentration of dexmedetomidine in the formulations was selected based on the solubility of dexmedetomidine in each adhesive. The solubility of dexmedetomidine in Duro - Tak 387 / 87 - 2353 was found to be about 10 - 15%, while the solubility in Duro - Tak 87 - 2979 was found to be less than 2%. The solubility of the drug in the acid - functionalized acrylate adhesives was higher than that in the non - functionalized or hydroxyl - functionalized acrylate adhesives.

[0153] The in - vitro skin flux test was conducted as described above. The average in - vitro flux of dexmedetomidine is illustrated in Figures 8 and 9.

Table 7

Table 8

[0154] Example 6 In - vitro flux obtained from a dexmedetomidine transdermal composition formulation with a PIB / PB polymer containing PVP - CLM and Duro - Tak 387 / 87 - 2353 Another example of a dexmedetomidine transdermal composition formulation is shown in Table 9. To increase the solubility of the drug in the PIB / PB (e.g., Indopol H - 1900) adhesive, PVP - CLM and an acid (-COOH) - functionalized acrylate polymer (Duro - Tak 387 / 87 - 2352) were used. Formulations 18 - 21 with different loadings of Duro - Tak 387 / 87 - 2353 were prepared.

[0155] As shown in Figure 10, the acid (-COOH) - functionalized acrylate polymer (Duro - Ta Formulations containing k387 / 87 - 2353, Formulations 19, 20, and 21 are thought to have a lower initial flow rate compared to the formulation without Duro - Tak 2353 (Formulation 18). The in - vitro flow rate of dexmedetomidine did not change with 3% and 6% acid - functionalized adhesives, but a slight decrease in the in - vitro flow rate was observed with 9% acid - functionalized adhesives.

Table 9

[0156] Example 7 In - vitro flow rate obtained from transdermal composition formulations of dexmedetomidine with PIB / PB polymers containing PVP - CLM and levulinic acid Another example of a transdermal composition formulation of dexmedetomidine is shown in Table 10. To increase the solubility of the drug in a PIB / PB (e.g., Indopol H - 1900) adhesive in the presence of 20% PVP - CLM, the increase in dexmedetomidine solubility was investigated using various concentrations of acid. Formulations 22 - 25 containing various loads of levulinic acid were prepared.

Table 10

[0157] As shown in Figure 11, when the formulation contained 6.9% levulinic acid, the in - vitro flow rate of dexmedetomidine decreased dramatically. However, at a concentration of 1.75% levulinic acid, the in - vitro flow rate was comparable to that of low - concentration levulinic acid (i.e., 0.6% and 0.9%). The initial flow rate obtained from formulations containing levulinic acid (Formulations 22, 23, 24, and 25) was lower than that of the formulation without levulinic acid (Formulation 18). However, after 24 hours, the flow rate obtained from formulations containing levulinic acid (Formulations 22, 23, 24, and 25) is thought to be higher than that from the formulation without levulinic acid (Formulation 17). Crystals of dexmedetomidine were observed at levulinic acid concentrations of 1.75% or less.

[0158] Example 8 In vitro flux obtained from a transdermal composition formulation of dexmedetomidine with a PIB / PB polymer containing PVP-CLM and lauryl lactate or propylene glycol monolaurate Another example of a transdermal composition formulation of dexmedetomidine is shown in Tables 11 and 12. Dexmedetomidine has a solubility of 5-10% in lauryl lactate and propylene glycol monolaurate. Each of lauryl lactate and propylene glycol monolaurate increases the solubility of dexmedetomidine in the PIB / PB adhesive in the subject formulation. The in vitro flux profiles of Formulations 26-28 are shown in Figure 12. The in vitro flux profiles of Formulations 29-31 are shown in Figure 13. Formulations 26-31 were found to have needle crystals of dexmedetomidine. [Table 11] [Table 12]

[0159] Example 9 In vitro flux obtained from a transdermal composition formulation of dexmedetomidine with Duro-Tak 387 / 87-2287 containing levulinic acid, PVP K90 or Duro-Tak 387 / 87-2353 Examples of another series of transdermal dexmedetomidine formulations include transdermal compositions having 1% w / w dexmedetomidine with solubilizing agents that improve the physical stability of the composition. In these formulations, levulinic acid, PVP K90, and Duro-Tak 87-2353 were employed. The compositions of the formulations are shown in Tables 13, 14, and 15. The in vitro flux profiles for transdermal compositions having 1% w / w dexmedetomidine with 0.3% and 0.6% levulinic acid are shown in Figure 14(A). The in vitro flux profiles for transdermal compositions having 1% w / w dexmedetomidine with 5% and 10% PVP K90 are shown in Figure 14(B). The in vitro flux profiles for transdermal compositions having 1% w / w dexmedetomidine with 2% or 3% Duro-Tak 387 / 87-2353 are shown in Figure 14(C). From the in vitro flux profiles, levulinic acid increased permeation after 15 hours of application, PVP K90 delayed the transdermal flux of dexmedetomidine, while Duro-Tak 2353 slightly decreased the transdermal flux.

Table 13

Table 14

Table 15

[0160] Example 10 In vitro flux obtained from a transdermal dexmedetomidine composition formulation with Duro-Tak 87-9301 polymer containing levulinic acid, oleic acid, or Duro-Tak 387 / 87-2353 Examples of another series of dexmedetomidine transdermal formulations include transdermal compositions having 3% w / w dexmedetomidine and non-functionalized acrylate polymer Duro-Tak 87-9301 in combination with 3.3% levulinic acid, 5% oleic acid, or 15% Duro-Tak 387 / 87-2353. The composition of the formulations is shown in Table 16. The in vitro flux profiles for these formulations (Formulations 38, 39, and 40) compared to 3% dexmedetomidine in non-functionalized acrylate polymer Duro-Tak 87-9301 without an adhesive (Formulation 7) are illustrated in Figure 15. Compositions having only 3% dexmedetomidine and non-functionalized acrylate polymer Duro-Tak 87-9301 were supersaturated. Levulinic acid and oleic acid were used as solubilizers and permeation enhancers, increasing the flux at the start of the in vitro flux but decreasing over time. Similar to the 1% dexmedetomidine composition, Duro-Tak 87-2353 decreased the flux.

Table 16

[0161] Example 11 In vitro permeation of dexmedetomidine obtained from 1%, 2%, 3%, and 4% dexmedetomidine in a mixture of adhesives (15% Duro-Tak 2353 in Duro-Tak 2287) Dexmedetomidine transdermal composition formulations containing a mixture of a hydroxyl-functionalized acrylate polymer (e.g., Duro-Tak 87-2287) and an acid-functionalized acrylate polymer (e.g., Duro-Tak 87-2353) are summarized in Table 17. Formulations 41 - 44 containing various loads of dexmedetomidine were prepared.

Table 17

[0162] As shown in Figure 16, the in vitro flux of dexmedetomidine increased with an increase in the ratio of dexmedetomidine load.

