WO2008115590A1

WO2008115590A1 - Apparatus and method for transdermal delivery of a benzodiazepine

Info

Publication number: WO2008115590A1
Application number: PCT/US2008/003781
Authority: WO
Inventors: Frank Stonebanks
Original assignee: Alza Corporation
Priority date: 2007-03-21
Filing date: 2008-03-20
Publication date: 2008-09-25

Abstract

An apparatus and a method for transdermally delivering at least one compound from the benzodiazepine family ('benzodiazepine') is described. The apparatus includes a microprojection member having a plurality of skin-piercing microprojections, adapted to pierce the stratum corneum of a subject.

Description

APPARATUS AND METHOD FOR TRANSDERMAL DELΓVERY OF A BENZODIAZEPINE

TECHNICAL FIELD

[0001] The subject matter described herein relates generally to transdermal agent delivery systems and methods. More particularly, the subject matter relates to an apparatus and method for transdermal delivery of a benzodiazepine.

BACKGROUND OF THE INVENTION

[0002] Anxiety disorders are part of a heterogeneous group of psychiatric disorders that are characterized by their predominant symptom being that of anxiety. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSMTV), published by The American Psychiatric Association, 1994, Washington, DC, lists twelve (12) different types of Anxiety Disorders. These are as follows: Panic Disorder without Agoraphobia; Panic Disorder with Agoraphobia; Agoraphobia Without History of Panic Disorder; Specific Phobia; Social Phobia; Obsessive Compulsive Disorder; Posttraumatic Stress Disorder; Acute Stress Disorder; Generalized Anxiety Disorder; Anxiety Disorder Due to a General Medical Condition; Substance Induced Anxiety Disorder; and Anxiety Disorder, Not Otherwise Specified.

[0003] Panic Disorder is characterized by the presence of recurrent unexpected panic attacks, followed by at least a month of persistent concern about having another panic attack, in addition to worry about the possible implications or consequences of the panic attacks, or a significant behavioral change related to the panic attack. A panic attack is a discreet period of intense fear or discomfort in which four (4) or more of the following symptoms develop abruptly and reach a peak within ten (10) minutes. The symptoms are palpitations, sweating, trembling, shortness of breath, feeling of choking, chest pain, nausea, feeling dizzy, derealization, depersonalization, fear of losing control, fear of dying, parasthesias, and chills or hot flashes. [0004] The panic attack has a sudden onset and builds to a peak rapidly and is often accompanied by a sense of immediate danger or impending doom and an urge to escape. The panic attack differs from generalized anxiety in that the anxiety associated with the panic attack is intermittent and paroxysmal in nature and of greater severity. Panic attacks can occur in many different anxiety disorders, including Panic Disorder, Social Phobia, Specific Phobias, Post- Traumatic Stress Disorder and Acute Stress Disorder.

[0005] In Panic Disorder the frequency and severity of the panic attacks may vary widely. Some individuals may have frequent attacks, for example, daily or weekly, separated by periods without attacks. Other individuals may have only occasional panic attacks.

[0006] Panic Disorder is classified as with or without Agoraphobia. Agoraphobia is anxiety about being in situations in which escape would be difficult or even embarrassing, or in which the individual might not be able to obtain help. [0007] Agoraphobia can also occur without a history of panic disorder. In this disorder, the focus of fear is on the occurrence of severe panic-like symptoms or embarrassment as a result of these symptoms, rather than full formal panic attacks. The majority of individuals who have Agoraphobia also have a current diagnosis or history of Panic Disorder. However, Agoraphobia without a history of Panic Disorder is reported to be as common as Panic Disorder with Agoraphobia. [0008] Specific phobias are characterized by persistent and extreme fear of clearly defined, circumscribed objects or situations. Exposure to these particular objects or situations almost invariably produces an immediate anxiety, response, which may take the form of a panic attack. In children the anxiety may be expressed by tantrums, crying or clinging. The diagnostic criteria also require that the person recognize that the fear is excessive or unreasonable. In children this feature may be absent.

[0009] The essential feature of Social Phobia is marked and persistent fear of social situations in which embarrassment may occur. Exposure to this particular social situation will almost always produce an immediate anxiety response. This may take the form of a situationally predisposed panic attack. As in Specific Phobia, adolescents and adults with this disorder recognize that their fears are excessive or unreasonable but this is not the case with children. Individuals with Social Phobia have great concern about embarrassment and are often afraid that others will judge them to be anxious or even crazy or stupid. This may result in fear of public speaking because of the concern that others will notice that they are anxious or that they will be unable to speak articulately. Persons with this disorder may avoid eating, drinking or writing in public because of fear of embarrassment. Individuals with Social Phobia virtually always experience some symptoms of anxiety in the feared social situation and may have panic attacks, when exposed to the situation.

[0010] Obsessive Compulsive Disorder is a syndrome characterized by recurrent obsessions or compulsions that cause marked distress or take more than one hour a day or significantly interfere with the persons normal routine, occupational or academic functioning or usual social activities or relationships.

[0011] Obsessions are recurrent and persistent thoughts, impulses or images that are experienced at some point as intrusive and inappropriate and that cause marked anxiety and distress and are not simply excessive worries about real-life problems. The person attempts to ignore or suppress such thoughts, impulses or images or to neutralize them with some other thought or action and the person recognizes that the thought, impulses or images are a product of his or her own mind and not imposed from without.

