BR112016007327B1 - USE OF TRANSDERMAL DELIVERY DEVICE TO MANAGE PAIN - Google Patents

Abstract

METHODS AND COMPOSITIONS FOR PAIN CONTROL COMPRISING TRANSDERMAL DEXMEDETOMIDINE COMPOSITIONS. 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 amount of dexmedetomidine to a subject suffering from pain. In practicing the methods in accordance with 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 effective pain-relieving amount of dexmedetomidine to the subject. subject. Also provided are transdermal delivery devices configured to deliver enough dexmedetomidine to practice the methods of the present invention, as well as kits containing the transdermal delivery devices.

Description

CROSS-REFERENCE TO RELATED ORDERS

[0001] Pursuant to 35 U.S.C. §119(e), this application claims priority from the filing date of U.S. Provisional Application Serial No. 61/887,870 filed on October 7, 2013, the disclosure of which is incorporated herein by reference.

INTRODUCTION

[0002] Pain is the most common reason for visiting a physician in the United States. Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue, bone, nerve or cellular damage. Most pain resolves promptly once the painful stimulus is removed and the body has healed, but sometimes pain persists despite removal of the stimulus and apparent healing of the body. It is one of the main symptoms of many medical conditions and can significantly interfere with the overall quality and functioning of a person's life. Pain can also arise in the absence of any detectable stimulus, damage or disease. Pain is usually transient, lasting only until the noxious stimulus is removed or the underlying damage or pathology has healed, but some painful conditions can persist for years.

[0003] Dexmedetomidine is the S-enantiomer of medetomidine and is an a2-adrenergic receptor agonist that is used as a sedative drug in intensive care units and by anesthesiologists for intubated and non-intubated patients who require sedation for surgery or procedures short term. The α2-adrenergic receptor is a G protein-coupled receptor associated with the heterotrimeric Gi G protein that includes three highly homologous subtypes including α2a, α2b and a2c-adrenergic receptors. [alpha]2-adrenergic receptor agonists are implicated in sedation, analgesia, and muscle relaxation through effects on the central nervous system.

[0004] Dexmedetomidine is used in clinical settings as a sedative through parenteral, intravenous, and oral administration and therefore needs close supervision by a health care professional in a hospital setting. Dexmedetomidine is currently employed for sedation of intubated or mechanically ventilated subjects in a clinical (eg, hospital) setting as well as for sedation of non-intubated subjects as part of monitored anesthesia during surgery, radiography, or diagnostic procedures. Dexmedetomidine is also approved for continuous intravenous infusion in non-intubated individuals as long as it does not alter breathing.

SUMMARY

[0005] Aspects of the invention include methods of controlling pain in a subject by applying a transdermal delivery device containing a dexmedetomidine composition formulated to deliver an effective pain-relieving amount of dexmedetomidine to a subject in pain. In practicing the methods in accordance with 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 administer an effective amount of the dexmedetomidine to control pain in the subject. Also provided are transdermal delivery devices configured to deliver an effective amount of dexmedetomidine sufficient to practice the methods of the present invention, as well as kits containing the transdermal delivery devices.

BRIEF DESCRIPTION OF THE FIGURES

[0006] Figure 1 shows an example of a graph of the average flux of dexmedetomidine as a function of transdermal delivery device application time for a transdermal composition of dexmedetomidine with polyisobutylene/polybutene adhesive and cross-linked polyvinylpyrrolidone according to a modality.

[0007] Figure 2A shows an example of distributed amount of dexmedetomidine cumulative over time according to one embodiment. Figure 2B shows an example of a graph of mean dexmedetomidine flux as a function of transdermal delivery device application time for a transdermal composition of dexmedetomidine with a non-functionalized acrylate adhesive according to one embodiment. Figure 2C shows an example of using dexmedetomidine over time according to one modality.

[0008] Figure 3 shows an example of a graph of mean dexmedetomidine flux as a function of transdermal delivery device application time for a transdermal composition of dexmedetomidine with a non-functionalized acrylate adhesive according to one embodiment.

[0009] Figure 4 shows an example of a graph of the mean flux of dexmedetomidine as a function of transdermal delivery device application time for a transdermal composition of dexmedetomidine with a hydroxyl-functionalized acrylate adhesive containing vinyl acetate according to one embodiment .

[00010] Figure 5 shows an example of a graph of the average flux of dexmedetomidine as a function of time of application of the transdermal delivery device for a transdermal composition of dexmedetomidine with a hydroxyl acrylate adhesive functionalized according to another embodiment.

[00011] Figure 6 shows an example of a graph of the mean flux of dexmedetomidine as a function of transdermal delivery device application time for a dexmedetomidine transdermal composition with hydroxyl-functionalized acrylate adhesive and a hydroxyl-functionalized vinyl-containing acrylate adhesive acetate according to another embodiment.

[00012] Figure 7A-7B shows an example of a graph of mean dexmedetomidine flux as a function of transdermal delivery device application time for dexmedetomidine transdermal compositions with non-functionalized acrylate adhesive, a hydroxyl-functionalized acrylate adhesive and a functionalized hydroxyl acrylate adhesive containing vinyl acetate according to another embodiment.

[00013] Figure 8 shows an example of a graph of the average flux of dexmedetomidine as a function of time of application of the transdermal delivery device for a transdermal composition of dexmedetomidine with a carboxylic acid acrylate adhesive functionalized according to another embodiment.

[00014] Figure 9 shows an example of a graph of the average flux of dexmedetomidine as a function of time of application of the transdermal delivery device for a transdermal composition of dexmedetomidine with the acrylic adhesive with carboxyl group and hydroxyl group as functional group containing acetate vinyl according to another embodiment.

[00015] Figure 10 shows an example of a graph of the mean flux of dexmedetomidine as a function of transdermal delivery device application time for a dexmedetomidine transdermal composition having a polyisobutylene/polybutene adhesive with an acid acrylate adhesive functionalized carboxylic acid according to another embodiment.

[00016] Figure 11 shows an example of a graph of the average flux of dexmedetomidine as a function of time of application of the transdermal delivery device for a transdermal composition of dexmedetomidine having a polyisobutylene/polybutene adhesive with levulinic acid solubility enhancer according to another modality.

[00017] Figure 12 shows an example of a graph of the average flux of dexmedetomidine as a function of time of application of the transdermal delivery device for a transdermal composition of dexmedetomidine having a polyisobutylene/polybutene patch with lauryl lactate enhancer solubility according to another embodiment.

[00018] Figure 13 shows an example of a graph of mean dexmedetomidine flux as a function of transdermal delivery device application time for a dexmedetomidine transdermal composition having a polyisobutylene/polybutene patch with propylene glycol monolaurate enhancer solubility according to another embodiment.

[00019] Figure 14A shows an example of a graph of the average flux of dexmedetomidine as a function of the time of application of the transdermal delivery device for a transdermal composition of dexmedetomidine with a functionalized hydroxyl acrylate adhesive containing vinyl acetate with levulinic acid according with a modality.

[00020] Figure 14B shows an example of a graph of the average flux of dexmedetomidine as a function of time of application of the transdermal delivery device for a transdermal composition of dexmedetomidine with a hydroxyl-functionalized acrylate adhesive containing vinyl acetate with polyvinylpyrrolidone according to a modality.

[00021] Figure 14C shows an example of a graph of mean dexmedetomidine flux as a function of transdermal delivery device application time for a transdermal composition of dexmedetomidine with a hydroxyl-functionalized acrylate adhesive containing vinyl acetate with an acrylate adhesive functionalized form of carboxylic acid according to one embodiment.

[00022] Figure 15 shows an example of a graph of the mean flux of dexmedetomidine as a function of transdermal delivery device application time for a dexmedetomidine transdermal composition with acrylate pressure sensitive adhesive in the absence and presence of levulinic acid , oleic acid or a functionalized carboxylic acid acrylate adhesive according to one embodiment.

[00023] Figure 16 shows an example of a graph of the average flux of dexmedetomidine as a function of transdermal delivery device application time for a transdermal composition of dexmedetomidine with a hydroxyl-functionalized acrylate adhesive containing vinyl acetate with an acrylate adhesive carboxylic acid functionalized according to another embodiment.

[00024] Figure 17 shows an example of a graph of the mean flux of dexmedetomidine as a function of transdermal delivery device application time for a transdermal composition of dexmedetomidine with a hydroxyl-functionalized acrylate adhesive containing vinyl acetate with an acrylate adhesive functionalized form of carboxylic acid or oleic acid according to another embodiment.

[00025] Figure 18 shows an example of a graph of the mean flux of dexmedetomidine as a function of transdermal delivery device application time for a transdermal composition of dexmedetomidine with a hydroxyl-functionalized acrylate adhesive containing vinyl acetate with solubility enhancers such as as a carboxylic acid functionalized acrylate, lauryl lactate or oleic acid adhesive according to another embodiment.

[00026] Figure 19 shows the mean in vitro skin flux of dexmedetomidine as a function of time for the various formulations.

[00027] Figures 20 and 21 show the flux in two different skin samples of the various formulations.

DETAILED DESCRIPTION

[00028] Aspects of the invention include methods of controlling pain by applying a transdermal delivery device containing a dexmedetomidine composition formulated to deliver an effective pain-relieving amount of dexmedetomidine to a subject in pain. In practicing the methods in accordance with 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 administer an effective amount of the dexmedetomidine to control pain in the subject. Also provided are transdermal delivery devices configured to deliver an effective amount of dexmedetomidine sufficient to practice the methods of the present invention, as well as kits containing the transdermal delivery devices.

[00029] Before the present invention is described in more detail, it is to be understood that this invention is not limited to certain described embodiments, as such, of course, vary. It should also be understood that the terminology used in this document is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present invention will be limited only by the amended claims.

[00030] Where a range of values is provided, it is understood that each intervening value, to the tenth of a unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of the range and any other value established or intervening in that established range is encompassed in the invention. The upper and lower limits of these minor ranges may independently be included in the minor scales and are also encompassed in the invention, subject to any specifically excluded limits on the indicated range. Where the stated range includes one or both of the boundaries, ranges excluding either or both of the included boundaries are also included in the invention.

[00031] Certain ranges are presented here with numerical values being preceded by the term "about". The term "about" is used here to provide literal support for the exact quantity that precedes it, as well as a number that is close to or approximately the number that the term precedes. To determine whether a number is close to or approximately a specifically cited number, the uncited approximation or near number may be a number that, in the context in which it is presented, provides the substantial equivalent of the specifically cited number.

[00032] Unless defined otherwise, all technical and scientific terms used in this document have the same meaning as commonly understood by one skilled in the art to which this invention belongs. While any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention, representative illustrative materials and methods are now described.

[00033] All publications and patents cited in this specification in this document are incorporated by reference, as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, and the addendum is incorporated by reference to disclose and describe the methods and/ or materials in relation to which the publications are cited. Mention of any 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 precede such publication by virtue of prior invention. Additionally, the publication dates provided may differ from the actual publication dates which may need to be independently confirmed.

[00034] It should be noted that as used herein and in the appended claim, the singular forms "a", "an", and "the" include plural reference, unless the context clearly dictates otherwise. It is further noted that the claims may be worded to exclude any optional elements. As such, this statement is intended to serve as an antecedent basis for the use of such exclusive terminology as "only," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[00035] As may be apparent to those skilled in the art when reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated or combined with the features of any of the other various embodiments without from the scope or sense of the present invention. Any method recited in the order of events recited or in any other order that is logically possible can be performed.

[00036] In further describing various embodiments of the invention, methods for applying to a subject in pain a transdermal delivery device having a dexmedetomidine composition and maintaining the transdermal delivery device in contact with the subject in a manner sufficient to deliver a non-sedating amount of dexmedetomidine to distribution are first analyzed in greater detail. Next, transdermal delivery devices suitable for practicing the present methods are described. Kits that include transdermal delivery devices of interest are reviewed.

METHODS FOR MANAGING PAIN WITH TRANSDERMAL DELIVERY DEVICES HAVING A DEXMEDETOMIDINE COMPOSITION FORMULATED TO DELIVER AN EFFECTIVE AMOUNT OF DEXMEDETOMIDINE

[00037] Aspects of the invention include methods of controlling pain by applying a transdermal delivery device containing a dexmedetomidine composition formulated to deliver an effective pain-relieving amount of dexmedetomidine to a subject in pain. In practicing the methods in accordance with embodiments of the 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 administer an amount effective for relieving pain from the subject. dexmedetomidine to the subject. The term "transdermal" is used in its conventional sense to refer to the route of administration where an active agent (i.e., drug) is delivered through the skin (i.e., topical administration) or mucous membrane for systemic delivery. As such, transdermal dexmedetomidine compositions as described herein include compositions that are delivered to the subject throughout one or more of the subcutaneous, dermis, and epidermis, including the stratum corneum, stratum germinativeis, stratum spinosum, and stratum basale. Therefore, transdermal extended delivery devices containing a transdermal dexmedetomidine composition can be applied to any convenient location, such as, for example, arms, legs, buttocks, abdomen, back, neck, scrotum, vagina, face, behind the ear, buccally, as well as sublingually. When describing the methods of the present invention, the term "subject" is intended to mean the person or organism to which the transdermal composition is applied and maintained in contact. As such, subjects of the invention may include, but are not limited to, mammals, for example, humans and other primates, such as chimpanzees and other apes and ape species; and the like, where in certain embodiments the subject is human beings. The term subject is also intended to include a person or organism of any age, weight or other physical characteristics, where subjects can be an adult, a child, an infant or a newborn.

[00038] Transdermal administration of dexmedetomidine can be passive or active. By "passive" transport it is meant that the dexmedetomidine composition is distributed across the skin or mucous membrane in the absence of applied energy (e.g. friction or heat) and is primarily dependent on the permeability of the barrier (e.g. skin or mucous membrane) and delivery entropy. However, transdermal administration in accordance with certain embodiments, may also include active transport of the dexmedetomidine composition across the skin or mucous membrane. Active transport can be any convenient protocol sufficient to transport the composition across the skin or mucous membrane in conjunction with the applied energy and can include, but is not limited to, microneedle delivery, facilitated diffusion, electrochemically produced gradients, iontophoretic systems, among other protocols.

[00039] In embodiments of the invention, the methods include applying a transdermal delivery device having a dexmedetomidine composition to a subject in pain and maintaining the transdermal delivery device in contact with the subject in a manner sufficient to administer an amount effective for dexmedetomidine pain relief to the subject. By an effective pain-relieving amount is meant an amount that provides at least some, if not substantial, relief from the pain experienced by the subject, where, in some cases, the pain-relieving amount is a complete cessation of sensation or perception of pain. pain. The amount of pain relief can be quantified or otherwise assessed using any convenient protocol.