[0163] Example 12 In vitro permeation of dexmedetomidine obtained from a dexmedetomidine formulation containing oleic acid Another example of a transdermal composition formulation of dexmedetomidine is summarized in Table 18. Oleic acid was used to increase the solubility of dexmedetomidine in a hydroxyl-functionalized acrylate polymer (e.g., Duro-Tak 87-2287). Formulations 45 - 47 containing various loads of oleic acid and dexmedetomidine were prepared. [Table 18]

[0164] As shown in Figure 17, dexmedetomidine in formulations containing oleic acid has a higher flux than a dexmedetomidine composition without oleic acid (e.g., formulation 43). Oleic acid enhanced the permeation of dexmedetomidine through the skin. An increase in oleic acid from 5% to 7% (e.g., formulation 46) did not show an enhanced effect compared to a formulation containing 5% oleic acid (e.g., formulation 45). This may be the result of the contribution of oleic acid to the increased solubility of dexmedetomidine in the composition. The comparison between formulation 45 and formulation 47 shows that the in vitro flux increases with an increase in the ratio of drug load.

[0165] Example 13 In vitro permeation of dexmedetomidine obtained from a dexmedetomidine formulation containing levulinic acid A transdermal formulation of dexmedetomidine containing levulinic acid was prepared. The composition is shown in Table 19. [Table 19]

[0166] As shown in Figure 18, the in vitro flux of dexmedetomidine in formulations containing levulinic acid (formulations 48 and 49) increased with the ratio of dexmedetomidine load. The enhancing effect of levulinic acid on the permeation of dexmedetomidine through the skin was higher than that of oleic acid.

[0167] Table 20 summarizes the results of the in vitro permeation ratios of dexmedetomidine in Formulations 43, 45, and 48 compared to the amount of dexmedetomidine in the patch. Formulations 45 and 48 containing ruberic acid and oleic acid have demonstrated substantial enhancement in the permeation of dexmedetomidine under in vitro conditions.

Table 20

[0168] The solubility of dexmedetomidine in the hydroxyl-functionalized acrylate polymer was less than 1%. To increase dexmedetomidine, acid-functionalized acrylate polymers (e.g., Duro-Tak 2353), oleic acid, and ruberic acid were used. The solubilities of dexmedetomidine in Duro-Tak 2353, oleic acid, and ruberic acid were approximately 10 - 15%, 40%, and 60%, respectively. The amount of acid added to the formulation was adjusted according to the solubility of each component in the formulation.

[0169] After preparation, the presence of crystals was examined using a microscope. The results obtained from this microscopic examination showed that all formulations (Formulations 41 - 48) did not contain crystals.

[0170] The flux profiles of all formulations (Formulations 41 - 48) showed a distinct upward trend over time in flux during the first 24 hours (Figures 16 - 18). This was followed by a gradual decrease in flux over time. As such, the increase in flux during the first 24 hours may, in some cases, be useful for achieving a rapid and high initial therapeutic concentration in the body. When there is a decrease in flux over time, the decrease in flux may be due to crystallization of the drug in the adhesive induced by the moisture absorbed by the patch.

[0171] Example 14 In Vitro Flux Obtained from Various Liners The pressure-sensitive adhesive used in this example is a polyisobutylene / polybutene (PIB / PB) adhesive. The PIB / PB adhesive is a mixture of high molecular weight PIB (5% Oppanol B100), low molecular weight PIB (25% Oppanol B12), and a polybutene tackifier, such as Indopol H1900 or Panalan H-300e (20%) in an organic solvent, such as heptane (50%). The combination was mixed for about 3 days until the mixture became homogeneous. The exemplary dexmedetomidine transdermal composition formulations are shown in Table 21. The same formulations were coated on a release liner, but three different backing materials were laminated: backing 1 had an MVTR value of around 10 (g / m 2 / 24 h), backing 2 had an MVTR value of around 50 (g / m 2 / 24 h), and backing 3 had an MVTR value of around 150 (g / m 2 / 24 h). The average dexmedetomidine in vitro skin flux over time is illustrated in Figure 19. As shown in Figure 19, the dexmedetomidine in vitro skin flux was similar for backing 1 and 2. However, it was significantly lower for backing 3.

Table 21

[0172] Example 15 In vitro flux obtained from formulations containing lauryl lactate as a permeation enhancer Another series of examples of dexmedetomidine transdermal formulations include transdermal compositions having 2 - 4% w / w dexmedetomidine with a permeation enhancer to improve skin permeability. In these formulations, lauryl lactate (LL) and Duro-Tak 87-2287 were employed. The composition of the formulations is shown in Table 22. In vitro flux profiles for the transdermal compositions. Figures 20 and 21 show the flux in two different skin samples. From the in vitro flux profiles, LL shows its skin permeability enhancing effect. The flux is also proportional to the API loading.

Table 22

[0173] Example 16 Dexmedetomidine Transdermal System for Postoperative Analgesia after Aponeurotoma Resection For example, a randomized, double-blind, placebo-controlled, single-dose study of a dexmedetomidine transdermal system (DMTS) as described above or comparable to a 3-day placebo patch is conducted. The DMTS provides extended release of dexmedetomidine over a 3-day application period. Each DMTS has a surface area of 3 cm 2 and contains 0.73 mg of dexmedetomidine. In this study, subjects are administered two DMTSs for a total dexmedetomidine dose of 1.46 mg. Excipients in the DMTS include lauryl lactate and acrylate copolymer. A comparable placebo patch is identical to the DMTS except that it does not contain dexmedetomidine.

[0174] Subjects scheduled for surgical correction of unilateral hallux valgus (aponeurotoma of the first metatarsal bone without hammertoe) are selected up to 28 days prior to surgery. Eligible subjects are randomized in a 1:1 ratio to receive two DMTSs or two comparable placebo patches and are admitted to the clinical trial unit starting on the day before surgery and staying until 3 days after surgery. The surgery is performed at a hospital or outpatient surgical center. The surgical procedure (i.e., Austin aponeurotoma resection) and intraoperative anesthesia (Mayo block) are standardized.

[0175] In this study, subjects are randomized to receive two DMTSs or two comparable placebo patches. On Day 1, 12 ± 2 hours before the scheduled aponeurotoma resection, the patch is applied by trained study site staff to a hairless area of the subject's upper arm. The DMTS / Comparable placebo patch is applied after an overnight fast (in accordance with the requirements of the surgical center for the surgery). Two DMTS / Comparable placebo patches are worn for 3 days.

[0176] Following the surgery and the immediate postoperative recovery period, the subject returns to the clinical trial unit. During the three-day postoperative period in the clinical trial unit, the recovery procedures are standardized (including the use of rescue analgesics); the following are performed: pain assessment (using the NRS), sedation level assessment, safety assessment (vital signs including oxygen saturation [SpO2]), patch adhesion, and skin irritation. In addition, plasma concentrations of dexmedetomidine are obtained in a subset of subjects.

[0177] During the treatment period, the subject receives the application of two DMTS (1.46 mg dose) or two comparable placebo patches for three days. As needed, the subject receives rescue analgesic dosing.

[0178] The procedures and evaluations described below are performed during the treatment period; in addition to these procedures, AEs, vital signs, and concomitant medications will be evaluated throughout the study day.