[0012] Compulsions are repetitive behavior, such as handwashing or checking or mental acts such as counting or repeating words silently that the person feels driven to perform in response to an obsession or according to rules that must be applied rigidly. The person intends that these behaviors or mental acts will prevent distress or some dreaded event or situation however these behaviors or mental acts are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive.

[0013] Posttraumatic Stress Disorder (PTSD) is a syndrome characterized by clinically significant distress that results in disabling social and occupational dysfunction for periods of more than one month. The essential feature of PTSD is the development of characteristic symptoms following exposure to an extreme traumatic stressor involving direct personal experience of an event that involves actual or threatened death or serious injury, or other threat to one's physical integrity; or witnessing an event that involves death, injury, or a threat to the physical integrity of another person; or learning about the unexpected or violent death, serious injury, or threat of death or injury experienced by a family member or other close associate.

[0014] The patient's response to the event generally involves disorganized or agitated behavior. The characteristic symptoms resulting from the exposure to the extreme trauma include persistent re-experience of the traumatic event, persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness, as well as persistent symptoms of increased arousal and anxiety not exhibited by the patient before the traumatic incident. [0015] The traumatic event is most commonly re-experienced by way of recurrent and intrusive recollections of the events or recurrent distressing dreams of the event. PTSD can manifest itself chronically, defined as the presence of the full complement of symptoms for a period of 3 months or longer, or it may appear acutely, with each episode lasting less than 3 months. Occasionally, delayed-onset PTSD occurs, wherein at least 6 months have passed between the traumatic event and the onset of the above-described symptoms.

[0016] Furthermore, patients suffering from PTSD are at an increased risk for other debilitating psychiatric disorders, including Panic Disorder, Agoraphobia, Obsessive-Compulsive Disorder, Social Phobia, Major Depressive Disorder, and Substance Abuse. PTSD is also frequently associated with self-destructive, self-mutilating, and impulsive behavior resulting in injury to the patient, such as head trauma or burns.

[0017] The essential feature of Acute Stress Disorder is the development of characteristic anxiety, dissociation and other symptoms that occurs within one month after exposure to an extreme traumatic stressor. The types of stressors involved are similar to those involved in the development of PTSD. While experiencing the traumatic event or after the event the individual develops at least three of the following dissociative symptoms: a subjective sense of numbing, detachment or absence of emotional responsiveness; a reduction in awareness of his or her surroundings; derealization; depersonalization or dissociative amnesia. Following the trauma the event is persistently reexperienced and the individual displays marked avoidance of stimuli that may arouse recollections of the trauma and has marked symptoms of anxiety or increased arousal. [0018] The essential feature of this syndrome is the development of dissociative symptoms along with symptoms similar to those of PTSD as a result of exposure to a traumatic event. Individuals with Acute Stress Disorder may neglect basic health and safety needs and are at increased risk of developing PTSD and Major Depression.

[0019] The essential feature of Generalized Anxiety Disorder is excessive anxiety and worry occurring on more days than not for a period of at least six months about a number of events or activities. The individual with Generalized Anxiety Disorder finds it difficult to control the worry and other symptoms occur which may include restlessness, irritability, muscle tension and disturbed sleep. Individuals with this disorder may not always identify the worries as "excessive" but they experience subjective distress, have difficulty controlling the worry and may experience related impairment in social, occupational or other important areas of functioning.

[0020] This disorder occurs in both children and adults and was formally called Overanxious Disorders of Childhood. Children with this disorder tend to worry excessively about their competence or the quality of their performance and they may be overly coriforming, perfectionist and unsure of themselves.

[0021] Generalized Anxiety Disorder often co-occurs with Major Depressive Disorders or Dysthymic Disorders or other Anxiety Disorders or Substance-Related Disorder. Individuals with this disorder may often have associated somatic symptoms such as headaches or irritable bowel syndrome.

[0022] The essential feature of Anxiety Disorder Due to a General Medical Condition is clinically significant anxiety that is judged to be the direct physiological effect of a general medical condition. The symptoms may include generalized anxiety symptoms, panic attacks, or obsessions and compulsions. This syndrome is characterized not by the nature of the anxiety symptoms but by the judgment of the physician that they are the direct result of an underlying medical condition. Many examples of such medical condition are known to clinicians, such as thyroid disease, hypoglycemia, pulmonary embolism, cardiac arrhythmia, COPD, Vitamin B. sub.12 deficiency and encephalitis. [0023] Substance-induced Anxiety Disorder is characterized by prominent anxiety symptoms that are judged to be the direct physiological effect of a substance such as a drug of abuse, a medication or toxin exposure. The symptoms may include prominent anxiety, panic attacks, phobias or obsessions and compulsions and may occur during intoxication or during withdrawal. The symptoms are severe enough to cause clinically significant distress or impairment in social, occupational or other important areas of functioning. This condition is diagnosed only when the anxiety symptoms are in excess of those usually associated with the intoxication or withdrawal syndrome and are severe enough to warrant independent clinical attention. Many medications and drugs can cause anxiety symptoms during intoxication including: caffeine, cocaine, hallucinogens, anticholinergics, thyroid preparations, antipsychotic medications-and a variety of toxins. Anxiety symptoms can also occur in association with withdrawal from many classes of substances such as: alcohol, sedatives, anxiolytics or cocaine.

[0024] Anxiety Disorders Not Otherwise Specified includes disorders with prominent anxiety or phobic symptoms that do not meet criteria-for any specific Anxiety Disorder.

