NZ795347A - Method of treating epilepsy - Google Patents

Abstract

Alprazolam formulated as an inhaled condensation aerosol and method for treating epilepsy and/or seizures.

Description

Alprazolam ated as an inhaled condensation aerosol and method for treating epilepsy and/ or seizures.

NZ 795347 METHOD OF TREATING SY RELATED APPLICATIONS This application is a divisional of New Zealand Patent Application No. 778142, the entire contents of which are incorporated herein by cross-reference.

COPYRIGHT STATEMENT A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it s in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.

TECHNICAL FIELD The present ion relates generally to a method of ng epilepsy and/or seizure in a subject comprising administering to said subject in need thereof, a therapeutic dose of alprazolam via inhalation. More specifically, the invention relates to a method of treating epilepsy and/or e by administering a condensation alprazolam aerosol.

BACKGROUND There are about three million patients with epilepsy in the U.S. There are two types of epileptic seizures: l and generalized. Once diagnosed, patients are prescribed an anti-epileptic drug (AED). If two AEDs fail, the disease is considered tory or uncontrolled. One million patients live with rollable seizures because no ble treatment works for them. About 200,000 or 20% of the uncontrolled population have a warning system, or a predictive n, alerting them to the onset of sei zure activity.

Warnings signals can occur minutes or days before and may include: muscle jerks, déjà vu, changes in behavior such as a “mean streak,” visions or illusions, bad smells, anxiety, or flashing lights.

A seizure can be defined as abnormal, uncontrolled electrical activity in brain cells. Seizures can progress through four : prodrome, aura, ictal and post-ictal. The aura is a small partial e that is often ed by a larger event. Predictive patterns can occur during the prodrome and aura phases, which could allow those with such predictive patterns to be administered a drug to ameliorate or even abort e activity. To date, there are no office treatments indicated to treat seizures in these phases. The ictus or ictal phase is the main generalized seizure stage. What happens to the person during the seizure depends on where in the brain the disruption of neural activity occurs. Certain areas of the brain are more likely than others to be involved in seizure activity. The motor , which is responsible for body movement, and the temporal lobes, including the hippocampus, which is involved in memory, are ularly sensitive to mical changes (e.g., decreased oxygen level, metabolic imbalances, infection) that provoke abnormal brain cell activity. ing a e, the person enters into the postictal state. Drowsiness and confusion are commonly experienced during this phase. The postictal state is the period in which the brain recovers from the insult it has experienced.

Episodes of repetitive seizures are distinct from their usual seizure pattern.

Repetitive seizures comprise multiple seizures, such as 3 or more, within 24 hours in adults (12 hours in en). An episode may last from minutes to hours. These seizures are at a significantly higher risk for convulsive status epilepticus.

Benzodiazepines are seen as a treatment of choice for seizures. The drugs in this family have been observed as possessing sedative, tranquilizing and muscle relaxing properties. They are frequently classified as anxiolytic and skeletal muscle relaxants. They are thought to be useful in preventing, treating, or ameliorating the symptoms of anxiety, insomnia, agitation, es (such as those caused by epilepsy), muscle spasms and ty, the symptoms of drug withdrawal associated with the continuous abuse of central nervous system depressants, and exposure to nerve agents. Benzodiazepines are thought to act by binding to the GABAA receptor of a neuron, possibly g the receptor to change shape and making it more accessible to gamma-aminobutyric acid (GABA).

Rectal diazepam (DZ) gel (Diastat®) is approved for treatment of acute repetitive seizures (ARS). It is administered only by a trained caregiver or healthcare professional and it takes multiple steps to administer the gel. It is likely to be used only for ric patients. Onset of therapeutic action is 30-40 minutes after administration, with 70- 90 % bioavailability of the administered dosage. The peak plasma concentration occurs at 1.5 hours after stration. am has a long half-life of 46 hours; Desmethyl-DZ, the active metabolite, has a half-life of 71 hours. Sedation and somnolence are known side effects. ceutical compositions comprising one or more benzodiazepine drugs for nasal administration are disclosed in U.S. Patent 8,895,546. Intranasal and intramuscular delivery of iazepines such as midazolam or diazepam is not yet approved for treatment of ARS. It can take four steps to administer benzodiazepines intranasally. Onset of action can take 15-40 minutes, with only 40-80 % bioavailability of the administered . Side effects can include nasal irritation, amnesia, and blackbox respiratory depression.

Rectal, intranasal, and intramuscular administration of benzodiazepine drugs are administered in the post-ictal phase and address prevention of the next seizure, once the first seizure ends. It is desirable to identify and develop treatments that could be administered in the prodrome or aural stages of seizure activity to lessen the severity of, or even abort, the developing seizure. The t invention is directed toward overcoming or ameliorating one or more of the problems discussed above.