[00040] In some cases, the effective amount of dexmedetomidine that is delivered to the subject is a non-sedating amount. By "non-sedating" is meant that the dexmedetomidine composition is formulated to deliver an amount of dexmedetomidine to the subject that does not completely sedate the subject. In other words, a subject remains conscious and responsive the entire time dexmedetomidine is transdermally administered to the subject. In certain instances, during their administration of the transdermal dexmedetomidine composition, the subject remains in a cooperative, oriented, and tranquil state. In other instances, during administration of the transdermal dexmedetomidine composition, the subject remains alert and able to respond to commands (eg, oral or written commands). In still other instances, during administration of the transdermal dexmedetomidine composition, the subject is in an alert, cooperative, oriented, and tranquil state and is able to respond to commands (e.g., oral or written commands).

[00041] Appropriate protocols for determining the level of sedation may include, but are not limited to, the Ramsay Sedation Scale, the Vancouver Sedative Recovery Scale, the Cook and Palma Modified Glasgow Coma Scale, the Comfort Scale, New Sheffield Sedation Scale, Sedation and Agitation Scale, and Motor Activity Rating Scale, among other convenient protocols for determining the level of sedation.

[00042] In some embodiments, the methods may further include assessing the subject's level of sedation to determine whether any reduction in responsiveness or cognitive or motor activity resulted from administration of a transdermal delivery device formulated to administer a non-sedating amount of dexmedetomidine. The level of sedation can be assessed by any convenient protocol as mentioned above. In certain modalities, the level of sedation is assessed using the Ramsey Sedation Scale, (as described in Ramsay, et al. Controlled sedation with alphaxalone-alphadolone, British Med Journal1974; 2:656-659, whose disclosure is incorporated herein by reference). For example, each subject may be assessed by a qualified healthcare professional and scored for level of sedation according to the Ramsey Sedation Scale, summarized below.Ramsay Sedation Scale

[00043] In some embodiments, during administration of the transdermal dexmedetomidine compositions to the subject a subject's level of sedation is assessed and the subject is assigned a Ramsey score of 4 or less, such as a Ramsey score of 3 or less , such as a Ramsey score of 2 or less and which includes the subject being assigned a Ramsey score of 1. In certain instances, during administration of the transdermal dexmedetomidine composition, the subject exhibits a brisk response to gentle glabellar tapping or loud stimulation auditory. In other instances, during his administration of the transdermal dexmedetomidine composition, the subject is responsive to oral commands. In still other instances, during his administration of the transdermal dexmedetomidine composition, the subject is cooperative, oriented, and tranquil. In still other instances, during his administration of the dexmedetomidine transdermal composition, the subject is anxious, agitated or restless.

[00044] A subject's level of sedation can be assessed at any time during the methods. In some cases, the level of sedation is assessed while keeping the extended transdermal delivery device in contact with the subject at regular intervals, for example, every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours or some other interval. For example, the level of sedation can be assessed while maintaining the transdermal delivery device in contact with the subject, such as 15 minutes after applying the transdermal delivery device to the subject, 30 minutes after applying 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 including 8 hours after application of the transdermal delivery device.

[00045] The subject's level of sedation may be assessed one or more times during a dosing interval, such as 2 or more times, such as 3 or more times, including 5 or more times before, during, or after a dosing interval dosage. An upper limit to the number of times the subject can be evaluated during a dosing interval is, in some cases, 10 times or less, such as 7 times or less, such as 5 times or less, such as 3 times or less. and including 2 times or less. In certain embodiments, the amount of times the subject can be evaluated during a dosing interval varies, such as from 2 times to 10 times, such as from 3 times to 9 times, such as from 4 times to 8 times and including from 5 times to 7 times.

[00046] In certain embodiments, the level of sedation can be monitored during the time the transdermal delivery device is maintained in contact with the subject, such as through heart rate monitors, breathing monitors, or by visual observation, including with the aid of a video monitor.

[00047] In some embodiments, the subject being controlled is in a non-sedated state and is awake, alert, oriented, coherent, and able to respond to verbal or written commands, including questions or requests. For example, the subject may be in an unsedated state when administration begins. In other embodiments, the subject is in a non-sedated state when administration begins and remains in a non-sedated state for one or more dosing intervals (i.e., the time period the dexmedetomidine transdermal delivery devices of interest are held in contact with the subject). In still other embodiments, the subject is in a non-sedated state when administration begins and remains in a non-sedated state throughout the control protocol.

[00048] In still other embodiments, the amount of dexmedetomidine that is delivered to the subject is a sedating amount. By "sedative" it is meant that the dexmedetomidine composition is formulated to deliver an amount of dexmedetomidine to the subject that causes the subject to become sedated. In these modalities, the patient may have a Ramsey scale of 5 or more, including 6.

[00049] As summarized above, in practicing the methods according to embodiments of the invention, 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 administer a effective amount of dexmedetomidine to control pain in the subject. The term "pain" is used in its conventional sense to refer to the unpleasant sensory and emotional experiences associated with actual or potential tissue damage or described in these terms as such damage (e.g., as defined by the International Association for the Study of Pain ). Pain can also involve the unpleasant sensory and emotional experience that the damage is not clearly located or its existence cannot be evidenced. In certain cases, pain includes any sensory experience that causes distress (physical, psychological, emotional, mental, etc.) in a subject. Pain indications, in accordance with embodiments of the invention, may include, but are not limited to, neuralgia such as trigeminal neuralgia, myalgia, hyperalgesia, hyperpathy, neuritis, neuropathy, neuropathic pain, idiopathic pain, acute pain sympathetically mediated pain, complex regional pain, chronic pain such as cancer pain, postoperative pain, postherpetic neuralgia, irritable bowel syndrome and other visceral pain, radiation pain, diabetic neuropathy, pain associated with muscle spasticity, complex regional pain syndrome (CRPS), sympathetically maintained pain, headache including migraine, allodynic pain, inflammatory pain such as pain associated with arthritis, gastrointestinal pain such as irritable bowel syndrome (IBS) and Crohn's disease. Pain, according to some embodiments, may be a symptom of an underlying physiological abnormality such as cancer, arthritis, viral infection such as herpes zoster, or physical trauma such as a burn, injury or surgery, chemotherapy-induced pain, peripheral neuropathy chemotherapy-induced chronic pain (CCIPN), radiotherapy pain.

[00050] In certain embodiments, the pain condition is neuropathic pain. The term "neuropathic pain" is used in its conventional sense to refer to pain caused by injury or disease affecting the somatosensory system. Neuropathic pain may be associated with paresthesia, dysesthesia, hypoesthesia, hyperesthesia, hypoalgesia, hyperalgesia, allodynia and/or other related phenomena. Neuropathic pain can be continuous or episodic. Neuropathic pain suitable to be managed with the present methods can be any type of neuropathic pain and includes, but is not limited to, postherpetic neuralgia, trigeminal neuralgia, distal sensory polyneuropathy-HIV, diabetic neuropathy, traumatic nerve injury, pain post-surgical pain, chemotherapy-induced pain, chronic painful chemotherapy-induced peripheral neuropathy (CCIPN), radiotherapy pain, sports injuries, pain associated with stroke, multiple sclerosis, syringomyelia, epilepsy, spinal cord injury, cancer, back pain phantom limb, carpal tunnel syndrome, sciatica, pudendal neuralgia, central pain syndrome, headache, migraine, back pain, chronic back pain, fibromyalgia, among other types of neuropathic pain.

[00051] As discussed above, methods include in some cases applying to a skin surface of a subject in pain, who may be unsedated, a transdermal delivery device that has a dexmedetomidine composition that contains dexmedetomidine and a sensitive adhesive to pressure and maintaining the transdermal delivery device in contact with the subject in a manner sufficient to administer an effective amount of dexmedetomidine over a period of time to control the subject's pain. As discussed above, the amount can be non-sedating or sedating as desired. A non-sedating amount may allow the patient to maintain responsiveness or alertness and may be related to a score that is not greater than 3, including 2 or less, on the Ramsay Sedation Scale. By "pain control" or "pain control" it is meant that there is at least a suppression or amelioration of pain, where suppression or amelioration refers to at least a reduction in the magnitude of pain.

[00052] In some embodiments, the methods include transdermal delivery of extended dexmedetomidine to the subject. By "extended transdermal delivery" is meant that the transdermal delivery is formulated to provide delivery of the dexmedetomidine composition over an extended period of time, such as over hours, days, and including weeks, including 1 hour or more, such as 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 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 including 168 hours or more. For the above intervals an upper timeout period 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 such as 48 hours or less and including 24 hours or less. In certain embodiments, extended transdermal delivery ranges such as from 0.5 hours to 168 hours, such as from 1 hour to 144 hours, such as from 1.5 hours to 120 hours, such as from 2 hours to 96 hours, such as such as from 2.5 hours to 72 hours, such as from 3 hours to 48 hours, such as from 3.5 hours to 24 hours, such as from 4 hours and 12 hours and including from 5 hours to 8 hours.

[00053] In some embodiments, the extended delivery transdermal administration of the dexmedetomidine composition includes multi-day delivery of a therapeutically effective amount of the dexmedetomidine active agent is applied to the skin of a subject. By multi-day delivery it is meant that the transdermal composition is formulated to deliver a therapeutically effective amount to a subject when the transdermal delivery device is applied to a subject's skin for a period of time that is 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 and including 30 days or more. In certain embodiments, transdermal delivery devices deliver a therapeutically effective amount of dexmedetomidine to a subject over a period of 10 days or longer. For multi-day delivery, an upper time limit period is in some cases 30 days or more, such as 28 days or more, such as 21 days or more, such as 14 days or more, such as 7 days or more and including 3 days or more. In certain embodiments, multi-day transdermal delivery ranges, such as 2 days to 30 days, such as 3 days to 28 days, such as 4 days to 21 days, such as 5 days to 14 days, and including from 6 days to 10 days.

[00054] Depending on the specific protocol employed, pain control according to embodiments of the invention may include one or more control dosage ranges. The term "dosage interval" is used herein in its conventional sense to mean the duration of a single administration of applying and maintaining the transdermal delivery device in contact with the subject. In other words, a dosing interval begins with the application of the transdermal dexmedetomidine composition to the skin or mucous membrane of the subject and ends with the removal of the transdermal dexmedetomidine composition from contact with the subject. As such, a dosing interval is the period of time that an amount of dexmedetomidine is in contact with the subject's skin or mucous membrane, and may last for about 0.5 hour 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 about of 48 hours or longer, such as about 72 hours or longer, such as about 96 hours or longer, such as 120 hours or longer, such as 144 hours or longer, and including about 168 hours or longer. An upper cut-off period for the duration of dosing intervals 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 including 24 hours or less. In certain embodiments, the duration of dosing intervals varies, such as 0.5 hours to 168 hours, such as 1 hour to 144 hours, such as 1.5 hours to 120 hours, such as 2 hours to 96 hours , such as from 2.5 hours to 72 hours, such as from 3 hours to 48 hours, such as from 3.5 hours to 24 hours, such as from 4 hours and 12 hours and including from 5 hours to 8 hours.

[00055] The term "control protocol" as used herein refers to one or more sequential dosage intervals sufficient to produce the desired therapeutic effect of the transdermal dexmedetomidine composition. In certain embodiments, protocols may include multiple dosing intervals. By "multiple dosage intervals" is meant more than one transdermal delivery device is applied and maintained in contact with the subject in a sequential manner. Thus, a 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 invention, control regimens can include two or more dosage intervals, three or more dosage intervals, four or more dosage intervals, five or more dosage intervals, including ten or more dosage intervals. .

[00056] The duration between dosing intervals in a multiple dosing interval control protocol may vary, depending on the physiology of the subject or control protocol, as determined by a health care professional. For example, the duration between dosing intervals in a multidose control protocol can be predetermined and follow regular intervals. As such, the time between dosing intervals can vary and can be 1 day or longer, such as 2 or more days, such as 3 days or more, such as 4 days or more, such as 5 days or more, such as 6 days or more, such as 7 days or more, such as 10 days or more including 30 days or more. An upper cut-off period between dosing intervals is, in some cases, 30 days or more, such as 28 days or more, such as 21 days or more, such as 14 days or more, such as 7 days or more, and including 3 days or more. In certain embodiments, the time between dosing intervals varies, such as 2 days to 30 days, such as 3 days to 28 days, such as 4 days to 21 days, such as 5 days to 14 days and including from 6 days to 10 days.

[00057] In certain instances, the duration between dosing intervals may depend on the plasma concentration of dexmedetomidine during the time that the transdermal delivery device is not in contact with the subject between dosing intervals. For example, a subsequent dose interval can begin when the plasma concentration of dexmedetomidine drops below a certain threshold.

[00058] In certain embodiments, transdermal delivery devices deliver a therapeutically effective amount of dexmedetomidine to a subject over a period of 10 days.

[00059] As described above, aspects of the invention include controlling pain in a subject by applying a transdermal delivery device containing a dexmedetomidine composition to a subject formulated to administer an effective amount of dexmedetomidine. In some embodiments, the methods include maintaining the transdermal delivery device in contact with a subject in a manner sufficient to deliver a target dosage of dexmedetomidine to control pain in the subject, such as, for example, delivering a target dosage as determined by the total drug exposure or average daily drug exposure that will control pain. The term target dosage is meant the desired amount of permeated dexmedetomidine. Depending on the desired therapeutic effect of the transdermal dexmedetomidine composition, the management protocol, the physiology of the subject, and the level of sedation in the subject at the time of administration, drug exposure for pain management may vary. In certain embodiments, exposure to the target drug of dexmedetomidine is an amount that is within the subject's therapeutic window, where in some embodiments the therapeutic window is a non-sedating therapeutic window.

[00060] The term "non-sedative therapeutic window" is used herein to refer to the range of dexmedetomidine dosage that is therapeutically effective in controlling a subject's pain that results in little, if any, sedation. In other words, the non-sedating therapeutic window of dexmedetomidine for a specific individual subject being treated to control pain is the range of dexmedetomidine concentrations defined as below an amount considered to be "fully sedating" or "inducing total sedation" and above an amount considered to be "ineffective" to control pain in the subject in certain embodiments of the invention, a therapeutically ineffective sedative amount provides a systemic amount of dexmedetomidine that enables the desired control while maintaining a Ramsay Score of 4 or less at subject. For example, in controlling pain in a subject, the non-sedating target dosage of dexmedetomidine can range from 50 µg/day to 350 µg/day, such as from 100 µg/day to 340 µg/day, such as from 145 µg/day. 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 including 50 μg/day to 250 μg/day over the course of a dosing interval (e.g., a dosing interval of 168 hours). In certain embodiments, the target dosage of dexmedetomidine ranges from 147 µg/day to 290 µg/day over a dosing interval (e.g., a dosing interval of 168 hours or longer).

[00061] In some embodiments, the target dosage is an amount that, when applied to a subject, provides a systemic amount of dexmedetomidine that yields a desired mean plasma concentration of dexmedetomidine at specific times during pain management. In other embodiments, the target dosage is an amount that, when applied to a subject, provides an average steady-state plasma concentration of dexmedetomidine during a dosing interval or control protocol. In other embodiments, the target dosage is an amount that, when applied to a subject, provides a given rate of delivery of dexmedetomidine to the subject in vivo.