[0025] Significant progress has been made in developing more effective and better-tolerated measures to minimize anxiety disorders. Anti-anxiety disorder drugs are well-known. Benzodiazepines remain one of the mainstays of the treatment armamentarium for anxiety and anxiety disorders either alone or in combination with other psychopharmacologic agents. Woods, J. H. et al. Pharmacol Rev. 1992:44: 151-347, Shoder R. I. and Greenblatt D. J. N. Engl. J. Med. 1993:328: 1398- 1405. Hollister etal. J. Clin. Psychopharmacol. 1993; 13(suppl.):15-1695.

[0026] While not wishing to be bound by theory, it is believed that benzodiazepines effect anxiety disorders through a complex process involving many different neuroreceptors and the biochemical pathways that are regulated by a benzodiazepine are varied and complex. Benzodiazepine-associated neuroreceptors include neurochemical receptors such as Gamma Amino Butyric Acid ("GABA") receptors, and specifically GABA-A receptors. Neurotransmitters are chemicals that enable the brain cells to transmit impulses from one to another. They are released from brain cells by electrical signals. Once released, the neurotransmitters signal inhibition or excitation of neighboring brain cells. GABA is the major inhibitory neurotransmitter. The function of GABA is to slow or calm things down. Benzodiazepines increase the efficiency of GABA, thus causing greater inhibition or calming. Benzodiazepines work by binding to a specific recognition site on the GABA-A receptor. The benzodiazepines operate widely in the brain, affecting emotional reactions, memory, thinking, control of consciousness, muscle tone and coordination. Binding of the benzodiazepines have no effect on the GABA-A receptor (which is a ligand-gated chloride channel) in the absence of GABA, but potentiates the response to GABA by increasing the frequency of channel opening. The compounds have different indications due to their different pharmacokinetic properties (primarily duration of action - some benzodiazepines also have active metabolites which further prolong the duration). [0027] Despite this progress, there remains a need for benzodiazepine treatment therapies that provide a rapid onset of action combined with an improved tolerability profile. Currently available benzodiazepine therapies as well as those in development are effective, but lack the rapid onset of action combined with an improved tolerability profile desirable in this patient population. Intravenous and subcutaneous injections, and even sub-lingual oral tablets, all come with side effects that specifically impact the patient's ability to take the medicine. Intravenous and subcutaneous injections are problematic from the point of view of self-administration; sub-lingual tablets work fast, but present significant after taste concerns, as well as the fact that oral tablets are often difficult to ingest for an anxiety disorder sufferer, as he/she is often nauseous and unable to tolerate / swallow a pill. (80-90% of anxiety disorder patients also suffer from emesis). Thus, there remains a need to identify new approaches to prevent or treat anxiety and related disorders.

[0028] The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.

SUMMARY OF THE INVENTION

[0029] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

[0030] In one aspect, a device for transdermally delivering at least one compound from the benzodiazepine family

("benzodiazepine") is provided. The device is comprised of a microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient, and at least one benzodiazepine disposed on said microprojection member for communication with the plurality of microprojections.

[0031] In one embodiment, the benzodiazepine is contained in a biocompatible coating disposed on all or a portion of the external surfaces of the microprojections.

[0032] In another embodiment, the benzodiazepine is contained in a reservoir in contact. with said microprojection member.

[0033] In still another embodiment, the plurality of microprojections comprised a plurality of hollow microprojections having an external surface enclosing an interior surface, and the benzodiazepine is contained in a biocompatible coating disposed on all or a portion of interior surfaces of the microprojections.

[0034] In another embodiment, the benzodiazepine is selected from the group consisting of lorazepam, alprazolam, diazepam, midazolam, clonazepam, bromazepam, clobazam, fiunitrazepam, nitrazepam, oxazepam, temazepam, triazolam, and escitalopram.

[0035] In another aspect, a method for transdermally delivering at least one benzodiazepine is described. A microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient is provided, and applying the member to a skin site on a patient, whereby the plurality of microprojections pierce the stratum-corneum for delivery of the benzodiazepine.

[0036] In one embodiment, the member is applied to a patient prior to, during, or after an anxiety disorder.

[0037] In another embodiment, the member is applied to a patient before, during, or after Panic Disorder without

Agoraphobia.

[0038] In another embodiment, the member is applied to a patient before, during, or after Panic Disorder with Agoraphobia.

[0039] In another embodiment, the member is applied to a patient before, during, or after Agoraphobia Without History of

Panic Disorder.

[0040] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following descriptions.

[0041] The devices and methods of the present invention will have improved tolerability over known treatments of anxiety disorders. The present invention does not have the noxious taste or illicit the nausea experienced with intranasal treatments, does not require needles like subcutaneous or intravenous injections and has a faster onset than oral medications. Further, the present invention does not elicit the nausea experienced with oral treatments. During an anxiety disorder attack, 80-90% of patients experience nausea and vomiting, making it difficult to take oral medications. [0042] The devices and methods of the present invention further provide for the rapid and sustained relief of anxiety disorders over alternative methods of delivery. The present invention enables rapid uptake and distribution of a drug, and therefore, is fast acting and delivers a higher does in the first minutes of treatment, on the order of less than 15 minutes. This profile is comparable to injections and intranasal formulations that act in 10 and 5 minutes, respectively, but without the negative side effect profile of injections and intranasal formulations, and it is superior to oral medications that can take 30-60 minutes.

BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Fig. 1 is a perspective view of a portion of one example of a microprojection member;

[0044] Fig. 2 is a perspective view of a microprojection member where a coating is deposited on the outer surface of each microprojection in the array;

[0045] Fig. 3 is a side sectional view of a microprojection member having a drug reservoir and an adhesive backing;

[0046] Fig. 4 is a perspective view of a microprojection having a standard hollow needle-like configuration, where the interior and/or exterior of the microprojections include an agent for delivery;

[0047] Fig. 5A is an exploded perspective view of a microprojection member enclosed in a retainer and an applicator;

[0048] Fig. 5B is a side sectional view of a retainer having a microprojection member disposed therein.

DETAILED DESCRIPTION OF THE INVENTION

I. DEFINITIONS

[0049] Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified materials, methods or structures as such may, of course, vary. Thus, although a number of materials and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.

[0050] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

[0052] Further, all publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0053] Finally, as used in this specification and the appended claims, the singular forms "a, "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "an active agent" includes two or more such agents; reference to "a microprojection" includes two or more such microprojections and the like. [0054] The term "transdermal", as used herein, means the delivery of an agent into and/or through the skin for local or systemic therapy.

[0055] The term "transdermal flux", as used herein, means the rate of transdermal delivery.

[0056] The term "benzodiazepine family" ("benzodiazepine") intends an agent that acts by binding to GABA receptors, and in one embodiment GABA-A receptors, or acts by preventing or reducing the initiation of an anxiety disorder response, or has a benzodiazepine chemical structural component to the agent. Examples of benzodiazepines include, without limitation, of lorazepam, alprazolam, diazepam, midazolam, clonazepam, bromazepam, clobazam, fiunitrazepam, nitrazepam, oxazepam, temazepam, triazolam, and escitalopram. It will be appreciated that the term is intended to encompass the agent in any form, including, but not limited to, a free base, a free acid, a salt, or as a component of a complex. It is also to be understood that more than one benzodiazepine can be incorporated into the agent source, reservoirs, and/or coatings described herein below, and that the use of the term "benzodiazepine" in no way excludes the use of two or more such agents. [0057] The term "microprojections", as used herein, refers to piercing elements which are adapted to pierce or cut through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers, of the skin of a living animal, particularly a mammal and more particularly a human.

[0058] The term "patient", as used herein, refers to an individual afflicted with an anxiety disorder.

[0059] The term "anxiety disorder", as used herein, refers to the anxiety disorders that are part of a heterogeneous group of psychiatric disorders that are characterized by their predominant symptom being that of anxiety and includes, but it not limited to, Panic Disorder without Agoraphobia; Panic Disorder with Agoraphobia; Agoraphobia Without History of Panic Disorder; Specific Phobia; Social Phobia; Obsessive Compulsive Disorder; Post-traumatic Stress Disorder; Acute Stress Disorder; Generalized Anxiety Disorder; Anxiety Disorder Due to a General Medical Condition; Substance Induced Anxiety Disorder; and Anxiety Disorder, Not Otherwise Specified.

II. Apparatus for Delivery

[0060] In one embodiment, a device for delivery of a benzodiazepine is provided. The device includes a plurality of microprojections (or array thereof) that are adapted to pierce through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers. A portion of such an array from an exemplary device is shown in Fig. 1. A microprojection member 10 is comprised of an array of microprojections, such as microprojections 12,14. The microprojections extend at a substantially 90° angle from a substrate 16 having openings, such as openings 18, 20. The microprojections typically have a length of less than about 1000 microns, and preferably a length of less than about 500 microns, more preferably, less than about 250 microns. The width (designated "W" in Fig. 1) of each microprojection is typically in the range of approximately 25 - 500 microns and the thickness of each microprojection is generally in the range of approximately 10-100 microns. The microprojections may be formed in different shapes, such as needles, blades, pins, punches, and combinations thereof.

[0061] The microprojection member can be formed by etching or punching a plurality of microprojections from a sheet or substrate, such as substrate 16, and folding or bending the microprojections out of the plane of the sheet. The microprojection member can also be formed in other known manners, such as by forming one or more strips having microprojections along an edge of each of the strip(s) as disclosed in U.S. Patent No. 6,050,988, which is hereby incorporated by reference in its entirety.

[0062] In one embodiment, the microprojection member is constructed out of stainless steel, titanium, nickel titanium alloys, or similar biocompatible materials. In another embodiment, the microprojection member is constructed out of a non- conductive material, such as a polymeric material. The microprojection member when formed from a conductive material can be coated with a non-conductive material, such as Parylene^®, or a hydrophobic material, such as Teflon^®, silicon, or the like. [0063] The microprojection member, in one embodiment, has a micro projection density of at least approximately 10 microprojections/cm², more preferably, in the range of at least approximately 200 - 2000 microprojections/cm². [0064] The device is designed for transdermal delivery of a benzodiazepine, which is administered to a subject desirous of anxiety disorder control. The agonist is administered into the underlying epidermis layer, or epidermis and dermis layers, of a sub_ject via slits or cuts made by the microprojections through the stratum corneum The benzodiazepine is disposed on the device in a way that permits delivery of the agent from the device into the slits made m the stratum corneum For example, in one embodiment shown in Fig 2, each microprojection, such as microprojections 24, 26, in an array 28 can be coated with a biocompatible coating 30 The biocompatible coating may partially or completely cover the microprojections and may be applied to the microprojections before or after the microprojections are formed