SUMMARY The present invention provides s for treating epilepsy and/or seizure in a mammal subject comprising administering a therapeutically effective dose of alprazolam via oral inhalation. The alprazolam is delivered in the form of an l, e.g., condensation aerosol, through an oral inhalation route. In some embodiments, the patient is human.

The alprazolam aerosol contains particles of olam having a particle size distribution. In one embodiment, at least 80% by weight of the alprazolam particles have a size less than 5 microns. In another embodiment, at least 90% by weight of the alprazolam particles have a size less than 5 microns. In another embodiment, at least 50% by weight of the alprazolam particles have a size less than 2 micron. In another embodiment, at least 50% by weight of the alprazolam l particles have a size less than 1 micron. The alprazolam may be substantially ent free, or ent free in some embodiments.

The alprazolam dose administered to the subject exhibits unique Cmax and Tmax properties. For example, the alprazolam exhibits a plasma Tmax between from about 2 minutes to about 15 minutes post administration. In some embodiments, the Tmax is less than 15 s post administration, preferably less than 5 minutes post stration, or more preferably less than 2 minutes post administration. The Cmax is at least 5 ng/mL following oral administration. For example, the Cmax is at least 12 ng/mL following oral administration, or at least 30 ng/mL ing oral administration.

The orally dosed alprazolam ts bioavailability that is similar to that of an intravenous administration. For example, the dosed alprazolam aerosol exhibits bioavailability from about 80-125% of that ed with alprazolam administered intravenously.

The alprazolam may be self-administered at onset of one or more ms of an epileptic attack, or wherein the alprazolam is self-administered before onset of one or more symptoms of an epileptic attack, or wherein the alprazolam is self-administered after onset of one or more symptoms of an epileptic . The one or more symptoms of epilepsy include seizure; and/or wherein the ent protects t seizure, reduces or ameliorates the intensity of seizure, reduces or ameliorates the frequency of seizure, interrupts the seizure cycle and/or prevents occurrence or re-occurrence of seizure.

Other embodiments include those wherein the seizure comprises an epileptic seizure, a breakthrough seizure, or other seizure; wherein the seizure comprises a partial ) or generalized seizure; such as those wherein the partial seizure comprises a complex partial seizure, simple partial seizure, or a seizure originating within neural networks limited to one brain hemisphere; or wherein the generalized seizure originates at some point within bilaterally distributed neural networks or evolves from a l e.

The method also comprises stration of the alprazolam condensation aerosol when the subject is a patient in the prodrome or aura phase of seizure, such as when a patient is subjectively encing a sensory aura or an experiential aura, including wherein the sensory aura comprises a somatosensory, visual, ry, olfactory, gustatory, epigastric or cephalic aura; or wherein the experiential aura ses an affective, mnemonic, hallucinatory, or illusory aura. Another embodiment of the method is one wherein the subject is a patient with cluster or acute repetitive seizures, prolonged focal partial seizures, or juvenile myoclonic epilepsy.

The invention may be a rescue tion for the treatment of epilepsy and/or e. Upon actuation of the device described herein, the patient obtains a dose of alprazolam that provides immediate symptomatic relief.

The effect of the dosed olam may be maximal within 2 to 15 minutes of inhalation of alprazolam. For example, the maximal effect may occur within 5 minutes of inhalation or within 2 minutes of inhalation of alprazolam.

Embodiments include those wherein epileptiform activity is absent within 15 minutes of inhalation of olam; and/or wherein epileptiform activity is absent for at least six hours after inhalation of alprazolam.

Various modifications and additions can be made to the ments discussed without ing from the scope of the invention. For example, while the ments described above refer to particular features, the scope of this invention also includes embodiments having different combination of features and ments that do not include all of the above described features.

A further understanding of the nature and advantages of particular embodiments may be realized by reference to the ing portions of the specification and the drawings, in which like reference numerals are used to refer to similar components.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a raph of a device for the oral inhalation administration of alprazolam.

Figure 2 shows cut-away schematic views of the device before and after inhalation initiates aerosol formation.

Figure 3 shows photographs of aerosol generation at various time points after heating initiation in accordance with one ment of the invention.

Figure 4 shows a graph of particle size distribution of alprazolam condensation aerosol emitted from a device in accordance with one embodiment of the invention.

Figures 5A and 5B show graphs of mean plasma concentration in phase 1 and phase 2a clinical trials respectively, in ance with one embodiment of the invention.

Figure 6 shows a graph of the mean standardized photosensitivity rage (SPR) over time in accordance with one embodiment of the invention.

Figures 7A and 7B show EEG traces of a representative patient prior to and after dosing with alprazolam condensation l in accordance with one embodiment of the invention.