[0179] On Day 1, the intensity of pain is scored by the subject, the sedation level is evaluated by the investigator / site staff, the use of rescue analgesics is evaluated starting at 4 hours postoperatively; blood samples are collected for PK analysis, and adhesion is evaluated.

[0180] On Days 2 and 3, the intensity of pain is scored by the subject, the sedation level is evaluated by the investigator / site staff, the use of rescue analgesics is evaluated; blood samples are collected for PK analysis, and patch adhesion is evaluated.

[0181] On the fourth day, prior to the removal of the placebo patch comparable to DMTS, the intensity of pain is scored by the subject, the level of sedation is evaluated by the investigator / site staff, and the use of rescue analgesic medications is evaluated; blood samples are collected for PK analysis, and patch adhesion is evaluated. Then the placebo patch comparable to DMTS is removed. After patch removal, blood samples are collected for PK analysis, and remote cardiac monitoring is discontinued; the patch application site is evaluated for skin irritation (if the skin irritation score is >0 one hour after patch removal, a follow-up visit for observation will be scheduled). After the one-hour skin irritation assessment, visible residues from the application area of the patch are removed with a damp cloth.

[0182] After all the test procedures are completed, the subject is discharged from the clinic on the fourth day.

[0183] In the above test, it was observed that the use of DMTS as described above effectively manages the pain of patients resulting from aponeurotic fibroma resection.

[0184] Example 17 TPU-006 for Postoperative Analgesia Following Aponeurotic Fibroma Resection A phase 2 proof-of-concept (POC) study of TPU-006, a transdermal patch of dexmedetomidine for 3 days (the formulation provided above), was conducted to determine the efficacy of the patch for the management of postoperative pain resulting from aponeurotic fibroma resection. Specifically, the analgesic efficacy and safety of TPU-006 after aponeurotic fibroma resection were evaluated in a double-blind placebo-controlled single-dose study. A total of 87 patients received the (active or placebo) patch.

[0185] Preliminary results demonstrated that TPU-006 provided effective pain control across several parameters and did not result in unexpected safety events in the post-operative setting. Treatment with TPU-006 demonstrated statistically significant findings of lower pain scores over the course of the study and reduced use of rescue opioid medication compared to placebo. TPU-006 was well tolerated with no unexpected serious adverse events and minimal to no application site skin irritation or drowsiness. Patients treated with TPU-006 did not require rescue opioid medication. Decreased use of stools resulted in less experience of constipation and nausea.

[0186] TPU-006 has been shown to offer the potential to improve current post-operative or chronic pain management practices. TPU-006 has also been shown to offer a much-needed strategy to reduce the use of narcotic analgesics. The ease of administration (application and removal) as seen in this study means that the TPU-006 patch could be used in both inpatient and outpatient settings.

[0187] Example 18 Percutaneous dexmedetomidine for postoperative analgesia after bunionectomy A 3-day dexmedetomidine transdermal delivery device (2×3 cm) having a dexmedetomidine composition as described above and a pressure sensitive adhesive. 2 The efficacy of the patch for the management of postoperative pain following bunionectomy was investigated using a dexmedetomidine patch (a patch containing dexmedetomidine). Specifically, a double-blind, placebo-controlled, single-dose study evaluated the analgesic efficacy and safety of a dexmedetomidine transdermal delivery device following bunionectomy surgery. The patches were applied to 87 patients, where the patch was either a dexmedetomidine patch or a placebo. Each transdermal delivery device was applied to the subjects 10 to 14 hours before each patient underwent Austin bunionectomy surgery with standard intraoperative anesthesia. The transdermal delivery devices caused little to no skin irritation, and subjects were well hydrated and experienced low levels of constipation and nausea.

[0188] The pain was evaluated in patients at each time point from immediately after surgery to 72 hours postoperatively using the Numerical Rating Scale (NRS) for pain intensity values and the cumulative pain intensity (NRSSPI). The pain was also evaluated based on the time and first use of rescue analgesics and the total use of rescue medications.

[0189] The results of the study revealed that the transdermal delivery device with the dexmedetomidine composition provided effective pain control over several parameters and did not produce unexpected safety events in the postoperative setting. Figure 22 shows the control of pain intensity over time comparing the dexmedetomidine-containing transdermal delivery device with placebo and the patients' numerical rating scale. As shown in Figure 22, patients administered dexmedetomidine showed lower pain evaluations up to 72 hours postoperatively compared to those administered placebo. In addition to having lower pain evaluations, a lower proportion of patients who applied the patch with the dexmedetomidine composition required rescue medication in the first 6 hours postoperatively. Patients with the patch containing dexmedetomidine required rescue medication less frequently compared to placebo. Figure 23 shows the time to first use of rescue medication to compare patients with transdermal delivery devices having a dexmedetomidine-containing composition and those having a placebo. As shown in Figure 23, patients with the placebo patch required rescue medication earlier than patients with the dexmedetomidine-containing patch. Table 23 below summarizes the use of rescue medication (oxycodone) by patients who applied a placebo transdermal delivery device and those who applied a dexmedetomidine-containing transdermal delivery device. As summarized in Table 23, fewer patients required rescue medication when applying a transdermal delivery device containing dexmedetomidine compared to applying a placebo patch at all times examined (0 - 24 hours, 0 - 48 hours, and 0 - 72 hours).

Table 23

[0190] The pharmacokinetic parameters of dexmedetomidine administration by the transdermal delivery device were also evaluated in conjunction with the pain assessment described above. The average plasma concentration of dexmedetomidine was highest on the first postoperative day and lowest on the third day. Figures 24A - B compare the relationship between the average plasma concentration of dexmedetomidine and the pain intensity integrated with the substituted numerical values. Figure 24A shows the numerical pain ratings (last observation carried forward imputed, LOCF, substituted to adjust for the contribution to the NRSPI of rescue medication) derived from patients to whom a transdermal delivery device with a dexmedetomidine composition and a placebo were applied. Figure 24B shows the plasma concentration of dexmedetomidine in patients to whom a transdermal delivery device with a dexmedetomidine composition was applied. As shown in Figures 24A - 24B, the difference in pain intensity between dexmedetomidine and placebo was constant over a range of approximately four - fold the average plasma concentration of dexmedetomidine. In other words, the pain - reducing effect of dexmedetomidine remained almost constant over a difference of approximately four - fold in plasma concentration.

[0191] Figure 25 shows the sedation status of patients to whom a transdermal delivery device containing dexmedetomidine was applied compared to patients to whom a placebo patch was applied, according to the Wilson sedation assessment scale. As shown in Figure 25, the transdermal delivery device containing dexmedetomidine applied to the subjects showed the pain reduction described above with sub - sedating amounts of dexmedetomidine.

[0192] Example 19 Evaluation of the Pharmacokinetics and Pharmacodynamics of a Transdermal Delivery Device Containing Dexmedetomidine in Human Subjects Method The first part was an open - label, single - ascending - dose study comparing the IV administration of Precedex (trademark) administered over 10 minutes, dexmedetomidine IV infusion (1 μg / kg), and DMTS (dexmedetomidine transdermal delivery device) (below the maximum tolerated dose, MTD), and the second part was a randomized, crossover study.