[0065] The coating 30 on the microprojections can be formed by a variety of known methods One such method is dipcoatmg, where the microprojections are partially or totally immersed into a formulation containing a benzodiazepine For example, a coating solution containing a suitable solvent (aqueous or non-aqueous), a benzodiazepine, and any additional solution components, is prepared and applied to the microprojections Alternatively, the entire device can be immersed into the coating solution An apparatus for coatmg a microprojection array is described m U S Publication No 2002/0132054, coating methods are also taught in US2004/0062813, both of which are incorporated by reference herein m its entirety The coating device applies the coating solution only to the microprojections and not upon the substrate/sheet from which the microprojections project Other coating techniques such as microfluidic spray or printing techniques can be used to precisely deposit a coatmg on the tips of the microprojections The micropro_jections may further include means adapted to receive and/or increase the volume of the coating such as apertures, grooves, surface irregularities, or similar modifications, wherein the means provides increased surface area upon which a greater amount of coatmg may be deposited A coating solution can also be applied to the microprojections by spraying Spraying can encompass formation of an aerosol suspension of the coating composition, where droplets having a size of about 10 to about 200 picoliters is sprayed onto the microprojections and then dried

[0066] The coating formulation includes a benzodiazepine in any desired amount The coating formulation is applied to the microprojections to obtain a dry solid, biocompatible coatmg that contains in the range of between about 1 μg - 1000 ug, even more preferably, m the range of 10 - 100 μg, of the benzodiazepine The coating thickness is dependent upon the density of the microprojections per unit area, the viscosity and concentration of the coating formulation, as well as the coating method In general, coatmg thickness less than 50 micrometers are desired, and a preferred average coating thickness is less than about 30 micrometers, as measured perpendicularly from the microprojection surface

[0067] Another embodiment of a microprojection device is shown in cross-sectional view in Fig 3 In this embodiment, device 40 includes a microprojection member 42 comprised of a plurality of microprojections, such as microprojections 44, 46 The microprojections extend from a substrate 48, which is in contact with a reservoir 50 containing a benzodiazepine Reservoir 50 is in fluid communication with openings between and adjacent the microprojections, such as openings 52, 54 Preferably, the number of openings per unit area through which the agent passes is at least approximately 10 openmgs/cm² and less than about 2000 openmgs/cm² Agent in reservoir 50 is delivered through the openings and into the slits m the stratum corneum of a subject formed upon piercing with the array of microprojections A backing layer 56 is disposed on the skin proximal side of the agent reservoir, and can additionally include an adhesive (not shown) for adhering the device to the

[0068] Another embodiment of a microprojection for use m a device for delivery of a benzodiazepine to a subject is shown in Fig 4 In this embodiment, a device as described above, includes an array of microprojections, where each microprojection is in the shape of a hollow needle, like needle 60 shown in Fig 4 Needle 60 has an exteπor surface 62, an interior surface 64, and a skm-piercmg distal tip 66 The interior surface 64 of the microprojection is coated with a coatmg formulation to form a solid, dry coating 68 When the microprojection is inserted into the skin, interstitial fluid from the surrounding tissue can come in contact with the coating 68, thereby dissolving the coating and releasing the benzodiazepine incorporated into the solid coating. In alternative embodiments, not shown here but detailed in U.S. Publication No. 2005/0031676 Al, incorporated by reference herein, the needle includes slits, perforations, or other openings, and/or is formed of a porous material to facilitate entry of interstitial fluid and dissolution of the benzodiazepine.

[0069] Figs. 5A-5B show an embodiment of a microprojection member 70 suspended in a retainer ring 72 by adhesive tab

76, as described in detail in U.S. Publication No. 2002/0091357 Al, which is incorporated by reference herein in its entirety.

In use, the retainer ring is placed against the skin and the microprojection member 70 is downwardly displaced for contact with patient's skin. Preferably, the microprojection member is applied to the patient's skin using an impact applicator 78, such as shown in Fig. 5A, and described in U.S. Publication No. 2002/0123675 Al, which is incorporated by reference herein in its entirety.

[0070] Alternative embodiments of microprojection members that can be employed for delivery of the benzodiazepine can also include, but are not limited to, the members disclosed in U.S. Patent Nos. 6,083,196, 6,050,988, and 6,091,975, which are incorporated by reference herein in their entirety.

[0071] Other microprojection members that can be employed include members formed by etching silicon using silicon chip etching techniques or by molding plastic using etched micro-molds, such as the members disclosed U.S. Patent No.

5,879,326, which is incorporated by reference herein in its entirety.

[0072] An apparatus designed to cause the microprojections to impact the stratum corneum with an impact power of at least

0.05 joules per cm² in 10 milliseconds or less is described in U.S. Publication No. 2005/0234401 Al, which is incorporated by reference herein. The apparatus includes an applicator device for repeatable impact application of a microprotrusion array, to achieve predefined and consistent penetration of the microprotrusions into the skin.

[0073] In the embodiments described with respect to Figs. 2-4, a biocompatible, solid dry coating containing the benzodiazepine is formed on the microprojections. As briefly described above, the solid coating is deposited from a coating formulation that can contain various additional components, now to be described.

[0074] In one embodiment, the coating formulation includes at least one buffer. Examples of such buffers include, without limitation, ascorbic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid, maleic acid, phosphoric acid, tricarballylic acid, malonic acid, adipic acid, citraconic acid, glutaratic acid, itaconic acid, mesaconic acid, citramalic acid, dimethylolpropionic acid, tiglic acid, glyceric acid, methacrylic acid, isocrotonic acid, p-hydroxybutyric acid, crotonic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine and mixtures thereof.