[00062] In some embodiments, applying and maintaining a transdermal delivery device containing a dexmedetomidine composition in contact with a subject includes delivering a target amount of dexmedetomidine, such as, for example, an average cumulative amount of dexmedetomidine delivered to the over a dosing interval (e.g., 7 days or longer). The term "target cumulative amount" is meant the total amount of dexmedetomidine that is delivered to the subject through the skin and may vary due to skin or mucous membrane permeability and the metabolic activity of the application site. In some embodiments, the cumulative average amount of dexmedetomidine may be 5 µg/cm2 or more, such as 25 µg/cm2 or more, such as 50 µg/cm2 or more over a 7-day administration interval, such as 75 μg/cm2 or more, such as 100 μg/cm2 or more, such as 125 μg/cm2 or more and including 200 μg/cm2 or more across the dosing range. For average cumulative amount of dexmedetomidine distribution over a dosing interval, an upper limit is, in some instances, 500 μg/cm2 or less, such as 400 μg/cm2 or less, such as 300 μg/cm2 or less, such as 200 µg/cm2 or less, such as 100 µg/cm2 or less and including 50 µg/cm2 or less. In certain embodiments, the average cumulative amount of dexmedetomidine delivery over a dosage range varies such as from 5 µg/cm2 to 500 µg/cm2, such as from 25 µg/cm2 to 400 µg/cm2 and including from 50 µg /cm2 to 300 µg/cm2.

[00063] Methods within certain embodiments may include applying to the subject a transdermal delivery device containing a dexmedetomidine composition and maintaining the transdermal dexmedetomidine composition in contact with the subject in a manner sufficient to provide an average plasma concentration ranging from 0.05 ng/ml to 0.5 ng/ml over a dosage range, such as from 0.1 ng/ml to 0.45 ng/ml, such as from 0.15 ng/ml to 0, 4 ng/ml, such as from 0.2 ng/ml to 0.35 ng/ml and including from 0.25 ng/ml to 0.3 ng/ml. For example, the transdermal delivery device can be held in contact with the subject sufficiently to deliver an average plasma concentration ranging from 0.16 ng/mL to 0.36 ng/mL over a dosing interval. (e.g., a dosing interval of 168 hours or more). In other embodiments, the methods include maintaining the transdermal dexmedetomidine composition in contact with the subject in a manner sufficient to provide an average plasma concentration ranging from 0.05 ng/mL to 0.5 ng/mL throughout the course of the control protocol (i.e., over one or more dosing intervals), such as from 0.1 ng/mL to 0.45 ng/mL, such as from 0.15 ng/mL to 0.4 ng /ml, such as from 0.2 ng/ml to 0.35 ng/ml and including from 0.25 ng/ml to 0.3 ng/ml throughout the control protocol. For example, the transdermal delivery device can be held in contact with the subject sufficiently to deliver an average plasma concentration ranging from 0.16 ng/ml to 0.36 ng/ml throughout the entire delivery protocol. treatment.

[00064] In certain embodiments, the methods may also include determining the plasma concentration of dexmedetomidine in the subject while controlling the subject's pain. Plasma concentration can be determined using any convenient protocol, such as, for example, by liquid chromatography mass spectrometry (LCMS). The plasma concentration of dexmedetomidine can be determined at any desired time. In some embodiments, the plasma concentration of dexmedetomidine can be monitored throughout the entire time the transdermal delivery device is maintained in contact with the subject, such as real-time data collection. In other cases, the dexmedetomidine plasma concentration is monitored while keeping the transdermal delivery device in contact with the subject by collecting data at regular intervals, e.g., collecting data every 0.25 hour, every 0, 5 hour, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours, including every 72 hours or some other interval. In still other instances, the plasma concentration of dexmedetomidine is monitored while maintaining the transdermal delivery device in contact with the subject by collecting data according to a specific schedule after application of the transdermal delivery device to the subject. For example, the plasma concentration of dexmedetomidine can 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 device 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 including 168 hours after applying the transdermal delivery device transdermal delivery to the subject.

[00065] In certain embodiments, the plasma concentration of dexmedetomidine is determined before the transdermal delivery device is applied to a subject, such as, for example, to determine the basal plasma concentration of dexmedetomidine. For example, plasma concentration can be determined 5 minutes before application of the transdermal delivery device, such as 10 minutes before, such as 30 minutes before, such as 60 minutes before, such as 120 minutes before, such as 240 minutes before and including 480 minutes prior to application of the transdermal delivery device. As detailed below, the methods can include multiple dosing intervals where applying and maintaining the transdermal delivery device in contact with the subject can be repeated. In these embodiments, plasma concentration can be determined after a first transdermal delivery device is removed and before a second transdermal delivery device is applied.

[00066] The blood plasma concentration of dexmedetomidine may be determined one or more times in any given measurement period, such as 2 or more times, 3 or more times, including 5 or more times in each measurement period. An upper limit for the number of times the blood plasma concentration of dexmedetomidine is determined in any given mediation period is, in some cases, 10 times or less, such as 7 times or less, such as 5 times or less, such as like 3 times or less and including 2 times or less. In certain embodiments, the amount of times the blood plasma concentration of dexmedetomidine is determined in any given mediation period varies, such as from 2 times to 10 times, such as from 3 times to 9 times, such as from 4 times to 8 times and including from 5 times to 7 times.

[00067] Methods for controlling pain in accordance with certain embodiments may include applying to the subject a transdermal delivery device containing a dexmedetomidine composition and maintaining the transdermal dexmedetomidine composition in contact with the subject in a manner sufficient to maintain a dexmedetomidine transdermal flux that is within 30% or more of the peak dexmedetomidine transdermal flux after reaching peak transdermal flux. As such, once the transdermal delivery devices of interest arrive at peak dexmedetomidine transdermal flux, the transdermal delivery device is configured to maintain a flow of dexmedetomidine to the subject that is at least 30% of the peak flow during the course of any given dosage interval, such as at least 35%, such as at least 40% and including at least 50% of peak flow during the course of any given dosage interval. In other words, once peak flow is achieved by the transdermal delivery device in accordance with these particular embodiments, the transdermal flux of dexmedetomidine to the subject does not drop below 30% or more of peak flow at any time during the interval. of dosage.

[00068] For example, the dexmedetomidine transdermal composition can be held in contact with the subject in a manner sufficient to maintain the dexmedetomidine transdermal flux that is within 80% or more of the peak dexmedetomidine transdermal flux, such as within 85% or greater, such as within 90% or greater, such as within 95% and including within 99% of peak dexmedetomidine transdermal flux after reaching peak transdermal flux. In certain embodiments, the transdermal flux of dexmedetomidine does not decrease after reaching peak flow and maintains a rate of 100% of peak dexmedetomidine flux from the time peak flow is reached until the end of a given interval. dosage.

[00069] The flux of an active agent through transdermal administration is the rate of penetration of the active agent through the skin or mucous membrane of the subject. In some cases, the flow of dexmedetomidine can be determined by the equation: where J is the skin flux, C is the concentration gradient across the skin or mucous membrane, and P is the permeability coefficient. Skin flux is the change in the cumulative amount of drug entering the body through the skin or mucous membrane over time.

[00070] In some cases, the transdermal dexmedetomidine composition is held in contact with the subject in a manner sufficient to provide a peak flux of 0.05 µg/cm2/H or greater, such as 0.1 µg/cm2/ H or greater, such as 0.5 μg/cm2/H or greater, such as 1 μg/cm2/H, such as 2 μg/cm2/H, such as 3 μg/cm2/H or greater, such as 5Dμg/ cm2/H or greater, such as 7.5 µg/cm2/H or greater and including maintaining the single-layer dexmedetomidine transdermal composition in contact with the subject in a manner sufficient to provide a peak flux of 10 µg/cm2/ H or greater. For the peak flow of dexmedetomidine transdermal delivery, an upper limit is, in some cases, 10 μg/cm2/H or less, or, such as 9 μg/cm2/H or less, or, such as 8 μg/cm2 /H or less, or, such as 7 μg/cm2/H or less, or 6 μg/cm2/H or less, or, such as 5 μg/cm2/H or less, and including 2 μg/cm2/H or any less. In certain embodiments, the peak flux of transdermal delivery of dexmedetomidine ranges such as from 0.05 µg/cm2/hr to 10 µg/cm2/hr, such as from 1 µg/cm2/hr to 9 µg/cm2/hr and up to 2 μg/cm2/h to 8 μg/cm2/h.

[00071] As such, where the transdermal dexmedetomidine composition is maintained in contact with the subject sufficiently to provide a transdermal flux of dexmedetomidine that is within at least 30% of the peak transdermal dexmedetomidine flux, the transdermal layer composition single can be held in contact with the subject sufficiently to deliver a flux that is 0.15 μg/cm2/h or greater after reaching a peak transdermal flux of 0.5 μg/cm2/h, such as 0.18 μg/cm2/hr or greater after reaching a peak transdermal flux of 0.6 μg/cm2/hr, such as 0.225 μg/cm2/hr or greater after achieving a peak transdermal flux of 0.75 μg/cm2 /h, such as 0.27 μg/cm2/h or greater after reaching a peak flow of 0.9 μg/cm2/h, such as 0.3 μg/cm2/h or greater after reaching a peak flow of peak flow of 1.0 μg/cm2/h, such as 1.5 μg/cm2/h after reaching a peak flow of 5 μg/h of 2g/cm or greater including keeping the dexmedetomidine transdermal composition in contact with the object sufficiently to provide a flux that is 3.0 µg/cm2/hr or greater after reaching the peak flux of 10.0 µg/cm2/hr.

[00072] Depending on the amount of dexmedetomidine present in the transdermal composition, the subject's physiology, the target site of application, the time required to reach peak dexmedetomidine flux may vary. In some cases, peak dexmedetomidine flux is reached 2 hours or more after application of the transdermal delivery device to the subject, such as 4 hours or more, such as 6 hours or more, such as 12 hours or more, such as such as 18 hours or more and including 24 hours or more after application of the transdermal delivery device to the subject. In other cases, peak dexmedetomidine flux is reached, such as 168 hours or earlier, such as 144 hours or earlier, such as 120 hours or earlier, such as 96 hours or earlier, such as 72 hours or earlier , such as 48 hours or earlier, such as 24 hours or earlier, such as 12 hours or earlier, such as 8 hours or earlier, such as 4 hours or earlier and including 2 hours or earlier. In some embodiments, peak dexmedetomidine flux is achieved within 24 hours of applying the transdermal delivery device to the subject.

[00073] In certain embodiments, during pain management in the subject the transdermal composition remains in contact with the subject sufficient to deliver a steady state average flux of dexmedetomidine to the subject. The term "steady state" is used in its conventional sense to mean that the amount of dexmedetomidine released from the transdermal composition maintains a substantially constant average flux of dexmedetomidine. As such, the flux of dexmedetomidine from the transdermal delivery devices of interest increases or decreases by 30% or less at any time while the transdermal delivery device is maintained in contact with the subject, such as 20% or less, such as 15% or less, such as 12% or less, such as 10% or less, such as 6% or less, such as 5% or less, such as 4% or less, and including 1% or less at any time while the transdermal delivery device is held in contact with the subject.

[00074] When the transdermal dexmedetomidine composition is kept in contact with the subject long enough to provide an average steady-state flux of dexmedetomidine, the average steady-state flux of dexmedetomidine can 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 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 including 168 hours or more. To maintain an average steady-state flow of dexmedetomidine, an upper limit is, in some cases, for 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 including 2 hours or less.

[00075] In these embodiments, the transdermal delivery device is configured to deliver a constant flow, such as by introducing a concentration gradient across the skin or mucous membrane or delivering an excess dose amount of dexmedetomidine. For example, the dexmedetomidine transdermal compositions of interest can include a dose of dexmedetomidine that is 5% or more in excess of the normal dosage amount, such as 10% or more, such as 15% or more, such as 20% or more. and including 25% or more in excess of the normal dosage amount. For excess amount of dexmedetomidine present in the transdermal delivery device to provide a steady flow, an upper limit is in some cases 50% or less excess, such as 45% or less excess, such as 25% or less in excess, such as 20% or less in excess and including 10% or less in excess of the normal dosage amount. Although the dexmedetomidine transdermal compositions of interest may include an excess in order to provide a constant flux, the excess dosage amount is not absorbed as part of the dosing interval and is not sufficient to result in a dosage that is fully sedating (i.e. , the dosage of dexmedetomidine delivered to the subject remains a non-sedating amount). As such, in some embodiments where the dexmedetomidine transdermal composition is maintained sufficiently to provide a constant flux, 25% or less of the dexmedetomidine available in the transdermal composition cannot be used, such as 20% or less, 15% or less, 10% or less, 5% or less and including 1% or less of the dexmedetomidine available in the transdermal composition cannot be used during the dosing interval.

[00076] Methods for controlling pain in a subject in accordance with certain modalities may include applying to the subject a transdermal delivery device containing a dexmedetomidine composition configured to deliver a non-sedating amount of dexmedetomidine and maintaining the dexmedetomidine composition transdermally in contact with the subject sufficiently to provide an average in vivo flux of dexmedetomidine of about 0.005 to about 5 µg/cm^hr, such as about 0.01 to about 4 µg/cm^hr, about 0.02 to about 3 µg/cm²hr, about 0.05 to about 2.5 µg/cm²hr, about 0.1 to about 2 µg/cm²hr, and up to and including about 0. 1 to about 1μg/cm2•hr anytime after application of the transdermal delivery device. In some embodiments, the methods include applying the transdermal dexmedetomidine composition to the subject and maintaining the transdermal composition in contact with the subject in a manner sufficient to provide an average in vivo flux of dexmedetomidine of from about 0.005 to about 2.0 µg/cm^hr 24 hours after application, such as about 0.01 to about 1.75 µg/cm^hr, about 0.02 to about 1.5 µg/cm^hr, about 0 .05 to about 1.25 µg/cm^hr and including from about 0.1 to about 1 µg/cm^hr 24 hours after application. In still other embodiments, the methods include applying the transdermal dexmedetomidine composition to the subject and maintaining the transdermal composition in contact with the subject in a manner sufficient to provide an average in vivo flux of dexmedetomidine of from about 0.005 to about 2. 0 µg/cm2^hr 168 hours after application, from about 0.01 to about 1.75 µg/cm^hr, from about 0.02 to about 1.5 µg/cm^hr, from about from about 0.05 to about 1.25 µg/cm^h and including from about 0.1 to about 1 µg/cm^h 168 hours after application.