[0193] The first part of the trial was designed to evaluate increasing the dose of DMTS until the MTD was determined. Three subjects were to be enrolled in each dose cohort. Dosing could be repeated if deemed appropriate. When the MTD was reached, one additional cohort was to be enrolled by subjects with BMI ≥ 18 kg / m 2 and BMI < 22 kg / m 2 Each subject was to receive 3 days of DMTS application followed by a 3-day washout period (starting when the patch was removed). In the first dose cohort (cohort 1), subjects were administered 2 DMTS. If 2 DMTS were not tolerated in cohort 1, the dose was to be reduced to 1 DMTS in cohort 2. If 1 DMTS was not tolerated in cohort 2, the trial was to be terminated. Instead, if 2 DMTS were tolerated in cohort 1, the dose was to be increased by 1 DMTS in the next cohort, and subjects in cohort 2 were to each be administered 3 DMTS. As long as the dose in the previous cohort was tolerated, the dose was to be increased by 1 DMTS with each subsequent cohort. In this way, the dose was to be increased up to a maximum of 8 DMTS. If the dose was not tolerated at any time, the increase in dose was to be stopped, and the dose tolerated in the previous cohort was to be considered the MTD. The increase in DMTS dose occurred only after the Safety Monitoring Committee reviewed the 72-hour safety data from the immediately preceding cohort and found that the dose was tolerated. If deemed appropriate, additional subjects could be enrolled to obtain additional safety data and enable a decision regarding dose escalation.

[0194] In the second part of the trial, 12 subjects with a BMI of 22 - 29 kg / m 2 , including the boundaries, were to be enrolled and randomized to one of the following treatment sequences: · Sequence A: IV infusion of Precedex (trademark) dexmedetomidine, 2 DMTS (6 cm 2 ) · Sequence B: 2 DMTS (6 cm 2) Intravenous (IV) infusion of Precedex (trademark) dexmedetomidine.

[0195] All 12 subjects were to receive both DMTS and intravenous (IV) administration of Precedex (trademark) dexmedetomidine; the two administrations were separated by a 3-day washout period. The washout period was based on the adverse events (AEs) observed during a 72-hour period after discontinuation of DMTS, as determined in test TPU-DMT-01-1501, similar to the plasma half-life (T 1 / 2 ) of dexmedetomidine following administration of DMTS. For both parts of the study, subjects were selected up to 28 days prior to administration of the study drug. Eligible subjects were housed at the clinic during the study for blood sampling to measure plasma concentrations of dexmedetomidine. Assessments of sedation level, safety, and patch adhesion were also performed throughout the study.

[0196] Each DMTS had a surface area of 3 cm 2 and contained 0.73 mg of dexmedetomidine. In Part 1, subjects received two DMTS in cohorts 1 and 2, one DMTS in cohorts 3 and 4, two DMTS in cohort 5, three DMTS in cohort 6, four DMTS in cohort 7, and three DMTS in cohort 8. In Part 2, subjects received two DMTS. In both parts of the study, each DMTS was applied to the hairless part of the upper arm on Day 1 and left in place for 3 days.

[0197] The plasma concentrations of dexmedetomidine at each time point were summarized for the cohorts in Part 1 and for the treatment in Part 2 using the arithmetic mean, standard deviation (SD), median, range, 95% confidence interval, geometric mean, and coefficient of variation (%CV).

[0198] Pharmacokinetic and pharmacodynamic results In Part 1 of the study, across 8 cohorts, the geometric mean C max values ranged from 58.5 to 274 pg / mL, and the geometric mean AUC 0-infThe values ranged from 3353 to 11085 pg×hour / mL, and these values increased gradually with the dose. Median T max The values ranged from 14 to 30 hours and median T 1 / 2 ranged from 7.9 to 16.4 hours. In the second part of the study, by DMTS treatment, geometric mean C max was 115.1 pg / mL, geometric mean AUC 0-inf value was 6130 pg×hour / mL, median T max value was 24.0 hours and median T 1 / 2 was 12.1 hours.

[0199] In the comparison, by IV infusion of Precedex (trademark) dexmedetomidine, geometric mean C max value was 993.3 pg / mL, geometric mean AUC 0-inf value was 1478 pg×hour / mL, median T max value was 0.17 hours, median T max value was 2.0 hours. The mean (SD) clearance of dexmedetomidine (measured following IV infusion of Precedex (trademark) dexmedetomidine) was 54.6 (9.46) L / hour. The geometric mean bioavailability of DMTS (6 cm 2 ) was determined to be 330.8 μg, and the corresponding dosing rate was 4.6 μg / hour.

[0200] In the first part, across all cohorts, the sedation levels at most time points corresponded to a Wilson sedation score of 1 (fully awake and with orientation maintained). Across all cohorts, scores of 2 (drowsy) or 3 (eyes closed but arousable to command) were observed at sporadic time points. No subjects with a sedation score of 4 (eyes closed but arousable to light physical stimulation) or 5 (eyes closed and not arousable to light physical stimulation) were present in any cohort at any time point.

[0201] In the second part, DMTS (6 cm 2)During the treatment, most of the 11 subjects had a Wilson sedation score of 1 at all times, no more than 2 subjects had a score of 2 or 3 at any time, and no subject had a score of 4 or 5 at any time. By intravenous drip treatment with Precedex (trademark) dexmedetomidine, most of the subjects had a Wilson sedation score of 2 at the end of the drip, a score of 2 or 3 continued at 1 hour after the drip, and a score of 2 continued at 2 hours after the drip. At 2 hours later, most of the subjects had a score of 1, except at 4 hours after the drip when most of the subjects had a score of 2 or 3.

[0202] Non-limiting embodiments as examples of the present disclosure Aspects including embodiments of the present subject matter described above may be useful alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the present disclosure numbered 1 to 171 are provided below. As will be apparent to those skilled in the art when reading the present disclosure, each of the individually numbered aspects may be used with or in combination with any of the individually numbered aspects preceding or following it. This is intended to provide support for all such combinations of aspects and is not limited to the combinations of aspects explicitly provided below. 1. A method of managing pain in a subject, the method comprising applying to the skin surface of the subject a transdermal delivery device comprising a dexmedetomidine composition comprising dexmedetomidine and a pressure-sensitive adhesive, the method being sufficient to manage pain in the subject.

[0203] 2. The method according to clause 1, wherein the pain is selected from the group consisting of surgical pain, perioperative pain, postoperative pain, cancer pain, acute pain, chronic pain, nociceptive pain, somatic pain, visceral pain, neuropathic pain, labor pain, or combinations thereof.

[0204] 3. The method according to clause 2, wherein the pain is surgical pain.

[0205] 4. The method according to clause 3, wherein the surgical pain results from a surgical procedure selected from the group consisting of median sternotomy, laparoscopy, mastectomy, arthroplasty, osteotomy, cancer surgery, knee surgery, and shoulder surgery.

[0206] 5. The method according to clause 3, wherein the surgical pain results from dental surgery.

[0207] 6. The method according to clause 5, wherein the dental surgery is a surgical extraction of one or more molars.

[0208] 7. The method according to clause 3, wherein the surgical procedure is osteotomy.

[0209] 8. The method according to clause 7, wherein the osteotomy is an aponeurotoma resection.