[0075] In another embodiment, the coating formulation includes at least one antioxidant, which can be a sequestering agent, such sodium citrate, citric acid, EDTA (ethylene-dinirrilo-tetraacetic acid) or free radical scavengers such as ascorbic acid, methionine, sodium ascorbate and the like. Preferred antioxidants comprise EDTA and methionine. The concentration of the antioxidant is in the range of approximately 0.01-20 wt. % of the coating formulation. Preferably the antioxidant is in the range of approximately 0.03-10 wt. % of the coating formulation.

[0076] The coating formulation can additionally include at least one surfactant, which can be zwitterionic, amphoteric, cationic, anionic, or nonionic, including, without limitation, sodium lauroamphoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (TMAC), benzalkonium, chloride, polysorbates, such as Tween 20 and Tween 80, other sorbitan derivatives, such as sorbitan laurate, alkoxylated alcohols, such as laureth-4 and polyoxyethylene castor oil derivatives, such as Cremophor . The concentration of the surfactant is in the range of approximately 0.01-20 wt. % of the coating formulation. Preferably the surfactant is in the range of approximately 0.05-1 wt. % of the coating formulation.

[0077] The coating formulation can also include at least one polymeric material or polymer that has amphiphilic properties, which can comprise, without limitation, cellulose derivatives, such as hydroxyethylcellulose (HEC), hydroxypropylmethylcell-ulose (HPMC), hydroxypropycellulose (HPC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), or ethylhydroxy-ethylcellulose (EHEC), as well as a Pluronic™. The concentration of the polymer presenting amphiphilic properties in the coating formulation is preferably in the range of approximately 0.01-20 wt. %, more preferably, in the range of approximately 0.03-10 wt. % of the coating formulation. [0078] The coating formulation can optionally include a hydrophilic polymer selected from the following group: hydroxyethyl starch, carboxymethyl cellulose and salts of, dextran, poly(vinyl alcohol), poly(ethylene oxide), poly(2- hydroxyethylmethacrylate), poly(n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and like polymers. In a preferred embodiment, the concentration of the hydrophilic polymer in the coating formulation is in the range of approximately 1-30 wt. %, more preferably, in the range of approximately 1-20 wt. % of the coating formulation. [0079] The coating formulation can optionally include a biocompatible carrier, which can comprise, without limitation, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffinose, stachyose, mannitol, and other sugar alcohols. Preferably, the concentration of the biocompatible carrier in the coating formulation is in the range of approximately 2-70 wt. %, more preferably, in the range of approximately 5-50 wt. % of the coating formulation.

[0080] The coating formulation can also include a stabilizing agent, which can comprise, without limitation, a non-reducing sugar, a polysaccharide or a reducing sugar. Suitable non-reducing sugars for use in the methods and compositions of the invention include, for example, sucrose, trehalose, stachyose, or raffinose. Suitable polysaccharides for use in the methods and compositions of the invention include, for example, dextran, soluble starch, dextrin, and insulin. Suitable reducing sugars for use in the methods and compositions of the invention include, for example, monosaccharides such as, for example, apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinovose, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, hamamelose, idose, mannose, tagatose, and the like; and disaccharides such as, for example, primeverose, vicianose, rutinose, scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, sophorose, and turanose, and the like. Preferably, the concentration of the stabilizing agent in the coating formulation is at ratio of approximately 0.1-2.0: 1 with respect to the benzodiazepine, more preferably, approximately 0.25-1.0: 1 with respect to the benzodiazepine.

[0081] In another embodiment, the coating formulation includes a vasoconstrictor, which can comprise, without limitation, amidephrine, cafaminol, cyclopentamine, deoxyepinephrine, epinephrine, felypres^'sin, indanazoline, metizoline, midodrine, naphazoline, nordefrin, octodrine, omipressin, oxymethazoline, phenylephrine, pheπylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tyrnazoline, vasopressin, xylometazoline and the mixtures thereof. The most preferred vasoconstrictors include epinephrine, naphazoline, tetrahydrozoline indanazoline, metizoline, tramazoline, tymazoline, oxymetazoline and xylometazoline. As will be appreciated by one having ordinary skill in the art, the addition of a vasoconstrictor to the coating formulations and, hence, solid biocompatible coatings is particularly useful to prevent bleeding that can occur following application of the microprojection member or array and to prolong the pharmacokinetics of the benzodiazepine through reduction of the blood flow at the application site and reduction of the absorption rate from the skin site into the system circulation. The concentration of the vasoconstrictor, if employed, is preferably in the range of approximately 0.1 wt. % to 10 wt. % of the coating formulation.

[0082] In another embodiment, the coating formulation includes at least one "pathway patency modulator", which can comprise, without limitation, osmotic agents (e.g., sodium chloride), zwitterionic compounds (e.g., amino acids), and anti- inflammatory agents, such as betamethasone 21 -phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21 -phosphate disodium salt, methylprednisolone 21 -phosphate disodium salt, methylprednisolone 21-succinaate sodium salt, paramethasone disodium phosphate and prednisolone 21 -succinate sodium salt, and anticoagulants, such as citric acid, citrate salts (e.g., sodium citrate), dextrin sulfate sodium, aspirin and EDTA. [0083] In yet another embodiment, the coating formulation includes a solubilising/complexing agent, which can comprise alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, glucosyl-alpha-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxyproρyl-beta- cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, methyl-beta-cyclodextrin, sulfobutylether-alpha-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether-gamma-cyclodextrin. Most preferred solubilising/complexing agents are beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyl-beta- cyclodextrin, and sulfobutylether 7 beta-cyclodextrin. The concentration of the solubilising/complexing agent, if employed, is preferably in the range of approximately 1 wt. % to 20 wt. % of the coating formulation.