[00077] In certain embodiments, the methods include determining the transdermal flux of dexmedetomidine. The transdermal flux of dexmedetomidine can be determined using any convenient protocol, for example, protocols employing human cadaver skin with epidermal layers (stratum corneum and epidermis) in a Franz cell with donor and recipient sides joined and recipient solution containing phosphate buffer. The amount of permeated dexmedetomidine can be further characterized by liquid chromatography. The transdermal flux of dexmedetomidine can be determined at any time during the methods of the invention. In some embodiments, the transdermal flux of dexmedetomidine can be monitored the entire time the transdermal dexmedetomidine composition is maintained in contact with the permeation barrier (e.g., human cadaver skin), such as by real-time data collection . In other cases, the transdermal flux of dexmedetomidine is monitored by collecting data at regular intervals, e.g., collecting data every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every every 4 hours, every 12 hours, every 24 hours, including every 72 hours, or some other regular or irregular intervals. In still other cases, the transdermal flux of dexmedetomidine is monitored by collecting data according to a specific schedule. For example, the transdermal flux of dexmedetomidine can 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 transdermal delivery device application, 8 hours after transdermal delivery device application, 12 hours after transdermal delivery device application, 24 hours after transdermal delivery device application, 48 hours after transdermal delivery device application, 72 hours after transdermal delivery device application, 76 hours after transdermal delivery device application, 80 hours after transdermal delivery device application, 84 hours after device application of transdermal delivery device, 96 hours after application of the transdermal delivery device, 120 hours after application of the transdermal delivery device, and even 168 hours after application of the transdermal delivery device.

[00078] The transdermal flux of dexmedetomidine may be determined one or more times in any given measurement period, such as 2 or more times, 3 or more times, including 5 or more times in each measurement period. An upper limit for the number of times the transdermal flux of dexmedetomidine is determined is, in some cases, 10 times or less, such as 7 times or less, such as 5 times or less, such as 3 times or less, and including 2 times or less. In certain embodiments, the amount of times the transdermal flux of dexmedetomidine is determined varies, such as from 2 times to 10 times, such as from 3 times to 9 times, such as from 4 times to 8 times, and including from 5 times to 7 times.

[00079] In some embodiments, by keeping the transdermal dexmedetomidine composition in contact with the subject the average cumulative amount of permeated dexmedetomidine increases at a substantially linear rate over the dosing interval (e.g., 7 days or longer). By "substantially linear" is meant 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 rate of increase in cumulative permeate dexmedetomidine increases or decreases by 10% or less at any given time while maintaining the transdermal composition in contact with the subject, such as 8% or less, 7% or less, 6% or less, 5% or less, 3% or less, 2.5% or less, 2% or less, and including 1% or less at any time while maintaining the Dexmedetomidine Transdermal Composition in contact with the subject.

[00080] As described above, aspects of the invention include controlling pain in a subject by applying a transdermal delivery device containing a dexmedetomidine composition in contact with the subject for a period sufficient to deliver an effective pain-relieving amount of dexmedetomidine to the subject. In some embodiments, methods of controlling pain include maintaining a transdermal dexmedetomidine composition in contact with the subject in a manner sufficient to deliver a predetermined amount of dexmedetomidine to the subject. If the protocols include delivering a predetermined amount of dexmedetomidine to the subject, the amount of dexmedetomidine in the transdermal dexmedetomidine compositions of interest can range from 0.001 mg to 50 mg, from 0.005 to 40 mg, from 0.01 mg to 30 mg, from 0.05 to 20 mg, from 0.1 mg to 15 mg, from 0.5 mg to 12.5 mg and even from 0.5 mg to 10 mg.

[00081] In certain embodiments, the predetermined amount of dexmedetomidine delivered to the subject may be a percentage of the total amount of dexmedetomidine present in the transdermal dexmedetomidine compositions. For example, the predetermined amount of dexmedetomidine delivered to the subject can be 1% or greater than the total amount of dexmedetomidine present in the transdermal dexmedetomidine composition, such as 2% or greater, 5% or greater, 10% or greater, 25% or greater and including 50% or greater than the total amount of dexmedetomidine present in the dexmedetomidine transdermal composition. In other words, methods of controlling pain include maintaining a dexmedetomidine transdermal composition in 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 individual dosing range. . In these embodiments, the percentage of dexmedetomidine utilization is 5% or greater 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 a dosing interval. As described in more detail below, the subject's transdermal delivery devices are capable of high percentage usage. In other words, the subject's transdermal delivery devices are capable of delivering dexmedetomidine to the subject by leaving some residual dexmedetomidine in the transdermal delivery device after a certain dosing interval. The percentage of use can be 5% or more over the dosing range, such as 10% or more, 25% or more, 40% or more, 45% or more, and including 50% or more dexmedetomidine over the range of dosage. For percentage utilization, an upper limit over the dosing range is, in some cases, 90% or less, 50% or less, 25% or less, and even 5% or less, over the dosing range.

[00082] For example, if the subject's dexmedetomidine transdermal composition contains 1 mg of dexmedetomidine, methods of controlling the pain may include keeping the transdermal delivery device in contact with the subject in a manner sufficient to deliver 0.05 mg or more of dexmedetomidine in the dexmedetomidine transdermal composition over the dosing interval (e.g., 7 days or more), such as 0.1 mg or more, 0.25 mg or more, 0.4 mg or more, 0.45 mg or more and including 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, 0.95 mg or less of dexmedetomidine remains in the dexmedetomidine transdermal composition after 7 days or more, such as 0.9 mg or less, 0.75 mg or less, 0.6 mg or less, and up to 0.5 mg or less of dexmedetomidine remains in the dexmedetomidine transdermal composition after the dosing interval.

[00083] As described in more detail below, in certain embodiments the transdermal delivery devices include a single layer matrix dexmedetomidine composition that is configured to deliver a non-sedating amount of dexmedetomidine to a subject. Thus, methods in accordance with a given case include applying to a subject a transdermal delivery device with a single layer matrix dexmedetomidine composition and maintaining a single layer matrix dexmedetomidine composition in contact with the subject for a period sufficient to deliver an effective amount of dexmedetomidine to the subject.

[00084] In certain embodiments, each of the subject methods described in more detail below, may further include the step of removing the transdermal delivery device from contact with the subject at the conclusion of a dosing interval. For example, the transdermal delivery device can be removed from contact with the subject after keeping the transdermal delivery device in contact with the subject for 0.5 hour or more, 1 hour or more, 2 hours or more, 4 hours, or more, 8 hours or more, 12 hours or more, 24 hours or more, 36 hours or more, 48 hours or more, 60 hours or more, 72 hours or more, 96 hours or more, 120 hours or more including 144 hours or more more and even 168 hours or more. An upper limit for the amount of time the transdermal delivery device is held in contact with a subject prior to removal is, in some cases, 168 hours or less, 144 hours or less, 120 hours or less, 96 hours or less , 72 hours or less, 48 hours or less, 24 hours or less, 12 hours or less, 8 hours or less, 4 hours or less, and even 2 hours or less.

[00085] By "removing" the transdermal delivery device from contact with the subject, no amount of dexmedetomidine from the transdermal composition remains in contact with the subject, including any residual amount of dexmedetomidine left on the surface of the skin or mucous membrane when the transdermal delivery device was applied. In other words, when the transdermal delivery device is removed all traces of dexmedetomidine are no longer on the surface of the skin or mucous membrane at the site of application, resulting in zero dexmedetomidine transdermal flux in the subject.

[00086] As described above, a dosing interval is an individual administration, application and keeping of the transdermal delivery device in contact with the subject that begins with the application of the transdermal dexmedetomidine composition to the skin or mucous membrane of the subject and ends with the removing the transdermal delivery device from contact with the subject. In certain embodiments, protocols may include multiple dosing intervals. By "multiple dosage intervals" is meant more than one transdermal delivery device is applied and maintained in contact with the subject in a sequential manner. Thus, a 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 invention, control regimens can include two or more dosage intervals, three or more dosage intervals, four or more dosage intervals, five or more dosage intervals, including ten or more dosage intervals. .

[00087] The site on the subject to reapply the next transdermal delivery devices in multiple dosage control regimens may be the same or different from the site on the subject from which the previous transdermal delivery device was removed. For example, if a first transdermal delivery device is applied and maintained on the subject's leg, one or more subsequent transdermal delivery devices can be reapplied in the same position on the subject's leg. On the other hand, if a first transdermal delivery device was applied and maintained on the subject's leg, one or more subsequent transdermal delivery devices may be reapplied to a different position, such as the subject's abdomen or back. Subsequent dosages applied in multiple dose interval regimens may have the same or different dexmedetomidine formulation. In certain cases, a subsequent dosing interval in a control regimen may contain a higher or lower concentration of dexmedetomidine than the previous dosing interval. For example, the dexmedetomidine concentration can be increased at subsequent dosage intervals by 10% or more, 20% or more, 50% or more, 75% or more, 90% or more, and even 100% or more. An upper limit for the increase in dexmedetomidine concentration at subsequent dosing intervals is, in some cases, 10 times or less, 5 times or less, 2 times or less, 1 time or less, 0.5 times or less, and up to and including 0 .25 times or less.

[00088] Conversely, the concentration of dexmedetomidine may be lower at subsequent dosing intervals by 10% or more, 20% or more, 50% or more, 75% or more, 90% or more, and even 100% or more . An upper limit for the decrease in dexmedetomidine concentration at subsequent dosing intervals is, in some cases, 10 times or less, 5 times or less, 2 times or less, 1 time or less, 0.5 times or less, and up to and including 0 .25 times or less.

[00089] In other cases, a subsequent dosage interval may contain a different dexmedetomidine formulation than the previous dosage interval, such as a different pressure sensitive adhesive or the presence or absence of permeation enhancers as described above.

[00090] In certain embodiments, dexmedetomidine compositions for controlling neuropathic pain can be administered prior to, concurrent with, or subsequent to other therapeutic agents for treating or controlling pain. If provided at the same time as another therapeutic agent, the subject dexmedetomidine compositions may be administered in the same or different composition. Thus, the dexmedetomidine compositions of interest and other therapeutic agents can be administered to the subject through concomitant therapy. By "concomitant therapy" is meant administration to a subject so that the therapeutic effect of the combination of substances is caused in the subject undergoing therapy. For example, concomitant therapy can be achieved by administering the dexmedetomidine compositions of the invention and a pharmaceutical composition with at least one other agent, such as a donor control composition including, but not limited to, NSAIDS (aspirin, ibuprofen, naproxen, celecoxib, acetaminophen), cyclooxygenase inhibitors, opioids such as codeine, oxycodone, morphine, methadone, buprenorphine and fentanyl, anesthetics, antidepressants, anticonvulsants, topical agents, cannabinoids, N-methyl-D-Aspartate, among other neuromodulators, which in combination form a therapeutically effective dose, according to a particular dosage regimen. Administration of the separate pharmaceutical compositions can be carried out simultaneously or at different times (i.e., sequentially, in any order, on the same day, or on different days), provided that the therapeutic effect of the combination of these substances is caused in the subject undergoing therapy. .

[00091] Whenever dexmedetomidine is administered concomitantly with a second therapeutic agent to treat pain, the weight ratio of dexmedetomidine to the second therapeutic agent may vary from 1:2 to 1:2.5; 1:2.5 and 1:3; 1:3 and 1:3.5; 1:3.5 and 1:4; 1:4 and 1:4.5; 1:4.5 and 1:5; 1:5 and 1:10; and 1:10 and 1:25 or another variation. For example, the weight ratio of dexmedetomidine to the second therapeutic agent can range from 1:1 to 1:5; 1:5 and 1:10; 1:10 and 1:15; or 1:15 and 1:25. Alternatively, the weight ratio of the second therapeutic agent to dexmedetomidine ranges from 2:1 to 2.5:1; 2.5:1 to 3:1; 3:1 and 3.5:1; 3.5:1 and 4:1; 4:1 and 4.5:1; 4.5:1 and 5:1; 5:1 and 10:1; and 10:1 and 25:1 or other variation. For example, the ratio of the second therapeutic agent to dexmedetomidine can range from 1:1 to 5:1; 5:1 and 10:1; 10:1 and 15:1; or 15:1 and 25:1.

[00092] Depending on the second therapeutic agent to be administered and the condition indicated, simultaneous administration of dexmedetomidine may reduce the required amount of administration of the second therapeutic agent. For example, simultaneous administration of dexmedetomidine can reduce the amount of opioid or other analgesic needed to effectively treat or control pain, such as postoperative pain, chemotherapy-induced pain, or radiotherapy-induced pain. Simultaneous administration of dexmedetomidine can reduce the required amount of administration of the second therapeutic agent by 10% or more, such as by 25% or more, such as 35% or more, and even reduce the required amount of administration of the second therapeutic agent by 50% or more.

TRANSDERMAL DEXMEDETOMIDINE DELIVERY DEVICES CONTAINING A DEXMEDETOMIDINE COMPOSITION FOR THE CONTROL OF PAIN IN A SUBJECT

[00093] Aspects of the invention also include transdermal dexmedetomidine delivery devices for delivering an effective amount (e.g., a sedative or non-sedating amount) of dexmedetomidine to a subject suitable for practicing the subject methods. Transdermal delivery devices of interest include a composition with dexmedetomidine and a pressure sensitive adhesive. Dexmedetomidine is the S-enantiomer of medetomidine described by the formula:

[00094] Dexmedetomidine according to embodiments of the invention may be in the form of a free base, salt, solvate, hydrate or complex. For example, dexmedetomidine can be in the form of a pharmaceutically acceptable salt including, but not limited to, a mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide, esylate, p-toluenesulfonate, benzoate, acetate, phosphate, and sulfate salt. Dexmedetomidine according to some embodiments can be a free base. In other cases, dexmedetomidine may form a complex.

[00095] Depending on the application site, the type of pain being controlled and the physiology of the subject (e.g. body mass), the amount of dexmedetomidine in compositions of interest may vary, in some cases the amount of dexmedetomidine varies from 0.001 mg to 50 mg, from 0.005 mg to 40 mg, from 0.01 to 30 mg, from 0.05 to 20 mg and even from 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, 0.5% to 18% w/w, 1% to 15%, 2% to 12.5% w/w. p and including 3% to 10% w/w. In other embodiments, the amount of dexmedetomidine in the subject transdermal compositions is 10% by weight or less of the total weight of the transdermal composition, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, and up to 3% by weight or less of the total weight of the transdermal composition. In certain embodiments, dexmedetomidine compositions include an amount that is less than the saturation point of dexmedetomidine. In other embodiments, dexmedetomidine compositions include a saturated amount of dexmedetomidine. In yet other embodiments, dexmedetomidine compositions include a supersaturated amount of dexmedetomidine.