[0210] 9. The method according to any one of clauses 3 to 8, wherein the transdermal delivery device is applied to the skin surface before the onset of the pain.

[0211] 10. The method according to any one of clauses 3 to 9, wherein the method includes applying the device to the subject during the perioperative period.

[0212] 11. The method according to clause 9 or 10, wherein the transdermal delivery device is applied to the skin surface of the subject 12 to 24 hours before the surgical procedure.

[0213] 12. The method according to any one of clauses 1 to 11, wherein the method includes delivering a sub-anaesthetic dose of dexmedetomidine to the subject.

[0214] 13. The method according to clause 12, wherein the method includes delivering a sub-anaesthetic dose of dexmedetomidine to the subject for one or more days.

[0215] 14. The method according to clause 13, wherein the method includes delivering a sub-anaesthetic dose of dexmedetomidine to the subject for three or more days.

[0216] 15. The method according to any one of clauses 10 to 14, comprising delivering an incomplete sedation amount of dexmedetomidine to the subject in a manner sufficient to maintain a Wilson sedation score not exceeding 4 in the subject.

[0217] 16. The method according to clause 15, comprising delivering an incomplete sedation amount of dexmedetomidine to the subject in a manner sufficient to maintain a Wilson sedation score not exceeding 3 in the subject.

[0218] 17. The method according to any one of clauses 1 to 16, wherein the subject is awake and responsive to verbal commands.

[0219] 18. The method according to any one of clauses 1 to 17, comprising delivering dexmedetomidine to the subject by the transdermal delivery device at a rate ranging from about 5 μg / day to about 500 μg / day.

[0220] 19. The method according to any one of clauses 1 to 17, comprising delivering dexmedetomidine to the subject by the transdermal delivery device at a rate ranging from 1 mcg / hour to 10 mcg / hour.

[0221] 20. The method according to any one of clauses 1 to 19, comprising delivering dexmedetomidine to the subject in a manner sufficient to maintain an average plasma concentration of dexmedetomidine in the subject ranging from about 0.01 ng / mL to about 0.4 ng / mL.

[0222] 21. The method according to any one of clauses 1 to 20, further comprising co-administering to the subject a compound selected from the group consisting of analgesics, anesthetics, antidepressants, anticonvulsants, cannabinoids, N-methyl-D-aspartic acid, and neuromodulators, and combinations thereof. The method.

[0223] 22. The method according to clause 21, further comprising co-administering an anesthetic to the subject.

[0224] 23. The method according to clause 22, wherein the anesthetic is a general anesthetic.

[0225] 24. The method according to clause 21, wherein the general anesthetic is a non-opioid intravenous general anesthetic.

[0226] 25. The method according to any one of clauses 21 to 24, which is sufficient to reduce the amount of the co-administered compound by 10% or more.

[0227] 26. The method according to any one of clauses 1 to 24, which includes co-administering an opioid to the subject.

[0228] 27. The method according to clause 26, which reduces the amount of the opioid required to manage pain in the subject by 50% or more.

[0229] 28. The method according to any one of clauses 1 to 20, which is sufficient to replace some or all of one or more scheduled administrations of an opioid in an opioid pain management dosing regimen.

[0230] 29. The method according to any one of clauses 1 to 28, wherein the pressure-sensitive adhesive is an acrylate pressure-sensitive adhesive containing pendant hydroxyl functional groups.

[0231] 30. The method according to clause 29, wherein the dexmedetomidine composition further includes a permeation enhancer.

[0232] 31. The method according to clause 30, wherein the permeation enhancer is lauryl lactate.

[0233] 32. The method according to any one of clauses 1 to 31, wherein the transdermal delivery device includes a single-layer matrix containing the dexmedetomidine composition, and the single-layer matrix is formulated to deliver a non-sedating amount of dexmedetomidine to the subject.

[0234] 33. The method according to any one of clauses 1 to 31, wherein the transdermal delivery device is configured to deliver 20% or more of the dexmedetomidine in the dexmedetomidine composition.

[0235] 34. The method according to any one of clauses 1 to 33, wherein the amount of dexmedetomidine in the composition is 1 to 5% w / w.

[0236] 35. The method according to any one of clauses 1 to 33, wherein the amount of dexmedetomidine in the composition is 3% w / w.

[0237] 36. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average absorption amount of dexmedetomidine of 150 mcg to 600 mcg over 72 hours.

[0238] 37. The method according to clause 36, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average absorption amount of dex medetomidine of 175 mcg to 575 mcg over 72 hours.

[0239] 38. The method according to clause 36, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average absorption amount of dexmedetomidine of 192.7 mcg to 551.7 mcg over 72 hours.

[0240] 39. The method according to clause 36, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average absorption amount of dexmedetomidine of 224 mcg to 437 mcg over 72 hours.

[0241] 40. The method according to clause 36, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 278 mcg to 384 mcg over 72 hours.

[0242] 41. The method according to clause 36, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 304 mcg to 357 mcg over 72 hours.

[0243] 42. The method according to clause 36, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 320 mcg to 341 mcg over 72 hours.

[0244] 43. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 1 mcg / hour to 10 mcg / hour over 72 hours.

[0245] 44. The method according to clause 43, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 2 mcg / hour to 8 mcg / hour over 72 hours.

[0246] 45. The method according to clause 43, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 2.7 mcg / hour to 7.7 mcg / hour over 72 hours.

[0247] 46. The method according to clause 43, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 3.1 mcg / hour to 6.1 mcg / hour over 72 hours.

[0248] 47. The method according to clause 43, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of 3.9 mcg / hour to 5.3 mcg / hour.

[0249] 48. The method according to clause 43, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of 4.2 mcg / hour to 5.0 mcg / hour.

[0250] 49. The method according to clause 43, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of 4.4 mcg / hour to 4.7 mcg / hour.

[0251] 50. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine over 72 hours of 50 pg / mL to 250 pg / mL.

[0252] 51. The method according to clause 50, comprising maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine over 72 hours of 70 pg / mL to 225 pg / mL.

[0253] 52. The method according to clause 50, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine over 72 hours of 70.1 pg / mL to 205 pg / mL.

[0254] 53. The method according to clause 50, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration of 77 pg / mL to 153 pg / mL over 72 hours.

[0255] 54. The method according to clause 50, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration of 96 pg / mL to 134 pg / mL over 72 hours.

[0256] 55. The method according to clause 50, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration of 106 pg / mL to 125 pg / mL over 72 hours.

[0257] 56. The method according to clause 50, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration of 111 pg / mL to 119 pg / mL over 72 hours.

[0258] 57. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 3000 hour×pg / mL to 10000 hour×pg / mL over 72 hours.

[0259] 58. The method according to clause 57, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 3500 hour×pg / mL to 9000 hour×pg / mL over 72 hours.

[0260] 59. The method according to clause 57, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 3517 hour×pg / mL to 8954 hour×pg / mL.

[0261] 60. The method according to clause 57, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 4548 hour×pg / mL to 7712 hour×pg / mL.

[0262] 61. The method according to clause 57, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 5339 hour×pg / mL to 6921 hour×pg / mL.