[0084] In another embodiment, the coating formulation includes at least one non-aqueous solvent, such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethysulfoxide, glycerin, N,N-dimethylformamide and polyethylene glycol 400. Preferably, the non-aqueous solvent is present in the coating formulation in the range of approximately 1 wt. % to 50 wt. % of the coating formulation.

[0085] Other known formulation adjuvants can also be added to the coating formulations provided they do not adversely affect the necessary solubility and viscosity characteristics of the coating formulation and the physical integrity of the dried coating. Preferably, the coating formulations have a room temperature (about 20-25⁰C) viscosity less than approximately 500 centipoise and greater than 3 centipoise.

[0086] In another embodiment, the coating formulation includes a non-volatile counterion, wherein the non-volatile counterion causes the formation of a first species of the benzodiazepine that has improved solubility when the formulation is dried. The first species of the benzodiazepine dissolves quickly to provide rapid attainment of a therapeutically relevant blood level of the benzodiazepine.

[0087] In a preferred embodiment of the invention, the formulation further includes a counterion comprising a volatile counterion, wherein the volatile counterion causes the formation of a second species of the benzodiazepine that has reduced solubility when the formulation is dried. Thus, the second species of the benzodiazepine dissolves at a slower rate to provide sustained blood levels of the benzodiazepine.

[0088] Preferably, the non- volatile counterions of the invention include weak acids and weak bases, acidic zwitterions and basic zwitterions, and strong acids and strong bases. Also preferably, volatile counterions of the invention include weak acids or weak bases.

[0089] In one aspect of the invention, the addition of a non- volatile counterion results in the formation of a species of the benzodiazepine that has improved solubility. In another aspect of the invention, the addition of a volatile counterion results in the formation of a species of the benzodiazepine that has reduced solubility. In a preferred embodiment, the non-volatile counterion and the volatile counterion are added in approximately equimolar amounts.

[0090] In one embodiment of the invention, the non- volatile counterion comprises a non- volatile weak acid that presents at least one acidic pKa and a melting point higher than about 50oC or a boiling point higher than about 170 o C at Patm.

Preferably, such acids include citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, and fumaric acid.

[0091] In an alternate embodiment of the invention, the non-volatile counterion comprises a non-volatile weak base that presents at least one basic pKa and a melting point higher than about 50oC or a boiling point higher than about 170 o C at

Patm. Preferably, such bases include monoethanolomine, diethanolamine, triethanolamine, tromethamine, methylglucamine, glucosamine

[0092] In another embodiment of the invention, the non- volatile counterion comprises a non- volatile acidic zwitterion that presents at least two acidic pKa, and at least one basic pKa, so that there is at least one extra acidic group as compared to the number of basic groups. Preferably, such compounds include glutamic acid and aspartic acid. In an alternate embodiment of the invention, the non-volatile counterion comprises a non- volatile basic zwitterion that presents at least one acidic pKa, and at least two basic pKa's, so that there is at least one extra basic group as compared to the number of acidic groups. Preferably, such compounds include lysine, arginine, and histidine.

[0093] In yet another embodiment, the non-volatile counterion comprises a nonvolatile strong acid that presents at least one pKa lower than about 2. Preferably, such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid and methane sulfonic acid. In an alternate embodiment of the invention, the non-volatile counterion comprises a non- volatile strong base that presents at least one pKa higher than about 12. Preferably, such bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide.

[0094] In a further embodiment of the invention, the volatile counterion comprises a weak acid that presents at least one pKa higher than about 2 and a melting point lower than about 50oC or a boiling point lower than about 170oC at Patm.

Preferably, such acids include acetic acid, propionic acid, pentanoic acid and the like. In an alternate embodiment of the invention, the volatile counterion comprises a weak base that presents at least one pKa lower than about 12 and a melting point lower than about 50oC or a boiling point lower than about 170oC at Patm. Preferably, such bases include ammonia and morpholine.

[0095] In the noted embodiments, the volatile and non-volatile counterions are preferably present in amounts necessary to neutralize the charge present on the benzodiazepine at the pH of the formulation. Excess of counterion (as the free acid or base or as a salt) can be added to the benzodiazepine in order to control pH and to provide adequate buffering capacity. m. Methods of Use

[0096] In another aspect, a method for administering a benzodiazepine to a subject is provided. In the method, a device as described above in provided. The microprojection member is initially applied to the patient's skin to cause the microprojections to pierce the stratum corneum. The microprojection member is preferably left on the skin for a period lasting from 5 seconds to 24 hours. Following the desired wearing time, the microprojection member is removed. [0097] Preferably, the amount of benzodiazepine contained in the biocompatible coating (i.e., dose) or in a reservoir in communication with the microprojections is in the range of approximately 1 micrograms -1000 micrograms, more preferably, in the range of approximately 10-200 micrograms. Even more preferably, the amount of benzodiazepine contained in the biocompatible coating is in the range of approximately 10-100 micrograms per device.