[00096] In some embodiments of the invention, the dexmedetomidine compositions described herein are formulated to deliver a non-sedating amount of dexmedetomidine. As described above, by non-sedating it is meant that the dexmedetomidine composition is formulated to deliver an amount of dexmedetomidine to the subject that does not completely sedate the subject. In other words, a subject remains conscious and responsive throughout the entire time that dexmedetomidine is transdermally administered to the subject. In certain instances, during their administration of the transdermal dexmedetomidine composition, the subject remains in a cooperative, oriented, and tranquil state. In other instances, during administration of the transdermal dexmedetomidine composition, the subject remains alert and able to respond to commands (eg, oral or written commands). In still other instances, during administration of the transdermal dexmedetomidine composition, the subject is in an alert, cooperative, oriented, and tranquil state and is able to respond to commands (e.g., oral or written commands).

[00097] As described in more detail below, in some embodiments, the transdermal dexmedetomidine compositions of interest are formulated so that throughout the transdermal administration the subject can be assessed according to the Ramsey Sedation Scale and assigned a Ramsey score of 4 or less, a Ramsey score of 3 or less, a Ramsey score of 2 or less, and even that the subject is assigned a Ramsey score of 1. In certain instances, during administration of the transdermal dexmedetomidine composition, the subject exhibits an abrupt response to gentle glabellar tapping or loud auditory stimuli. In other instances, during administration of the transdermal dexmedetomidine composition, the subject responds to oral commands. In yet other instances, during his administration of the transdermal dexmedetomidine composition, the subject is cooperative, oriented, and tranquil. In still other cases, during his administration of the transdermal dexmedetomidine composition, the subject is anxious, agitated or restless.

[00098] In embodiments of the present invention, the dexmedetomidine transdermal compositions also include a pressure sensitive adhesive. Pressure sensitive adhesives can include, but are not limited to, polyisobutene adhesives, polyisobutylene adhesives, polyisobutene/polyisobutylene adhesive blends, carboxylated polymers, acrylic or acrylate copolymers such as carboxylated acrylate copolymers.

[00099] If the pressure sensitive adhesive includes polybutene, the polybutene may be saturated polybutene. Alternatively, the polybutene can be unsaturated polybutene. Furthermore, the polybutene can be a mixture or blend of saturated polybutene and unsaturated polybutene. In some embodiments, the pressure sensitive adhesive may include a composition that is, or is substantially the same as, the composition of Indopol® G-2, Indopol® G-3, Indopol® L-6, Indopol® G-8, Indopol® ® G-14, Indopol® H-7, Indopol® H-8, Indopol® H-15, Indopol® H-25, Indopol® H-35, Indopol® H-50, Indopol® H-100, Indopol® H -300, Indopol® H-1200, Indopol® H-1500, Indopol® H-1900, Indopol® H-2100, Indopol® H-6000, Indopol® H-18000, Panalane® G-14E, Panalane® H-300E and their combinations. In certain embodiments, the polybutene pressure sensitive adhesive Indopol® H-1900. In other embodiments, the polybutene pressure sensitive adhesive is Panalane® H-300E.

[000100] The acrylate copolymers of interest include copolymers of various monomers, such as "soft" monomers, "hard" monomers or "functional" monomers. Acrylate copolymers can be composed of a copolymer including biopolymer (i.e., made with two monomers), a terpolymer (i.e., made with three monomers), or a tetrapolymer (i.e., made with four monomers), or copolymers with a greater number of monomers. Acrylate copolymers can be crosslinked or non-crosslinked. Polymers can be crosslinked by known methods to provide desired polymers. The monomers from the acrylate copolymers can include at least two or more exemplary components selected from the group including acrylic acids, alkyl acrylates, methacrylates, copolymerizable secondary monomers or monomers with functional groups. The monomers ("soft" and "hard" monomers) can be methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, iso-octyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, acrylonitrile, methoxyethyl, methoxyethyl methacrylate and the like. 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 a vinyl acetate-acrylate copolymer. In some embodiments, the pressure sensitive adhesive can include a composition that is, or is substantially the same as the 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 their combinations. The term "substantially the same" as used herein refers to a composition that is a vinyl acetate-acrylate copolymer in an organic solvent solution. In certain embodiments, the acrylic pressure sensitive adhesive is Duro-Tak® 87-2054.

[000101] In certain embodiments, the pressure-sensitive adhesive is an acrylate adhesive that is a non-functionalized acrylate, hydroxyl-functionalized acrylate or an acid-functionalized acrylate. For example, the acrylate adhesive can be an acrylic adhesive with one or more -OH functional groups. When the acrylic adhesive has one or more -OH functional groups, in some cases the pressure sensitive adhesive may be a composition that is, or is substantially the same as, the composition of Duro-Tak® 87-4287, Duro-Tak® 87-2287, Duro-Tak® 87-2510 and Duro-Tak® 87-2516 and combinations thereof. The acrylate adhesive may alternatively be an acrylic adhesive with one or more -COOH functional groups. When the acrylic adhesive has one or more -COOH functional groups, in some cases the pressure sensitive adhesive may be a composition that is, or is substantially the same as, the composition of Duro-Tak® 87387, Duro-Tak® 87 - 2979 and Duro-Tak® 87-2353 and combinations thereof. Additionally, the acrylate adhesive may be a non-functionalized acrylic adhesive. When the acrylic adhesive is non-functionalized, in some cases the pressure sensitive adhesive may be a composition that is, or is substantially the same as, the composition of Duro-Tak® 87-9301.

[000102] The amount of pressure-sensitive adhesive in transdermal dexmedetomidine compositions of interest may vary, the amount of pressure-sensitive adhesive ranging from 0.1 mg to 2000 mg, 0.5 mg to 1500 mg, 1 to 1000 mg , 10 to 750 mg and even from 10 mg to 500 mg. Thus, the amount of pressure sensitive adhesive in the transdermal composition ranges from 1% to 99% w/w, 5% to 95% w/w, 10% to 95%, 15% to 90% w/w and including 20% to 85% w/w. In other embodiments, the amount of pressure sensitive adhesive in the subject transdermal compositions is 70% by weight or greater of the total weight of the transdermal composition, 75% by weight or greater, 80% by weight or greater, 85% by weight or greater, 90% by weight or greater, 95% by weight or greater, and including 97% by weight or greater of the total weight of the transdermal composition.

[000103] The weight ratio between the pressure-sensitive adhesive and dexmedetomidine in the object compositions can vary from 1:2 to 1:2.5; 1:2.5 and 1:3; 1:3 and 1:3.5 1:3.5 and 1:4; 1:4 and 1:4.5; 1:4.5 and 1:5; 1:5 and 1:10; 1:10 and 1:25; 1:25 and 1:50; 1:50 and 1:75; and 1:75 and 1:99 or another variation. For example, the weight ratio between pressure sensitive adhesive and dexmedetomidine in compositions of interest can vary between 1:1 and 1:5; 1:5 and 1:10; 1:10 and 1:15; 1:15 and 1:25; 1:25 and 1:50; 1:50 and 1:75 or 1:75 and 1:99. Alternatively, the weight ratio between dexmedetomidine and pressure sensitive adhesive in the subject compositions varies between 2:1 and 2.5:1; 2.5:1 and 3:1; 3:1 and 3.5:1; 3.5:1 and 4:1; 4:1 and 4.5:1; 4.5:1 and 5:1; 5:1 and 10:1; 10:1 and 25:1; 25:1 and 50:1; 50:1 and 75:1; and 75:1 and 99:1 or other variation. For example, the ratio of dexmedetomidine to pressure sensitive adhesive in compositions of interest can vary between 1:1 and 5:1; 5:1 and 10:1; 10:1 and 15:1; 15:1 and 25:1; 25:1 and 50:1; 50:1 and 75:1; or 75:1 and 99:1.

[000104] In some embodiments, transdermal dexmedetomidine compositions may further include one or more cross-linked hydrophilic polymers. For example, the cross-linked polymer can be an amine-containing hydrophilic polymer. Amine-containing polymers can include, but are not limited to, polyethyleneimine, amine-terminated polyethylene oxide, amine-terminated polyethylene/polypropylene oxide, dimethylaminoethyl methacrylate polymers, and dimethylaminoethyl vinyl methacrylate-pyrrolidone copolymers. In certain embodiments, the crosslinked polymer is crosslinked polyvinylpyrrolidone such as, for example, PVP-CLM.

[000105] The matrix may contain other additives depending on the adhesive used. For example, materials like PVP-CLM, K17 PVP, PVP K30, K90 PVP, which inhibit drug crystallization, have hygroscopic properties that improve wear duration and improve physical properties, e.g., cool flow, adhesion, cohesive strength of the sticker.

[000106] The amount of crosslinked polymer in the dexmedetomidine compositions of interest may vary, the amount of crosslinked polymer ranging from 0.1 mg to 500 mg, such as 0.5 mg to 400 mg, 1 to 300 mg, 10 to 200 mg and including 10 mg to 100 mg. Thus, the amount of cross-linked polymer in the transdermal composition ranges from 2% to 30% w/w, such as 4% to 30% w/w, 5% to 25%, such as 6% to 22.5% w/w and including 10 % to 20% w/w. In other embodiments, the amount of cross-linked polymer in the subject transdermal compositions is 8% by weight or greater of the total weight of the transdermal composition, such as 10% by weight or greater, 12% by weight or greater, 15% by weight or greater, 20% by weight or greater, 25% by weight or greater and including 30% by weight of the crosslinked polymer or greater of the total weight of the transdermal composition.

[000107] In certain embodiments, the object transdermal dexmedetomidine compositions further include a dexmedetomidine solubility enhancer. By "solubility enhancer" is meant a compound or composition that increases the solubility of dexmedetomidine in the subject compositions, for example to prevent any unwanted crystallization of dexmedetomidine in the composition. The dexmedetomidine solubilization enhancer is incorporated into the dexmedetomidine composition in an amount ranging from 0.01% to 20% (w/w), from 0.05% to 15% (w/w), as from 0.1% to 10% (w/w), 0.5% to 8% (w/w) and including from 1% to 5% (w/w).

[000108] Exemplary solubility enhancers include, but are not limited to acids, including 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, cyclopentane carboxylic acid; acylated amino acids. Other solubility enhancers of interest may include, but are not limited to, aliphatic alcohols, such as saturated or unsaturated higher alcohols having 12 to 22 carbon atoms (eg, oleyl alcohol or lauryl alcohol); fatty acid esters such as isopropyl myristate, diisopropyl adipate, lauryl lactate, propyl laurate, ethyl oleate, isopropyl palmitate; alcohol amines such as triethanolamine, triethanolamine hydrochloride and diisopropanolamine; alkyl ethers of polyhydric alcohol, such as alkyl ethers of 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, sorbitol, isosorbide, glycoside methyl, oligosaccharides and reducing oligosaccharides, where the number of carbon atoms of the unit of the alkyl group in the alkyl ethers of polyhydric alcohol is preferably 6 to 20; polyoxyethylene alkyl ethers, such as polyoxyethylene alkyl ethers in which the number of carbon atoms of the alkyl group unit is 6 to 20 and the number of repeating units (e.g. -O -CH2CH2-) of the polyoxyethylene chain is 1 to 9 such as, inter alia, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether and polyoxyethylene oleyl ether; glycerides (i.e., fatty acid esters of glycerol), such as glycerol esters of fatty acids having 6 to 18 carbon atoms, where the glycerides may be monoglycerides (i.e., glycerol molecule covalently linked to a fatty acid chain by an ester linkage), diglycerides (i.e., glycerol molecule covalently linked to two fatty acid chains by an ester linkage), triglycerides (i.e., glycerol molecule covalently linked to three fatty acid chains by an ester linkage) ) or combinations thereof, where the fatty acid components forming the glycerides include octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid (i.e., stearic acid) and oleic acid; medium chain fatty acid esters of polyhydric alcohols; lactic acid alkyl esters; dibasic acid alkyl esters; acylated amino acids; pyrrolidone; pyrrolidone derivatives and combinations thereof. Additional types of solubility enhancers may include lactic acid, tartaric acid, 1,2,6-hexanetriol, benzyl alcohol, lanolin, potassium hydroxide (KOH), tris(hydroxymethyl)aminomethane, glycerol monooleate (GMO), monolaurate of sorbitan (SML), sorbitan monooleate (SMO), laureth-4 (HTL) and combinations thereof. In certain embodiments, the solubility absorption enhancer is levulinic acid, lauryl lactate or propylene glycomonolaurate.

[000109] The formulation of the object transdermal dexmedetomidine composition may vary. For example, the compositions of the invention may be in the form of a liquid solution or suspension, syrup, gel, foam or any combination thereof for application by the transdermal delivery device.

[000110] In some embodiments, the transdermal delivery device is configured to include a single single layer matrix dexmedetomidine composition. By "individual layer" it is meant that the transdermal delivery device includes only an individual layer of the dexmedetomidine composition disposed on the surface of a substrate of the transdermal delivery device and does not include separate distinct layers for the pressure sensitive adhesive, dexmedetomidine composition transdermally, or if present, any solubility enhancers. Likewise, the single-layer transdermal delivery devices of the present invention do not further include a separate dexmedetomidine reservoir (i.e., active agent reservoir) separate from the pressure-sensitive adhesive. Thus, the single-layer transdermal delivery devices of the present invention can include in an individual matrix an amount of each component of the transdermal dexmedetomidine compositions necessary for practicing the subject methods, as described in greater detail below. For example, in some embodiments, the transdermal delivery devices of interest include a single layer dexmedetomidine matrix and a pressure sensitive adhesive that is configured to deliver a non-sedating amount of dexmedetomidine to a subject. In another embodiment, the single-layer transdermal delivery devices of interest include a dexmedetomidine single-layer matrix, a pressure-sensitive adhesive, and a solubility enhancer that is configured to deliver a non-sedating amount of dexmedetomidine to a subject. In another embodiment, the single layer transdermal delivery devices of interest include a single layer dexmedetomidine matrix, a pressure sensitive adhesive and a fatty acid ester that is configured to deliver a non-sedating amount of dexmedetomidine to a subject. In certain embodiments, the single layer transdermal delivery devices of interest include a single matrix with dexmedetomidine alone and a pressure sensitive adhesive. Depending on the duration of the dosing interval and the desired target dosing, the thickness of the individual layer matrices of interest may vary, in some cases ranging in thickness from 10 to 260 microns, such as from 15 to 250 microns, from 25 to 225 microns , from 50 to 200 microns, from 75 to 175 microns and including from 20 to 130 microns, such as from 35 to 110 microns.

[000111] The size of the object transdermal delivery devices may vary, in some cases, to cover the entire application site on the subject. Thus, the transdermal delivery device can have a length ranging from 1 to 100 cm, such as from 1 to 60 cm, and a width ranging from 1 to 100 cm, such as from 1 to 60 cm. As such, the area of the transdermal delivery device can range from 4 cm2 to 10,000 cm2, such as from 5 cm2 to 1,000 cm2, such as from 10 cm2 to 100 cm2, such as from 15 cm2 to 50 cm2, and including from 20 cm2 to 40 cm2. . In certain embodiments, the transdermal delivery device is sized to have an area of 30 cm 2 . In certain instances, the transdermal delivery device is insoluble in water. By water-insoluble, it is meant that the transdermal delivery device can be immersed in water for a period of 1 day or more, such as 1 week or more, including 1 month or more, and exhibits little or no dissolution, e.g. , no observable dissolution.