[0263] 62. The method according to clause 57, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 5735 hour×pg / mL to 6525 hour×pg / mL.

[0264] 63. The method according to clause 57, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 5972 hour×pg / mL to 6288 hour×pg / mL.

[0265] 64. The transdermal delivery device has a surface area of about 6 cm 2 The method according to any one of clauses 35 to 63.

[0266] 65. The method according to any one of claims 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount over 72 hours of 100 mcg to 400 mcg.

[0267] 66. The method according to claim 65, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount over 72 hours of 125 mcg to 375 mcg.

[0268] 67. The method according to claim 65, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount over 72 hours of 128.5 mcg to 367.8 mcg.

[0269] 68. The method according to claim 65, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount over 72 hours of 150 mcg to 292 mcg.

[0270] 69. The method according to claim 65, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount over 72 hours of 185 mcg to 256 mcg.

[0271] 70. The method according to claim 65, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount over 72 hours of 203 mcg to 238 mcg.

[0272] 71. The method according to claim 65, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount over 72 hours of 213 mcg to 228 mcg.

[0273] 72. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 0.5 mcg / hour to 6 mcg / hour.

[0274] 73. The method according to clause 72, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 1 mcg / hour to 5.5 mcg / hour.

[0275] 74. The method according to clause 72, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 1.8 mcg / hour to 5.1 mcg / hour.

[0276] 75. The method according to clause 72, comprising maintaining the position of the transdermal composition delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 2.1 mcg / hour to 4.1 mcg / hour.

[0277] 76. The method according to clause 72, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 2.6 mcg / hour to 3.6 mcg / hour.

[0278] 77. The method according to clause 72, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 2.8 mcg / hour to 3.3 mcg / hour.

[0279] 78. The method according to clause 72, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 3.0 mcg / hour to 3.2 mcg / hour over 72 hours.

[0280] 79. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine of 25 pg / mL to 150 pg / mL over 72 hours.

[0281] 80. The method according to clause 79, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine of 40 pg / mL to 140 pg / mL over 72 hours.

[0282] 81. The method according to clause 79, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine of 47 pg / mL to 137 pg / mL over 72 hours.

[0283] 82. The method according to clause 79, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine of 51 pg / mL to 102 pg / mL over 72 hours.

[0284] 83. The method according to clause 79, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine of 64 pg / mL to 90 pg / mL over 72 hours.

[0285] 84. The method according to clause 79, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration of 70 pg / mL to 83 pg / mL over 72 hours.

[0286] 85. The method according to clause 79, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration of 74 pg / mL to 79 pg / mL over 72 hours. 85. The method according to clause 79, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration of 74 pg / mL to 79 pg / mL over 72 hours.

[0287] 86. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 2000 hour×pg / mL to 7500 hour×pg / mL over 72 hours.

[0288] 87. The method according to clause 86, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 2250 hour×pg / mL to 6000 hour×pg / mL over 72 hours.

[0289] 88. The method according to clause 86, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 2345 hour×pg / mL to 5969 hour×pg / mL over 72 hours.

[0290] 89. The method according to clause 86, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average area under the plasma dexmedetomidine concentration curve of 3032 hour×pg / mL to 5141 hour×pg / mL over 72 hours.

[0291] 90. The method according to clause 86, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 3559 hour×pg / mL to 4614 hour×pg / mL.

[0292] 91. The method according to clause 86, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 3823 hour×pg / mL to 4350 hour×pg / mL.

[0293] 92. The method according to clause 86, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 3981 hour×pg / mL to 4192 hour×pg / mL.

[0294] 93. The method according to any one of clauses 65 to 92, wherein the transdermal delivery device has a surface area of about 4 cm 2

[0295] 94. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide dexmedetomidine with an average absorption amount over 72 hours of 50 mcg to 200 mcg.

[0296] 95. The method according to clause 94, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide dexmedetomidine with an average absorption amount over 72 hours of 60 mcg to 190 mcg.

[0297] 96. The method, wherein the method provides dexme The method according to clause 94, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide detomidine.

[0298] 97. The method according to clause 94, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 75 mcg to 146 mcg over 72 hours.

[0299] 98. The method according to clause 94, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 93 mcg to 128 mcg over 72 hours.

[0300] 99. The method according to clause 94, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 101 mcg to 119 mcg over 72 hours.

[0301] 100. The method according to clause 94, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average absorption amount of 107 mcg to 114 mcg over 72 hours.

[0302] 101. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 0.1 mcg / hour to 5 mcg / hour over 72 hours.

[0303] 102. The method according to clause 101, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 0.5 mcg / hour to 3 mcg / hour over 72 hours.

[0304] 103. The method according to clause 101, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 0.9 mcg / hour to 2.6 mcg / hour.

[0305] 104. The method according to clause 101, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 1.0 mcg / hour to 2.0 mcg / hour.

[0306] 105. The method according to clause 101, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 1.3 mcg / hour to 1.8 mcg / hour.

[0307] 106. The method according to clause 101, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 1.4 mcg / hour to 1.7 mcg / hour.

[0308] 107. The method according to clause 101, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption over 72 hours of from 1.5 mcg / hour to 1.6 mcg / hour.

[0309] 108. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum plasma concentration of dexmedetomidine over 72 hours of from 10 pg / mL to 80 pg / mL. Method.

[0310] The method according to clause 108, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration over 72 hours of 20 pg / mL to 70 pg / mL.

[0311] The method according to clause 108, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration over 72 hours of 23.4 pg / mL to 68.3 pg / mL.

[0312] The method according to clause 108, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration over 72 hours of 26 pg / mL to 51 pg / mL.

[0313] The method according to clause 108, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration over 72 hours of 32 pg / mL to 45 pg / mL.

[0314] The method according to clause 108, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration over 72 hours of 35 pg / mL to 42 pg / mL.

[0315] The method according to clause 108, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide dexmedetomidine having an average maximum plasma concentration over 72 hours of 37 pg / mL to 40 pg / mL.

[0316] 115. The method according to any one of clauses 1 to 35, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 1000 hour×pg / mL to 3500 hour×pg / mL.

[0317] 116. The method according to clause 115, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 1100 hour×pg / mL to 3000 hour×pg / mL.

[0318] 117. The method according to clause 115, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 1172 hour×pg / mL to 2985 hour×pg / mL.

[0319] 118. The method according to clause 115, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 1516 hour×pg / mL to 2571 hour×pg / mL.

[0320] 119. The method according to clause 115, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 1780 hour×pg / mL to 2307 hour×pg / mL.

[0321] 120. The method according to clause 115, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours of 1912 hour×pg / mL to 2175 hour×pg / mL.

[0322] 121. The method according to clause 115, comprising maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient for the method to provide an average area under the plasma dexmedetomidine concentration curve over 72 hours from 1991 hours×pg / mL to 2096 hours×pg / mL.

[0323] 122. The method according to any one of clauses 94 to 121, wherein the transdermal delivery device has a surface area of about 2 cm 2 .

[0324] 123. The method according to any one of clauses 1 to 122, further comprising administering to the subject an amount of a rehydration fluid.