[0098] In one embodiment, the benzodiazepine is delivered to the patient on a daily basis, or as needed to control an anxiety disorder. For patients undergoing any type of anxiety disorder, including Panic Disorder without Agoraphobia; Panic Disorder with Agoraphobia; Agoraphobia Without History of Panic Disorder; Specific Phobia; Social Phobia; Obsessive Compulsive Disorder; Post-traumatic Stress Disorder; Acute Stress Disorder; Generalized Anxiety Disorder; Anxiety Disorder Due to a General Medical Condition; Substance Induced Anxiety Disorder; and Anxiety Disorder, Not Otherwise Specified , the agonist is delivered prior to, during, and/or after the anxiety disorder, again as needed to control an anxiety disorder. In one embodiment, delivery of the benzodiazepine transdermally using the apparatus described herein provides beneficial pharmacokinetics, as evidenced by a larger area under the curve and longer blood circulation lifetime, when compared to the same dose administered subcutaneously.

[0099] It will be appreciated by one having ordinary skill in the art that in order to facilitate drug transport across the skin barrier, the present device can also be employed in conjunction with a wide variety of iontophoresis or electrotransport systems. Illustrative electrotransport drug delivery systems are disclosed in U.S. Pat. Nos. 5,147,296, 5,080,646, 5,169,382 and 5,169383, the disclosures of which are incorporated by reference herein in their entirety.

IV. Examples [00100] The following examples are illustrative in nature and are in no way intended to be limiting.

EXAMPLE 1 ADMINISTRATION OF LORAZEPAM TO ANIMALS

[00101] Delivery of the benzodiazepine lorazepam from a microprojection member is evaluated using a hairless guinea pig

(HGP) model. A microprojection device is formed via photo/chemical etching to have an area of 2 cm², a microprojection density with 320 microprojections/cm², and a projection length of 200 μm.

[00102] The microprojections are coated with a 25% aqueous solution of lorazepam at 40 ± 10 μm per 2 cm² array, with a solid coating limited to the first 100 μm of the microprojections. The coated microprojection array is attached to a flexible polymeric adhesive backing and then assembled onto a retainer ring. The assembly is then loaded on a reusable impact applicator at the time of application to the HGP.

[00103] An area of skin on each anesthetized HGP is shaved and the microprojection device is applied and the microprojections are caused to pierce the skin. The device is left in place for one hour. At various time intervals following patch application, blood samples are taken for determination of plasma lorazepam levels.

[00104] A group of HGP serve as a control and receive a subcutaneous injection of lorazepam. Bloαd samples are taken for determination of plasma lorazepam levels.

[00105] Another group of HGP receive an intravenous (IV) injection of lorazepam and blood samples are taken at various times to ascertain the area under the curve (AUC), and to serve as reference to calculate the total amounts absorbed/delivered following subcutaneous or microneedle array administration.

[00106] While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope.

Claims

WHAT IS CLAIMED IS:

1. A device for transdermally delivering a benzodiazepine, comprising: a microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient, and a benzodiazepine disposed on said microprojection member for communication with the plurality of microproj ections .

2. The device of claim 1, wherein said benzodiazepine is contained in a biocompatible coating disposed on all or a portion of the external surfaces of the microprojections.

3. The device of claim 1, wherein said benzodiazepine is contained in a reservoir in contact with said microprojection member.

4. The device of claim 1, wherein said plurality of microprojections comprised a plurality of hollow microprojections having an external surface enclosing an interior surface, and the benzodiazepine is contained in a biocompatible coating disposed on all or a portion of interior surfaces of the microprojections.

5. The device of claim 1, wherein said benzodiazepine is selected from the group consisting of lorazepam, alprazolam, diazepam, midazolam, clonazepam, bromazepam, clobazam, flunitrazepam, nitrazepam, oxazepam, temazepam, triazolam, and escitalopram.

6. A method for transdermally delivering a benzodiazepine, comprising: providing a microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient, and applying said member to a skin site on a patient, whereby said plurality of microprojections pierce the stratum-corneum for delivery of the benzodiazepine.

7. The method of claim 6, wherein said applying comprises applying to a patient prior to, during, or after an anxiety disorder.

8. The method of claim 6, wherein said applying comprises applying to a patient before, during, or after a Panic Disorder without Agoraphobia.

9. The method of claim 6, wherein said applying comprises applying to a patient prior to, during, or after a Panic Disorder with Agoraphobia.

10. The method of claim 6, wherein said applying comprises applying to a patient prior to, during, or after a Agoraphobia Without History of Panic Disorder.

11. The method of claim 6, wherein said providing comprises providing a microprojection member wherein said benzodiazepine is contained in a biocompatible coating disposed on all or a portion of the external surfaces of the microproj ections .

12. The method of claim 6, wherein said providing comprises providing a microprojection member wherein said benzodiazepine is contained in a reservoir in contact with said microprojection member.

13. The method of claim 6, wherein said providing comprises providing a microprojection member wherein said plurality of microprojections comprised a plurality of hollow microprojections having an external surface enclosing an interior surface, and the benzodiazepine is contained in a biocompatible coating disposed on all or a portion of interior surfaces of the microprojections.

14. The method of claim 6, wherein said providing comprises providing a microprojection member wherein said benzodiazepine is selected from the group consisting of lorazepam, alprazolam, diazepam, midazolam, clonazepam, bromazepam, clobazam, fiunitrazepam, nitrazepam, oxazepam, temazepam, triazolam, and escitalopram.