[000112] In certain embodiments, the transdermal delivery device, as described above, further includes an overlying backing layer. The superimposed support can be flexible so that it can be placed in close contact with the desired application site on the subject. The overlay support can be manufactured from a material that does not absorb the dexmedetomidine and does not allow the dexmedetomidine to be leached from the matrix. Overlapping support layers of interest may include, but are not limited to, nonwovens, fabrics, films (including sheets), porous bodies, foam bodies, paper, composite materials obtained by laminating a film to a nonwoven or fabric, and combinations thereof. .

[000113] Non-woven fabric may include 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 copolymers and styrene-ethylene-propylene-styrene copolymers; and their combinations. Fabrics can include cotton, rayon, polyacrylic resins, polyester resins, polyvinyl alcohol and combinations thereof. Films can include 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; plus cellophane, polyvinyl alcohol, ethylene vinyl alcohol copolymers, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluororesins, styrene-isoprene-styrene copolymers, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymers, polyamide and polysulfone; and their combinations. Papers may include impregnated paper, coated paper, woodfree paper, Kraft paper, Japanese paper, crystal paper, synthetic paper and combinations thereof.

[000114] Depending on the dosage range and the desired target dosage, the size of the superimposed support can vary and, in some cases, it is sized to cover the entire application site on the subject. Thus, the support layer can have a length ranging from 2 to 100 cm, such as from 4 to 60 cm, and a width ranging from 2 to 100 cm, such as from 4 to 60 cm. In certain cases, the overlying backing layer may be insoluble in water. By water-insoluble, it is meant that the backing layer can be immersed in water for a period of 1 day or more, such as 1 week or more, including 1 month or more, and exhibits little or no dissolution, e.g. no observable dissolution.

[000115] Transdermal delivery devices with a dexmedetomidine composition, according to the embodiments of the invention, are non-irritating to the subject's skin at the site of application. Skin irritation is referred to in this document in its general sense as referring to adverse effects, discoloration or damage to the skin, such as, for example, redness, pain, swelling or dryness. As such, in practicing methods with the transdermal delivery devices to the subject, skin quality remains normal and transdermal delivery is consistent throughout the entire dosage range.

[000116] In some embodiments, skin irritation is assessed to determine the quality and color of the skin at the application site and to determine whether any damage, pain, swelling, or dryness resulted from keeping the transdermal composition in contact with the subject. The skin can be assessed for irritation by any convenient protocol, such as, for example, using the Draize scale, as disclosed 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 can be evaluated at the transdermal application site for erythema or edema. For example, degrees of erythema and edema can be assigned based on visual observation or palpation:

[000117] Erythema:0 = no visible redness; 1 = very slight redness (barely noticeable); 2 = mild but definite redness; 3 = moderately intense redness; 4 = severe erythema (dark red discoloration of the skin) 5 = scab formation

[000118] Edema:0 = no visible reaction or swelling; 1 = very mild edema (swelling barely perceptible); 2 = mild edema (corners of the area are well defined due to swelling); 3 = moderate edema (swelling up to 1 mm); 4 = severe edema (swelling of more than 1 mm).

[000119] The application site can be assessed for skin irritation at any time during subject methods. In some cases, the skin is assessed for irritation while keeping the transdermal delivery device in contact with the subject by observing or palpating the skin at regular intervals, e.g., every 0.25 hour, every 0.5 hour, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours including every 72 hours, or some other interval. For example, the application site can be assessed for skin irritation while keeping the transdermal delivery device in contact with the subject, such as 15 minutes after applying the transdermal delivery device to the subject, 30 minutes after applying the device transdermal delivery device, 1 hour after transdermal delivery device application, 2 hours after transdermal delivery device application, 4 hours after transdermal delivery device application, 8 hours after transdermal delivery device application, 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 transdermal delivery device, 80 hours after transdermal delivery device application, 84 hours after transdermal delivery device application, 96 hours after transdermal delivery device application, 120 hours after transdermal delivery device application, including 168 hours after application of the transdermal delivery device.

[000120] In other embodiments, the transdermal application site is assessed for skin irritation after the transdermal delivery device has been removed from contact with the subject. For example, the application site can be evaluated for skin irritation 30 minutes after removing the transdermal delivery device, such as 1 hour after removing the transdermal delivery device, such as 2 hours after removing the delivery device transdermal, such as 4 hours after removing the transdermal delivery device, such as 8 hours after removing the transdermal delivery device, such as 12 hours after removing the transdermal delivery device, such as 24 hours after removing the device transdermal delivery device, such as 48 hours after removal of the transdermal delivery device, including 72 hours after removal of the transdermal delivery device.

[000121] In some embodiments, the transdermal application site is assessed for skin irritation before the transdermal delivery device is applied to a subject, such as recording skin color and texture before initiating a dosing interval. For example, the application site can be assessed for skin irritation 5 minutes prior to application of the transdermal delivery device, such as 10 minutes, such as 30 minutes, such as 60 minutes, such as 120 minutes, such as 240 minutes , and including 480 minutes prior to application of the transdermal delivery device. Where methods include multiple dose ranges applied sequentially, the application site may be evaluated for skin irritation after each transdermal delivery device is removed and before the subsequent transdermal delivery device is applied. For example, when a first transdermal delivery device is removed, the application site can be evaluated for skin irritation 2 hours, 24 hours and 48 hours after removal and prior to application of a second transdermal delivery device. A subsequent transdermal delivery device can be applied to the previous application site immediately after evaluating the skin for irritation or can be applied after a predetermined time after evaluating the skin for irritation, such as 4 hours, 12 hours, 24 hours , 48 hours, 72 hours, 96 hours, 120 hours, 144 hours or 168 hours after skin assessment for irritation.

[000122] The application site can be evaluated for skin irritation one or more times before, during or after a dosing interval, such as 2 or more times, such as 3 or more times, including 5 or more times before, during or after a dosing interval. An upper limit to the number of times the application site can be assessed for skin irritation before, during, or after a dosing interval is, in some cases, 10 times or less, such as 7 times or less, such as 5 times or less, such as 3 times or less, and including 2 times or less. In certain embodiments, the number of times the application site can be assessed for skin irritation before, during, or after a dosing interval varies, such as from 2 times to 10 times, such as from 3 times to 9 times, such as from 4 times to 8 times, and including from 5 times to 7 times. In certain embodiments, skin irritation can be monitored the entire time the transdermal delivery device is maintained in contact with the subject, such as by video monitoring.

Kits

[000123] Kits for use in practicing certain methods described in this document are also provided. In certain embodiments, kits include one or more transdermal delivery devices containing a dexmedetomidine composition with an amount of dexmedetomidine and pressure sensitive adhesive, as described above. In certain embodiments, kits include an adhesive overlay, as described above. In a given kit that includes two or more of the transdermal subject delivery devices, the compositions may be packaged individually or presented within a common container.

[000124] In certain embodiments, kits will also include instructions for practicing the subject's methods or means of obtaining them (for example, a website URL that directs the user to a web page that provides instructions), where such instructions may be printed on a substrate, where the substrate may be one or more of: a package insert, the package, reagent containers and the like. In subject kits, the one or more components are present in the same or different containers, as may be convenient or desirable.

[000125] The following examples are offered by way of illustration and not by way of limitation. Specifically, the following examples are of specific embodiments for carrying out the present invention. The examples are presented for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with regard to the numbers used (eg amounts, temperature, etc.), but some experimental errors and deviations must, of course, be considered.

experiments Materials and methods Preparation of Exemplary Dexmedetomidine Transdermal Formulations

[000126] The formulations were prepared by mixing dexmedetomidine and a pressure-sensitive adhesive in organic solvents (for example, 30-60% by weight of solids content in ethyl acetate, isopropyl alcohol, hexane or heptane), followed by mixing . Once a homogeneous mixture was formed, the solution was cast onto a non-stick paper (polyester sheets coated with 2-3 mils siliconised polyester or fluoropolymer) and dried at 60o - 80oC for 10-90 minutes. The single layer adhesive films were then laminated onto a PET backing, cut to the desired size, and bagged. In some cases, cross-linked polyvinylpyrrolidone (PVP-CLM), polyvinylpyrrolidone K90 (PVP K90), levulinic acid (LA), oleic acid (OA), lauryl lactate (LL), and propylene glycol monolaurate (PGML) were added to the adhesive composition. Transdermal Flow Tests

[000127] Human cadaver skin was used and the epidermal layers (stratum corneum and viable epidermis) were separated from the full thickness skin as a skin membrane. The samples were die cut with an arc punch to a final diameter of about 2.0 cm 2 . The release paper was removed and the patch was placed on top of the epidermis/stratum corneum with the dexmedetomidine adhesive layer facing the outer surface of the stratum corneum. Light pressure was applied to achieve good contact between the adhesive layer and the stratum corneum. The donor and recipient sides of the Franz cell were clamped and the recipient solution containing a pH 6.5 phosphate buffer and 0.01% gentamicin was added to the Franz cell. Cells were kept at 32oC -35oC for the duration of the experiment. Samples of the receptor solution were taken at regular intervals and the active agent concentration was measured by HPLC. The removed receiver solution was replaced with fresh solution to maintain immersion conditions. Flux was calculated from the slope of the graph of the cumulative amount of drug permeated into the receptor compartment versus time.

Examples Example 1 In-vitro flux obtained from dexmedetomidine transdermal composition formulations in PIB/PB polymers

[000128] The pressure sensitive adhesives used in this example are polyisobutylene/polybutene (PIB/PB) adhesives. PIB/PB adhesives are blends of high molecular weight PIB (5% Oppanol B100), low molecular weight PIB (25% Oppanol B12) and a polybutene bonding agent, e.g. Indopol H1900 or Panalane H- 300e (20%) in organic solvent, eg heptane (50%). The combination was mixed for about 3 days, until the mixture was homogeneous. Exemplary dexmedetomidine transdermal composition formulations are shown in Tables 1 and 2.

[000129] An in-vitro skin flux study was performed as described above with the transdermal delivery devices with different concentrations of dexmedetomidine as shown in Table 1. The mean in-vitro skin flux of dexmedetomidine versus time is illustrated in Figure 1. As depicted in Figure 1, the in-vitro skin flux of dexmedetomidine was high in the initial hours in the case of 1% formulation (Formulation 1) compared to higher drug loading (Formulations 2 and 3). Formulations 2 and 3 were found to have needle-like crystals of dexmedetomidine and therefore the flux profile is constant and does not change with drug loading. However, no crystals were observed in Formulation 1. Formulation 1 includes a saturated or supersaturated amount of dexmedetomidine.

[000130] The transdermal formulation of dexmedetomidine was also made using PIB made from Indopol H1900, as shown in Table 2. The results of in-vitro permeation of 1% dexmedetomidine from the dexmedetomidine formulation made with 20% ePVP-CLM in the patch of PIB/PB (Formulation 4) across skin having different skin permeabilities are illustrated in Figure 2. Figure 2(A) shows the cumulative amount of dexmedetomidine delivered over time. The in-vitro permeation of dexmedetomidine was skewed depending on skin permeability. The delivered amount of dexmedetomidine in-vitro could range from 4-35 ug/cm 2 at 8 hours and 15-67 ug/cm 2 at 24 hours. Figure 2(B) shows the flux or derivative of the cumulative amount of drug delivered over time. The rate of delivery of dexmedetomidine from Formulation 2 peaked at about 5-7 hours, then remained constant for at least 24 hours. In the case of highly permeable skin (Skin #14), the flow may be reduced due to depletion. Figure 2(C) shows the % of drug remaining in the patch over time. As depicted in Figure 2(C), the utilization of dexmedetomidine obtained from Formulation 4 was 20-70% after application of the patch for 24 h.Table 1 Table 2

Example 2 In-vitro flux obtained from dexmedetomidine transdermal composition formulations in non-functionalized acrylate polymers

[000131] The in-vitro flux of dexmedetomidine was measured using non-functionalized acrylate adhesive. An example of an experimentally used non-functionalized acrylate adhesive includes Duro-Tak 87-9301 non-functionalized acrylate polymer. An in-vitro skin flux study was performed as described above with transdermal delivery devices with different concentrations of dexmedetomidine in non-functional Duro-Tak 87-9301. Dexmedetomidine transdermal composition formulations are shown in Table 3. Mean in-vitro dexmedetomidine flux versus time is illustrated in Figure 3. As depicted in Figure 3, a higher dexmedetomidine load generated an in-vitro skin flux increased. Table 3

Example 3 In-vitro flux obtained from dexmedetomidine transdermal composition formulations in functionalized hydroxyl acrylate (-OH) polymers

[000132] The in-vitro flux of dexmedetomidine was measured using functionalized hydroxyl acrylate (-OH) patches. Examples of an experimentally used hydroxyl functionalized acrylate adhesive include hydroxyl functionalized acrylate polymers, e.g. Duro-Tak 87-4287, Duro-Tak 387/87-2510, Duro-Tak 387/87-2287 and Duro-Tak 387/87-2516. An in-vitro skin flux study was performed as described above with transdermal delivery devices with different concentrations of dexmedetomidine with different hydroxyl-functionalized acrylate adhesives.

[000133] Tables 4 and 5 show the formulations of the dexmedetomidine transdermal composition with different concentrations of dexmedetomidine in Duro-Tak 87-4287 (acrylate-vinyl acetate polymer) or Duro-Tak 387/87-2510 (acrylate-vinyl acetate polymer) ). Mean in-vitro fluxes of dexmedetomidine are illustrated in Figures 4 and 5. As depicted in Figures 4 and 5, the in-vitro flux of dexmedetomidine increased with dexmedetomidine loading in the formulation. Table 4 Table 5

[000134] Table 6 shows dexmedetomidine transdermal composition formulations containing 1% dexmedetomidine in other hydroxyl-functionalized acrylate polymers containing vinyl acetate, for example, Duro-Tak 87-2287 (no additional cross-linking polymer) and Duro -Tak 87-2516 (crosslinking polymer added). The in-vitro fluxes of dexmedetomidine are illustrated in Figure 6. As depicted in Figure 6, the in-vitro flux obtained by Duro-Tak 387/87-2287 was slightly higher than that obtained by Duro-Tak 387/87-2516, possibly resulting from the higher adhesion properties of Duro-Tak 387/87-2287 compared to Duro-Tak 387/87-2516.Table 6

Example 4 In-vitro flux obtained from formulations of the 1% dexmedetomidine transdermal composition in non-functionalized acrylate or hydroxyl (-OH) functionalized polymers

[000135] Another exemplary set of dexmedetomidine transdermal formulations are transdermal compositions that include 1% w/w dexmedetomidine with non-functionalized acrylate polymer (Duro-Tak 87-9301, Formulation 5), hydroxyl-functionalized acrylate polymer ( Duro-Tak 387/87-2510, Formulation 11) and hydroxyl-functionalized acrylate polymer containing vinyl acetate (Duro-Tak 87-4287, Formulation 8). The in-vitro flow experiments were performed for 3 days and 1 day and the results are shown in Figure 7A and 7B, respectively. As depicted in both Figures 7A and 7B, the in-vitro flux of dexmedetomidine was lower in non-functional patches compared to hydroxyl-functionalized patches with the same drug loading.