[0325] 124. The method according to clause 123, wherein the rehydration fluid is administered to the subject intravenously.

[0326] 125. The method according to clause 123, wherein the rehydration fluid is administered to the subject orally.

[0327] 126. The method according to any one of clauses 123 to 125, wherein the rehydration fluid is administered to the subject perioperatively.

[0328] 127. The method according to any one of clauses 123 to 125, wherein the rehydration fluid is administered in conjunction with applying the transdermal delivery device to the subject.

[0329] 128. The method according to any one of clauses 123 to 125, wherein the rehydration fluid is administered at a predetermined time before applying the transdermal delivery device to the subject.

[0330] 129. The method comprises intravenously administering the rehydration fluid to the subject at a first infusion rate for a first predetermined time, and intravenously administering the rehydration fluid to the subject at a second infusion rate for a second predetermined time, according to any one of clauses 123 to 128.

[0331] 130. The method comprises intravenously administering the fluid replacement fluid to the subject at a rate of 450 mL / hour to 550 mL / hour for 2 hours and intravenously administering the fluid replacement fluid to the subject at a rate of 100 mL / hour to 150 mL / hour for 12 hours after the first 2 hours, the method according to clause 129.

[0332] 131. The method comprises intravenously administering the fluid replacement fluid to the subject at a rate of 500 mL / hour for 2 hours and intravenously administering the fluid replacement fluid to the subject at a rate of 125 mL / hour for 12 hours after the first 2 hours, the method according to clause 130.

[0333] 132. The method comprises orally administering the fluid replacement fluid to the subject at a first drip rate for a first predetermined time and orally administering the fluid replacement fluid to the subject at a second drip rate for a second predetermined time, the method according to clause 125.

[0334] 133. The method comprises orally administering the fluid replacement fluid to the subject at a rate of 450 mL / hour to 550 mL / hour for 2 hours and orally administering the fluid replacement fluid to the subject at a rate of 100 mL / hour to 150 mL / hour for 12 hours after the first 2 hours, the method according to clause 132.

[0335] 134. The method comprises orally administering the fluid replacement fluid to the subject at a rate of 500 mL / hour for 2 hours and orally administering the fluid replacement fluid to the subject at a rate of 125 mL / hour for 12 hours after the first 2 hours, the method according to clause 130.

[0336] The method according to any one of clauses 1 to 134, further comprising co-administering an opioid to the subject.

[0337] 136. The method according to clause 135, wherein the opioid is administered orally to the subject.

[0338] 137. The method according to clause 135, wherein the opioid is administered intravenously to the subject.

[0339] 138. The method according to any one of clauses 135 to 137, wherein the opioid is oxycodone.

[0340] 139. The method according to any one of clauses 135 to 138, wherein the opioid is administered to the subject after applying the transdermal delivery device to the subject.

[0341] 140. The method according to any one of clauses 135 to 138, wherein the opioid is administered to the subject perioperatively in combination with a transdermal delivery device.

[0342] 141. The method according to any one of clauses 1 to 140, wherein the transdermal delivery device is applied to the skin surface of the subject before the onset of pain.

[0343] 142. The method according to clause 141, wherein the transdermal delivery device is applied to the skin surface of the subject more than 1 hour before the onset of pain.

[0344] 143. The method according to clause 141, wherein the transdermal delivery device is applied to the skin surface of the subject more than 12 hours before the onset of pain.

[0345] 144. The transdermal delivery device has a surface area of 1 cm 2 ~10 cm 2 The method according to any one of clauses 1 to 35.

[0346] 145. The transdermal delivery device has a size of 2 cm 2 ~6 cm2 The method according to any one of claims 1 to 35 having the surface area.

[0347] 146. The method according to any one of claims 1 to 145, wherein the pressure-sensitive adhesive contains a vinyl polymer.

[0348] 147. The method according to claim 146, wherein the vinyl polymer is selected from the group consisting of polyethylene, polypropylene, polyisobutylene, polybutene, polystyrene, polyvinyl chloride, polyvinyl acetate, polyvinyl alcohol, and organosilicon. The method according to claim 146, wherein the vinyl polymer is selected from the group consisting of polyethylene, polypropylene, polyisobutylene, polybutene, polystyrene, polyvinyl chloride, polyvinyl acetate, polyvinyl alcohol, and organosilicon.

[0349] 148. The method according to claim 146, wherein the pressure-sensitive adhesive contains polyisobutylene or polybutene or a combination thereof.

[0350] 149. The method according to claim 148, wherein the pressure-sensitive adhesive contains saturated polybutene.

[0351] 150. The method according to claim 148, wherein the pressure-sensitive adhesive contains unsaturated polybutene.

[0352] 151. The method according to any one of claims 1 to 145, wherein the pressure-sensitive adhesive contains an acrylic polymer, an acrylate copolymer, an acrylate-vinyl acetate copolymer, or polyacrylonitrile.

[0353] 152. The method according to any one of claims 1 to 145, wherein the pressure-sensitive adhesive contains a non-functionalized polymer.

[0354] 153. The method according to claim 152, wherein the pressure-sensitive adhesive contains a non-functionalized acrylate polymer.

[0355] 154. The method according to any one of claims 1 to 145, wherein the pressure-sensitive adhesive contains a polymer functionalized with a carboxylic acid or a hydroxyl group.

[0356] 155. The method according to clause 154, wherein the pressure-sensitive adhesive comprises a polymer functionalized with a carboxylic acid.

[0357] 156. The method according to clause 155, wherein the pressure-sensitive adhesive comprises an acrylate polymer functionalized with a carboxylic acid.

[0358] 157. The method according to clause 154, wherein the pressure-sensitive adhesive comprises a polymer functionalized with a hydroxyl group.

[0359] 158. The method according to clause 157, wherein the pressure-sensitive adhesive comprises an acrylate polymer functionalized with a hydroxyl group.

[0360] 159. The method according to any one of clauses 1 to 145, wherein the pressure-sensitive adhesive comprises a mixture of a polymer functionalized with a hydroxyl group and a polymer functionalized with a carboxylic acid.

[0361] 160. The method according to clause 159, wherein the pressure-sensitive adhesive comprises a mixture of an acrylate polymer functionalized with a hydroxyl group and an acrylate polymer functionalized with a carboxylic acid.

[0362] 161. The method according to any one of clauses 1 to 145, wherein the pressure-sensitive adhesive is substantially the same as, or consists of, a group selected from Duro-Tak® 87-9301, Duro-Tak® 87-2353, Duro-Tak® 87-2510, Duro-Tak® 87-2516, Duro-Tak® 87-4287, Duro-Tak® 87-2052, Duro-Tak® 87-2194, Duro-Tak® 87-2677, Duro-Tak® 87-201A, Duro-Tak® 87-2979, and Duro-Tak® 87-2074.

[0363] 162. The method according to any one of clauses 1 to 161, wherein the pressure-sensitive adhesive comprises crosslinked polyvinylpyrrolidone or crosslinked polyacrylic acid or a combination thereof.

[0364] 163. The method according to any one of clauses 1 to 162, wherein the method comprises delivering a sedative amount of dexmedetomidine to the subject.

[0365] 164. The method according to any one of clauses 135 to 138, wherein the opioid is administered to the subject before applying the transdermal delivery device to the subject.

[0366] 165. The method according to any one of clauses 135 to 138, wherein the opioid is administered to the subject simultaneously while applying the transdermal delivery device to the subject.

[0367] 166. A kit for managing pain in a subject, the kit comprising (a) one or more transdermal delivery devices, each transdermal delivery device comprising a dexmedetomidine composition comprising dexmedetomidine and a pressure-sensitive adhesive, and a backing layer, and (b) instructions for using two or more of the transdermal delivery devices in a method for managing pain in a subject according to any one of clauses 1 to 165. The kit comprising.

[0368] 167. The kit according to clause 166, further comprising a rehydration fluid composition.

[0369] 168. The kit according to clause 166, wherein the rehydration fluid is an oral rehydration fluid.

[0370] 169. The kit according to clause 166, wherein the rehydration fluid composition is an intravenous rehydration fluid composition.

[0371] The kit according to any one of clauses 167 to 169, wherein the fluid composition for rehydration comprises normal saline.

[0372] The kit according to any one of clauses 167 to 169, wherein the fluid composition for rehydration comprises dextrose.

[0373] The kit according to any one of clauses 166 to 171, further comprising instructions for rehydrating the subject.

[0374] The kit according to any one of clauses 166 to 172, further comprising one or more opioids for co - administration to the subject.

[0375] The kit according to clause 173, wherein the opioid is oxycodone.

[0376] The foregoing invention has been described in some detail for purposes of clarity of understanding and by way of illustration and example, but it will be readily apparent to those skilled in the art, in light of the teachings of the present invention, that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims.

[0377] Accordingly, the foregoing merely illustrates the principles of the invention. It will be well understood by those skilled in the art, although not explicitly described or shown herein, that one can embody the principles of the invention and devise various combinations included within its spirit and scope. Further 、All of the exemplifications and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to further the art, and are to be construed as not being limited to such specifically recited exemplifications and conditions. Moreover, all descriptions in this specification that cite the specific examples as well as the principles, aspects, and embodiments of the invention are intended to encompass their structural and functional equivalents. Further, such equivalents are intended to include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function regardless of structure. Accordingly, the scope of the invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the invention are embodied by the appended claims.

Claims

1. A transdermal delivery device for managing postoperative pain in a subject, comprising: a dexmedetomidine composition comprising dexmedetomidine and a pressure-sensitive adhesive; Backing layer and Including, a transdermal delivery device is applied to a skin surface of the subject prior to surgery and maintained in contact with the skin surface of the subject for at least 72 hours after application to the skin surface; dexmedetomidine is administered to the subject in an amount of about 50 μg / day to about 350 μg / day to manage postoperative pain; administration of a certain amount of dexmedetomidine reduces postoperative pain experienced by a subject for at least 72 hours after surgery; The device.

2. The transdermal delivery device of claim 1, wherein the pain results from a bone model surgical procedure or a soft tissue model surgical procedure.

3. The percutaneous delivery device of claim 1 or 2, wherein the pain results from a surgical procedure selected from the group consisting of median sternotomy, laparoscopy, mastectomy, arthroplasty, osteotomy, cancer surgery, knee surgery, and shoulder surgery.

4. A percutaneous delivery device as described in claim 3, wherein the surgical procedure is osteotomy.

5. A percutaneous delivery device as described in claim 4, wherein the osteotomy is a bunionectomy.

6. A transdermal delivery device described in any one of claims 1 to 5, maintained in contact with the skin surface of the subject in a manner sufficient to provide an average absorption of dexmedetomidine over 72 hours of 150mcg to 600mcg.

7. A transdermal delivery device described in any one of claims 1 to 5, maintained in contact with the skin surface of the subject in a manner sufficient to provide an average absorption of dexmedetomidine over 72 hours of 100mcg to 400mcg.

8. A transdermal delivery device described in any one of claims 1 to 7, maintained in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 1 mcg / hour to 10 mcg / hour over 72 hours.

9. A transdermal delivery device described in any one of claims 1 to 8, maintained in contact with the skin surface of the subject in a manner sufficient to provide a mean area under the plasma dexmedetomidine concentration curve over 72 hours of 3000 hr x pg / mL to 10000 hr x pg / mL.

10. A transdermal delivery device described in any one of claims 1 to 9, which administers dexmedetomidine to the subject while administering a quantity of hydration fluid to the subject.

11. The method of claim 10, wherein the hydration fluid is administered to the subject at a first infusion rate for a first predetermined time period; 11. The transdermal delivery device of claim 10, wherein the hydration fluid is administered to the subject at a second drip rate for a second predetermined time period.

12. The transdermal delivery device of claim 10, wherein the hydration fluid is administered orally to the subject.

13. A transdermal delivery device described in any one of claims 1 to 12, wherein dexmedetomidine is administered to the subject while simultaneously administering an opioid to the subject.

14. The transdermal delivery device of claim 13, wherein the opioid is oxycodone.

15. A transdermal delivery device described in any one of claims 1 to 14, wherein the transdermal delivery device is applied to the skin surface of the subject 0.5 hours to 30 hours before surgery.

16. A transdermal delivery device described in any one of claims 1 to 15, wherein the transdermal delivery device is applied to the skin surface of the subject 1 to 24 hours before surgery.

17. The transdermal delivery device of any one of claims 1 to 16, wherein the device has a surface area of ​​1 cm 2 to 10 cm 2 .

18. The transdermal delivery device of any one of claims 1 to 17, wherein the transdermal delivery device provides a peak flux to the subject of 5 μg / cm 2 / hour or less.

19. The transdermal delivery device of claim 18, wherein the peak flow rate is reached more than two hours after application of the transdermal delivery device to the skin surface of the subject.

20. The transdermal delivery device of any one of claims 1 to 19, wherein the transdermal delivery device provides the subject with an average flow rate of dexmedetomidine of approximately 0.005 to 2 μg / cm 2 / hour 24 hours after application of the transdermal delivery device to the skin surface of the subject.

21. A transdermal delivery device described in any one of claims 1 to 20, wherein the transdermal delivery device provides the subject with an average maximum plasma concentration of dexmedetomidine over 72 hours of 50 pg / mL to 250 pg / mL.

22. A transdermal delivery device described in any one of claims 1 to 21, wherein the amount of postoperative pain reduction is measured by a numerical pain rating scale and the transdermal delivery device reduces the numerical pain rating scale rating by approximately 1 for at least 72 hours after surgery.

23. A transdermal delivery device described in any one of claims 1 to 22, wherein administration of dexmedetomidine reduces postoperative pain experienced by subjects not using sedatives (Wilson sedation score of 1).

24. A transdermal delivery device described in any one of claims 1 to 23, wherein administration of dexmedetomidine continues to reduce postoperative pain experienced by the subject after the transdermal delivery device is removed from the skin surface.

25. The transdermal delivery device of claim 24, wherein when the transdermal delivery device is removed 72 hours after application to the skin surface, administration of dexmedetomidine continues to reduce postoperative pain experienced by the subject for at least 10 hours after the transdermal delivery device is removed from the skin surface.

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