Example 5 In-vitro flux obtained from dexmedetomidine transdermal composition formulations in acid-functionalized (-COOH) or acid/hydroxyl-functionalized (-COOH/OH) acrylate polymers

[000136] The in-vitro flux of dexmedetomidine was measured using acid-functionalized (-COOH) or acid/hydroxyl-functionalized (-COOH/OH) acrylate adhesives. Examples of functionalized acid acrylate (-COOH) adhesive used in this study is Duro-Tak 387/87-2353 (no acrylate crosslinking polymer added). The acid/hydroxyl (-COOH/OH) functionalized acrylate adhesive used in this study is Duro-Tak 87-2979 (acrylate-added vinyl acetate crosslinking polymer).

[000137] Tables 7 and 8 show the formulations of the transdermal composition of dexmedetomidine with different polymers of acrylate acid (-COOH) functionalized or functionalized with acid/hydroxyl (-COOH/OH). The concentration of dexmedetomidine in the formulations was selected based on the solubility of dexmedetomidine in each patch. The solubility of dexmedetomidine in Duro-Tak 387/87-2353 was found to be about 1015%, while that in Duro-Tak 87-2979 was found to be about less than 2%. Drug solubility in acid-functionalized acrylate adhesives was greater than in non-functionalized or hydroxyl-functionalized acrylate adhesives.

[000138] The in-vitro skin flow study was performed as described above. Mean in-vitro dexmedetomidine fluxes are illustrated in Figures 8 and 9. Table 7 Table 8

Example 6 In-vitro flux obtained from dexmedetomidine transdermal composition formulations in PIB/PB polymers containing PVP-CLM and Duro-Tak 387/87-2353

[000139] Another example of formulating the transdermal composition of dexmedetomidine is shown in Table 9. In order to increase the solubility of the drug in the PIB/PB patch (for example, Indopol H-1900), PVP-CLM and polymer of (-COOH) functionalized acid acrylate (Duro-Tak 387/87-2353). Formulations 18 to 21 were prepared with different loadings of Duro-Tak 387/87-2353.

[000140] As shown in Figure 10, Formulations containing acid acrylate polymer (-COOH) functionalized (Duro-Tak 387/87-2353), Formulations 19, 20 and 21, seem to have a lower initial flux compared to Formulations without Duro-Tak 2353 (Formulation 18). The in-vitro flux of dexmedetomidine did not change with 3% and 6% acid-functionalized adhesive, however, at 9% acid-functionalized adhesive, a slight decrease in in-vitro flux was observed.Table 9

Example 7 In-vitro flux obtained from dexmedetomidine transdermal composition formulations in PIB/PB polymers containing PVP-CLM and levulinic acid

[000141] Another example of dexmedetomidine transdermal composition formulation is shown in Table 10. In order to increase the solubility of the drug in the PIB/PB patch (eg Indopol H-1900) in the presence of 20% PVP-CLM , various acid concentrations were used to test the increased solubility of dexmedetomidine. Formulations 22 to 25 were prepared with different loadings of levulinic acid.Table 10

[000142] As depicted in Figure 11, the in-vitro flux of dexmedetomidine was dramatically reduced when the formulation included 6.9% levulinic acid. However, at a concentration of 1.75% levulinic acid, the in-vitro flux was comparable to lower concentrations of levulinic acid (ie, 0.6% and 0.9%). The initial flux obtained from the formulations containing levulinic acid (Formulation 22, 23, 24 and 25) was lower than that of the formulation without levulinic acid (Formulation 18). However, after 24 hours, the flux obtained from the formulations containing levulinic acid (Formulations 22, 23, 24 and 25) appears to be greater than that of the formulation without levulinic acid (Formulation 17). Dexmedetomidine crystals have been observed at levulinic acid concentrations of 1.75% and less.

Example 8 In-vitro flux obtained from dexmedetomidine transdermal composition formulations in PIB/PB polymers containing PVP-CLM and lauryl lactate or propylene glycomonolaurate

[000143] Another example of dexmedetomidine transdermal composition formulations are shown in Tables 11 and 12. Dexmedetomidine has a solubility of 5 to 10% in lauryl lactate and propylene glycomonolaurate. Each of lauryl lactate and propylene glycomonolaurate increases the solubility of dexmedetomidine in the PIB/PB adhesive in the subject formulations. The in-vitro flow profiles of Formulations 26 to 28 are shown in Figure 12. The in-vitro flow profiles of Formulations 29 to 31 are shown in Figure 13. Formulations 26 to 31 were found to have similar dexmedetomidine crystals the needle. Table 11 Table 12

Example 9 In-vitro flux obtained from formulations of the dexmedetomidine transdermal composition in polymers of Duro-Tak 387/872287 containing levulinic acid, PVP K90 or Duro-Tak 387/87-2353

[000144] Another set of examples of the transdermal formulation of dexmedetomidine includes transdermal compositions with 1% w/w of dexmedetomidine with a solubilizer to improve the physical stability of the composition. In these formulations, levulinic acid, PVP K90 and Duro-Tak 87-2353 were used. The formulation compositions are shown in Tables 13, 14 and 15. The in-vitro flux profiles for the 1% dexmedetomidine transdermal compositions with 0.3% and 0.6% levulinic acid are shown in Figure 14(A ). The in-vitro flux profiles for the 1% dexmedetomidine transdermal compositions with 5% and 10% PVP K90 are shown in Figure 14(B). The in-vitro flux profiles for the 1% dexmedetomidine transdermal compositions 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 application for 15 hours, PVP K90 delayed the transdermal flux of dexmedetomidine, while Duro-Tak 2353 slightly reduced the transdermal flux.Table 13 Table 14 Table 15

Example 10 In-vitro flux obtained from formulations of the transdermal composition of dexmedetomidine in polymers of Duro-Tak 387/879301 containing levulinic acid, oleic acid or Duro-Tak 387/87-2353

[000145] Another set of examples of dexmedetomidine transdermal formulation includes transdermal compositions with 3% w/w of dexmedetomidine and Duro-Tak 87-9301 non-functionalized acrylate polymer in combination with 3.3% levulinic acid, 5% of oleic acid or 15% Duro-Tak 387/87-2353. Formulation compositions are shown in Table 16. In-vitro flux profiles for these formulations (Formulations 38, 39 and 40) compared to 3% dexmedetomidine in non-functionalized acrylate polymer of Duro-Tak 87-9301 without additive (Formulation 7) are illustrated in Figure 15. Compositions with only 3% dexmedetomidine and Duro-Tak 87-9301 non-functionalized acrylate polymer were supersaturated. Levulinic acid and oleic acid were used as a solubilizer and permeation enhancer. and higher flow at the beginning of the in-vitro flow, but decreasing with time. As with the 1% dexmedetomidine compositions, Duro-Tak 87-2353 reduced flow.Table 16

Example 11 In-vitro permeation of dexmedetomidine obtained from 1%, 2%, 3% and 4% dexmedetomidine in the patch mix (15% Duro-Tak2353 in Duro-Tak 2287)

[000146] Dexmedetomidine transdermal composition formulations containing the mixture of hydroxyl-functionalized acrylate polymer (for example, Duro-Tak 87-2287) and acid-functionalized acrylate polymer (for example, Duro-Tak 87-2353) are summarized in Table 17. Formulations 41 to 44 were prepared with different loadings of dexmedetomidine. Table 17

[000147] As depicted in Figure 16, the in-vitro flux of dexmedetomidine increased with increasing percentage of dexmedetomidine load.

Example 12 In-vitro permeation of dexmedetomidine obtained from dexmedetomidine formulations containing oleic acid

[000148] Another example of dexmedetomidine transdermal composition formulations is summarized in Table 18. In order to increase the solubility of dexmedetomidine in hydroxyl-functionalized acrylate polymer (eg Duro-Tak 87-2287), oleic acid was used. Formulations 45 to 47 were prepared with different loadings of oleic acid and dexmedetomidine.Table 18

[000149] As depicted in Figure 17, dexmedetomidine in formulations containing oleic acid has a greater flux than a dexmedetomidine composition (eg, Formulation 43) that does not contain oleic acid. Oleic acid increased the permeation of dexmedetomidine through the skin. An increase in oleic acid from 5% to 7% (eg, Formulation 46) did not show an enhancing effect compared to the formulation containing 5% oleic acid (eg, Formulation 45). This may be the result of the contribution of oleic acid to increasing the solubility of dexmedetomidine in the composition. A comparison of Formulation 45 and Formulation 47 shows that the in-vitro flux increases with increasing percent drug loading.

Example 13 In-vitro permeation of dexmedetomidine obtained from dexmedetomidine formulations containing levulinic acid

[000150] Dexmedetomidine transdermal formulations were also prepared with levulinic acid. The composition is shown in Table 19.Table 19

[000151] As shown in Figure 18, the in-vitro flux of dexmedetomidine in formulations containing levulinic acid (Formulations 48 and 49) increased with the percentage of dexmedetomidine loading. The effect of increasing levulinic acid on the permeation of dexmedetomidine through the skin was greater than that of oleic acid.

[000152] The results of the percentage of in-vitro penetration of dexmedetomidine in Formulations 43, 45 and 48 in relation to the amount of dexmedetomidine in the patch are summarized in Table 20. Formulations 45 and 48, which contain levulinic acid and oleic acid, demonstrate a substantial improvement in the permeation of dexmedetomidine under in-vitro conditions.Table 20

[000153] The solubility of dexmedetomidine in the hydroxyl-functionalized acrylate polymer was less than 1%. In order to increase dexmedetomidine, an acid-functionalized acrylate polymer (eg Duro-Tak2353), oleic acid and levulinic acid were used. The solubility of dexmedetomidine in Duro-Tak2353, oleic acid and levulinic acid was around 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.

[000154] After preparation, the presence of crystal was examined using a microscope. The results obtained from this microscopic examination indicated that all formulations (Formulations 41 to 48) did not contain crystals.

[000155] The flux profile of all formulations (Formulations 41 to 48) showed a clear increasing trend in flux with time during the first 24 hours (Figures 16 to 18). This is followed by a gradual decrease in flow over time. As such, the increase in flow during the first 24 hours can, in certain cases, be helpful in rapidly achieving a higher initial therapeutic concentration in the body. Whenever there is a decrease in flux with time, the decrease in flux may be due to crystallization of the drug in the patch induced by water absorbed into the patch.

Example 14 In-vitro flow obtained from different supports

[000156] The pressure sensitive adhesives used in this example are polyisobutylene/polybutene (PIB/PB) adhesives. PIB/PB adhesives are blends of high molecular weight PIB (5% Oppanol B100), low molecular weight PIB (25% Oppanol B12) and a polybutene bonding agent, e.g. Indopol H1900 or Panalane H- 300e (20%), in an organic solvent, e.g. heptane (50%). The combination was mixed for about 3 days, until the mixture was homogeneous. Exemplary dexmedetomidine transdermal composition formulations are shown in Table 21. The same formulation was coated on release paper but laminated with three different backing materials: backing 1 has an MVTR value (g/m2/24hr) around 10 , support 2 has an MVTR value around 50 (g/m2/24hr), and support 3 has an MVTR value around 150(g/m2/24hr).

[000157] The mean in-vitro skin flux of dexmedetomidine over time is illustrated in Figure 19. As depicted in Figure 19, the in-vitro skin flux of dexmedetomidine was similar for strut 1 and 2. But it is significantly smaller with support 3. Table 21

Example 15 In-vitro flux obtained from formulations with lauryl lactate as a potentiator

[000158] Another set of examples of dexmedetomidine transdermal formulation includes transdermal compositions with 2-4% w/w of dexmedetomidine with an enhancer to improve skin permeability. In these formulations, lauryl lactate (LL) and Duro-Tak 87-2287 were used. Formulation compositions are shown in Table 22. In-vitro flux profiles for transdermal compositions. Figures 20 and 21 show the flux in two different skin samples. By in-vitro flux profiles, LL shows its skin permeability enhancing effect. The flow is also proportional to the API load.Table 22

[000159] Despite the attached clauses, the disclosure established in this document is also defined by the following clauses: 1. Method of controlling pain in a subject, the method comprises the application to a surface of the skin of a subject suffering pain from a transdermal delivery device comprising: a dexmedetomidine composition, the dexmedetomidine composition comprising: dexmedetomidine; and a pressure sensitive adhesive; and a backing layer, wherein the dexmedetomidine composition is formulated to deliver an effective pain-relieving amount of dexmedetomidine to the subject. 2. Method in accordance with clause 1, wherein the pain is selected from the group consisting of idiopathic pain, acute pain, sympathetic nervous system mediated pain, complex regional pain and neuropathic pain and combinations thereof. 3. Method according to clause 2, wherein the pain is neuropathic pain. 4. Method according to clause 3, in which the neuropathic pain is associated with the sympathetic nervous system. 5. Method in accordance with clause 3, wherein neuropathic pain is selected from the group consisting of cancer pain, postoperative pain, pain associated with an infection, pain associated with herpes zoster infection and pain associated with HIV infection. 6. The method of clause 5, wherein the method comprises delivering a non-sedating amount of the dexmedetomidine to the subject. 7. The method of clause 6, wherein the method comprises delivering a non-sedating amount of the dexmedetomidine to the subject. 8. The method of any one of clauses 6 or 7, wherein the method comprises delivering a non-sedating amount of the dexmedetomidine to the subject for 1 day or more. 9. The method of clause 8, wherein the method comprises delivering a non-sedating amount of the dexmedetomidine to the subject for 3 days or longer. 10. The method of clause 9, wherein the method comprises delivering a non-sedating amount of the dexmedetomidine to the subject for 7 days or longer. 11. Method according to any one of clauses 6 to 10, wherein the method comprises dispensing a non-sedating amount of the dexmedetomidine to the subject in a manner sufficient to maintain the Ramsay Scale of no greater than 3 in the subject. 12. The method of clause 11, wherein the method comprises dispensing a non-sedating amount of dexmedetomidine to the subject in a manner sufficient to maintain the Ramsay Scale no greater than 2 in the subject. 13. The method of clause 1, wherein the method comprises delivering a sedative amount of dexmedetomidine to the subject. 14. Method according to clause 1, in which the subject is alert and able to respond to oral commands. 15. The method of clause 1, wherein the method comprises delivering dexmedetomidine to the subject with the transdermal delivery device at a rate ranging from about 5 µg/day to about 500 µg/day. 16. The method of clause 15, wherein the method comprises delivering dexmedetomidine to the subject with the transdermal delivery device at a rate ranging from about 145 µg/day to about 300 µg/day. 17. The method of clause 1, wherein the method comprises delivering dexmedetomidine to the subject in a manner sufficient to maintain an average plasma concentration of the dexmedetomidine in the subject from about 0.01 ng/mL to about 0. 4 ng/mL. 18. The method of clause 1, wherein the method further comprises co-administering to a subject a compound selected from the group consisting of analgesics, anesthetics, antidepressants, anticonvulsants, topical agents, cannabinoids, N-methyl- D-Aspartate and neuromodulators and combinations thereof. 19. The method of clause 18, wherein the method further comprises co-administering an analgesic to a subject. 20. Method according to clause 19, wherein the analgesic is an opioid. 21. Method according to clause 18, wherein the co-administered compound is formulated into the dexmedetomidine composition. 22. The method of clause 1, wherein the pressure sensitive adhesive comprises a vinyl polymer. 23. Method according to clause 22, wherein the vinyl polymer is selected from the group consisting of polyethylene, polypropylene, polyisobutylene, polybutene, polystyrene, polyvinyl chloride, polyvinyl acetate, polyvinyl alcohol, and organosilicones and combinations of the same. 24. The method of clause 22, wherein the pressure sensitive adhesive comprises polyisobutylene or polybutene and combinations thereof. 25. The method of clause 24, wherein the pressure sensitive adhesive comprises saturated polybutene. 26. The method of clause 24, wherein the pressure sensitive adhesive comprises unsaturated polybutene. 27. The method of clause 1, wherein the pressure sensitive adhesive comprises an acrylic polymer, acrylate copolymer, acrylate-vinyl acetate copolymer or polyacrylonitrile. 28. The method of clause 1, wherein the pressure sensitive adhesive comprises a non-functionalized polymer. 29. The method of clause 28, wherein the pressure sensitive adhesive comprises a non-functionalized acrylate polymer. 30. The method of clause 1, wherein the pressure sensitive adhesive comprises a carboxylic acid or hydroxyl functionalized polymer. 31. The method of clause 30, wherein the pressure sensitive adhesive comprises a carboxylic acid functionalized polymer. 32. The method of clause 31, wherein the pressure sensitive adhesive comprises a carboxylic acid functionalized acrylate polymer. 33. The method of clause 39, wherein the pressure sensitive adhesive comprises a hydroxyl functionalized polymer. 34. The method of clause 33, wherein the pressure sensitive adhesive comprises a hydroxyl functionalized acrylate polymer. 35. The method of clause 1, wherein the pressure sensitive adhesive comprises a mixture of a hydroxyl functionalized polymer and a carboxylic acid functionalized polymer. 36. The method of clause 35, wherein the pressure sensitive adhesive comprises a blend of hydroxyl functionalized acrylate polymer and a carboxylic acid functionalized acrylate polymer. 37. Method according to clause 1, wherein the pressure sensitive adhesive is substantially the same as or is selected from the group consisting of Duro-Tak® 87-9301, Duro-Tak®87-2353, Duro-Tak®87- 2510, Duro-Tak®87-2516 and 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. 38. The method of clause 1, wherein the pressure sensitive adhesive comprises crosslinked polyvinylpyrrolidone or crosslinked polyacrylic acid or combinations thereof. 39. The method of clause 1, wherein the transdermal delivery device comprises a single layer matrix comprising the dexmedetomidine composition, the single layer matrix being formulated to deliver a non-sedating amount of dexmedetomidine to the subject. 40. The method of clause 1, wherein the transdermal delivery device is configured to deliver 30% or more of the dexmedetomidine in the dexmedetomidine composition. 41. The method of clause 1, wherein the transdermal delivery device is configured to deliver 50% or more of the dexmedetomidine in the dexmedetomidine composition. 42. The method of clause 1, wherein the amount of dexmedetomidine in the composition is 3% w/w or less. 43. The method of clause 1, wherein the dexmedetomidine composition consists of the dexmedetomidine and the pressure sensitive adhesive. 44. Transdermal delivery device for controlling pain in a subject, the transdermal delivery device comprising: a dexmedetomidine composition formulated to deliver a pain relieving effective amount of dexmedetomidine to a subject, wherein the dexmedetomidine composition comprises: dexmedetomidine ; and a pressure sensitive adhesive; and a backing layer. 45. The transdermal delivery device of clause 44, wherein the dexmedetomidine composition is formulated to deliver dexmedetomidine to a subject for 6 hours or longer. 46. The transdermal delivery device of clause 45, wherein the dexmedetomidine composition is formulated to deliver dexmedetomidine to a subject for 1 day or longer. 47. The transdermal delivery device of clause 46, wherein the dexmedetomidine composition is formulated to deliver dexmedetomidine to a subject for 7 days or longer. 48. The transdermal delivery device of clause 44, wherein the amount of dexmedetomidine in the composition is 20% w/w or less. 49. The transdermal delivery device of clause 48, wherein the amount of dexmedetomidine in the composition is 10% w/w or less. 50. The transdermal delivery device of clause 44, wherein the dexmedetomidine composition comprises a saturated amount of dexmedetomidine. 51. The transdermal delivery device of clause 44, wherein the dexmedetomidine composition comprises a supersaturated amount of dexmedetomidine. 52. The transdermal delivery device of clause 44, wherein the transdermal delivery device is configured to deliver a non-sedating amount of dexmedetomidine to a subject at a rate ranging from about 10 µg/day to about 1000 µg /day. 53. The transdermal delivery device of clause 52, wherein the transdermal delivery device is configured to deliver a non-sedating amount of dexmedetomidine to a subject at a rate ranging from about 145 µg/day to about 300 µg /day. 54. The transdermal delivery device of clause 44, wherein the transdermal delivery device is configured to deliver dexmedetomidine in a manner sufficient to maintain an average plasma concentration of dexmedetomidine in a subject of about 0.01 ng/ mL to about 0.4 ng/mL. 55. The transdermal delivery device of clause 44, wherein the transdermal delivery device is configured to deliver a non-sedating amount of dexmedetomidine to a subject. 56. The transdermal delivery device of clause 55, wherein the transdermal delivery device is configured to deliver dexmedetomidine to a subject in a manner sufficient to maintain an assignment of a Ramsay Scale of no greater than 2 or 3 on the subject. 57. The transdermal delivery device of clause 56, wherein the transdermal delivery device is configured to deliver dexmedetomidine to a subject in a manner sufficient to maintain an assignment of a Ramsay Scale of no greater than 2. 58. Transdermal delivery device according to clause 56, wherein the transdermal delivery device is configured to deliver dexmedetomidine to a subject in a manner sufficient to maintain an assignment of a Ramsay Scale of no greater than 3. 59. Delivery Device transdermal delivery device according to clause 56, wherein the transdermal delivery device is configured to deliver a sedative amount of dexmedetomidine to a subject 60. Transdermal delivery device according to clause 44, wherein the transdermal delivery device is configured to deliver 30% or more of the dexmedetomidine to the subject over an extended period of time. 61. The transdermal delivery device of clause 44, wherein the transdermal delivery device is configured to deliver 90% or more of the dexmedetomidine to the subject over an extended period of time. 62. The transdermal delivery device of clause 44, wherein the pressure sensitive adhesive comprises a vinyl polymer. 63. Transdermal delivery device according to clause 62, wherein the vinyl polymer is selected from the group consisting of polyethylene, polypropylene, polyisobutylene, polybutene, polystyrene, polyvinyl chloride, polyvinyl acetate, polyvinyl alcohol, and organosilicones. 64. The transdermal delivery device of clause 63, wherein the pressure sensitive adhesive comprises polyisobutylene or polybutene and combinations thereof. 65. The transdermal delivery device of clause 64, wherein the pressure sensitive adhesive comprises saturated polybutene. 66. The transdermal delivery device of clause 64, wherein the pressure sensitive adhesive comprises unsaturated polybutene. 67. The transdermal delivery device of clause 44, wherein the pressure sensitive adhesive comprises an acrylic polymer, acrylate copolymer, acrylate vinyl acetate copolymer or polyacrylonitrile or a mixture thereof. 68. The transdermal delivery device of clause 67, wherein the pressure sensitive adhesive comprises a non-functionalized polymer. 69. The transdermal delivery device of clause 68, wherein the pressure sensitive adhesive comprises a non-functionalized acrylate polymer. 70. The transdermal delivery device of clause 67, wherein the pressure sensitive adhesive comprises a carboxylic acid or hydroxyl functionalized polymer or combinations thereof. 71. The transdermal delivery device of clause 70, wherein the pressure sensitive adhesive comprises a carboxylic acid functionalized polymer. 72. The transdermal delivery device of clause 71, wherein the pressure sensitive adhesive comprises a carboxylic acid functionalized acrylate polymer. 73. The transdermal delivery device of clause 70, wherein the pressure sensitive adhesive comprises a hydroxyl functionalized polymer. 74. The transdermal delivery device of clause 73, wherein the pressure sensitive adhesive comprises a hydroxyl functionalized acrylate polymer. 75. The transdermal delivery device of clause 67, wherein the pressure sensitive adhesive comprises a mixture of a hydroxyl functionalized polymer and a carboxylic acid functionalized polymer. 76. The transdermal delivery device of clause 67, wherein the pressure sensitive adhesive comprises a mixture of a hydroxyl functionalized acrylate polymer and a carboxylic acid functionalized acrylate polymer. 77. Transdermal delivery device according to clause 44, wherein the pressure sensitive adhesive is substantially the same as or is selected from the group consisting of Duro-Tak® 87-9301, Duro-Tak®87-2353, Duro-Tak ®87-2510, Duro-Tak®87-2516, Duro-Tak®87-4287, Duro-Tak®87-2287, 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. 78. Transdermal delivery device according to clause 44, wherein the pressure sensitive adhesive comprises crosslinked polyvinylpyrrolidone or crosslinked polyacrylic acid. 79. Transdermal delivery device according to clause 44, wherein the dexmedetomidine composition comprises polyvinylpyrrolidone, PVP K90, levulinic acid, oleic acid, PGML, lauryl lactate or mixtures thereof. 80. The transdermal delivery device of clause 44, wherein the transdermal delivery device comprises a single layer matrix dexmedetomidine composition. 81. The transdermal delivery device of clause 44, wherein the dexmedetomidine composition consists of dexmedetomidine and the pressure sensitive adhesive. 82. A kit comprising: two or more transdermal delivery devices, each transdermal delivery device comprising: a dexmedetomidine composition formulated to deliver a pain-relieving effective amount of dexmedetomidine to a subject, the dexmedetomidine composition comprising: dexmedetomidine ; and a pressure sensitive adhesive; and a backing layer.

[000160] Although the invention set out above has been described in detail by way of illustration and example for the purpose of clarity of understanding, it is readily apparent to those skilled in the art in light of the teachings of this invention that certain changes and modifications can be made without deviating the spirit or scope of the appended claims.

[000161] In this sense, the above merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. In addition, all examples and conditional language reported herein are intended primarily to assist the reader in understanding the principles of the invention and concepts contributed by the inventors to further the art, and are to be construed as being without limitation to such specifically reported examples and conditions. Furthermore, all statements in this document relating to principles, aspects and embodiments of the invention, as well as specific examples thereof, are intended to cover their structural and functional equivalents. Furthermore, such equivalents are intended to include both currently known equivalents and future developed equivalents, that is, any developed elements that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention are embodied by the appended claims.

Claims (18)

1. Use of a dexmedetomidine composition, characterized in that it is in the preparation of a transdermal delivery device configured to passively deliver a therapeutically effective amount of dexmedetomidine to control pain in a subject, wherein the transdermal delivery device comprises: a dexmedetomidine composition, wherein the dexmedetomidine composition comprises: dexmedetomidine in an amount of 0.1% w/w to 10% w/w; a solubility enhancer in an amount of 0.1% w/w to 10% w/w, a pressure sensitive adhesive; and a backing layer in contact with the dexmedetomidine composition, the dexmedetomidine composition being formulated to passively deliver an effective pain-relieving amount of dexmedetomidine to the subject. 2. Use according to claim 1, characterized in that the pain is selected from the group consisting of idiopathic pain, acute pain, pain mediated by the sympathetic nervous system, complex regional pain and neuropathic pain and combinations thereof . 3. Use according to claim 2, characterized in that the pain is neuropathic pain. 4. Use according to claim 3, characterized by the fact that neuropathic pain is associated with the sympathetic nervous system. 5. Use according to claim 3, characterized in that neuropathic pain is selected from the group consisting of cancer pain, postoperative pain, pain associated with an infection, pain associated with herpes- zoster and pain associated with HIV infection. 6. Use according to claim 1, characterized in that it is configured to passively deliver a non-sedating amount of dexmedetomidine to the subject. 7. Use according to claim 6, characterized in that it is configured to passively deliver a non-sedating amount of dexmedetomidine to the subject for 1 day or more. 8. Use according to claim 7, characterized in that it is configured to passively deliver a non-sedating amount of dexmedetomidine to the subject for 3 days or more. 9. Use according to claim 8, characterized in that it is configured to passively deliver a non-sedating amount of dexmedetomidine to the subject for 7 days or more. 10. Use according to any one of claims 6 to 9, characterized in that it is configured to passively deliver a non-sedating amount of dexmedetomidine to the subject in a manner sufficient to maintain the Ramsay Scale no greater than 3 in the subject . 11. Use according to claim 1, characterized in that it is configured to passively deliver a sedative amount of dexmedetomidine to the subject. 12. Use according to claim 1, characterized in that it is configured to passively deliver dexmedetomidine to the subject with the transdermal delivery device at a rate ranging from 5 μg/day to 500 μg/day. 13. Use according to claim 1, characterized in that the pressure-sensitive adhesive comprises a vinyl polymer. 14. Use, according to claim 1, characterized in that the solubility enhancer is a compound selected from the group consisting of lauryl lactate, propylene glycol monolaurate, linolic acid, oleic acid, linolenic acid, stearic acid, isosteric acid, levulinic acid, palmitic acid, octanoic acid, de-canoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, stearic acid, N-lauroyl sarcosine, L-pyroglutamic acid, lauric acid, succinic acid, pyruvic acid, glutaric acid , sebacic acid and cyclopentane carboxylic acid. 15. Use according to claim 14, characterized in that the compound is lauryl lactate. 16. Use according to claim 14, characterized in that the compound is levulinic acid. 17. Use according to claim 1, characterized in that the pressure-sensitive adhesive is an acrylate pressure-sensitive adhesive with pendant hydroxyl functional groups. 18. Use according to any one of claims 1 to 17, characterized in that dexmedetomidine is present in the composition in an amount of 2% w/w to 3% w/w and the solubility enhancer is present in the composition in an amount from 1% w/w to 5% w/w.