Figure 8 shows a graph of the mean Visual Analogue Scale (VAS) for patients after dosing with alprazolam sation aerosol in accordance with one embodiment of the invention.

DETAILED DESCRIPTION While various s and features of certain embodiments have been summarized above, the following detailed description illustrates a few embodiments in further detail to enable one of skill in the art to practice such embodiments. The described examples are provided for rative purposes and are not intended to limit the scope of the invention.

In the following description, for the purposes of explanation, numerous specific details are set forth in order to e a thorough understanding of the described embodiments. It will be apparent to one skilled in the art, however, that other embodiments of the present invention may be practiced without some of these specific details. Several embodiments are described and claimed herein, and while various features are ed to different embodiments, it should be appreciated that the features described with respect to one embodiment may be incorporated with other ments as well. By the same token, however, no single feature or features of any described or claimed embodiment should be ered essential to every ment of the invention, as other embodiments of the invention may omit such features.

Unless otherwise indicated, all numbers used herein to express quantities, dimensions, and so forth used should be understood as being modified in all instances by the term "about." The modifier "about" is intended to have its regularly recognized meaning of approximately. In some embodiments, the term may be more precisely interpreted as meaning within a particular percentage of the modified value, e.g. "about" may in some embodiments mean ±20%, ±10%, ±5%, ±2%, or ±1 % or less.

In this application, the use of the singular includes the plural unless specifically stated otherwise, and use of the terms "and" and "or" means "and/or" unless otherwise indicated. Moreover, the use of the term "including," as well as other forms, such as "includes" and "included," should be considered non-exclusive. Also, terms such as "element" or "component" encompass both elements and components sing one unit and elements and components that comprise more than one unit, unless specifically stated otherwise.

"Aerodynamic diameter" of a given particle refers to the diameter of a spherical droplet with a density of 1 g/mL (the density of water) that has the same settling velocity as the given particle.

"Aerosol" refers to a collection of solid or liquid particles suspended in a gas.

"Aerosol mass concentration" refers to the mass of particulate matter per unit volume of aerosol.

"Condensation l" refers to an aerosol that has been formed by the vaporization of a ition and uent cooling of the vapor, such that the vapor condenses to form particles. al patient tidal volume" refers to 1 L for an adult patient and 15 mL/kg for a pediatric patient.

As used herein the phrase peutically effective amount" (or more simply "effective amount") includes an amount sufficient to provide a specific therapeutic response for which the drug is administered to a t in need of particular ent. The therapeutic effect could be any therapeutic effect ranging from prevention, symptom amelioration, symptom treatment, to disease termination or cure. The skilled clinician will recognize that the therapeutically effective amount of drug will depend upon the patient, the indication and the particular drug administered.

As used herein, the term re" includes commonly recognized types of seizures, including e seizures, nic seizures, clonic seizures, tonic seizures, tonicclonic seizures, and atonic seizures.

As used herein, the term "prevention" refers to a forestalling, including temporary forestalling, of the onset of a disorder. In the case of seizures, this can occur either with or without the benefit of a warning aura.

The term "anticonvulsant" includes treatment of seizures, protection against e, reduction or amelioration of the intensity of seizure, reduction or ration of the frequency of seizure, and/or prevention of the occurrence or re-occurrence of seizure. In this regard, treatment of seizure includes cessation of an ongoing seizure, reduction in the severity of an ongoing seizure, or reduction in the duration of an ongoing seizure. tion t e includes forestalling an oncoming seizure.

As used herein, the term “pharmacokinetics” (PK), refers to the chemical metabolism of a drug, its fate from the moment that it is administered up to the point at which it is tely eliminated from the body. Pharmacokinetics describes how the body affects a specific drug after administration through the mechanisms of absorption and distribution, metabolic changes of the substance in the body, and the s and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are ed by the route of administration and the dose of administered drug. These may affect the absorption rate.

“Pharmacodynamics” (PD), is the study of how the drug affects the organism, such as onset andduration of response to the drug. Both together influence dosing, benefit, and adverse effects, as seen in PK/PD models.

Alprazolam (API) is the international non-proprietary name for the compound 8-chloromethylphenyl-4H-[1,2,4]triazolo [4,3-α][1,4]-benzodiazepine or 8-chloro methylphenyl-4H-s-triazolo[4,3-α] [1,4]benzodiazepine (CAS Number 289817), molecular formula ClN4. It is an odorless white, crystalline powder that is practically insoluble in water, soluble in ethanol and ol, and freely soluble in form. Its structure is shown as Formula I.

A brand name for alprazolam is Xanax®. Alprazolam may be manufactured using the process disclosed in U.S. Patent 052. As used herein, the term “inhaled alprazolam” refers to a dose of alprazolam delivered by oral inhalation of a condensation aerosol from a device as described herein.

In one aspect, the invention provides methods for treating epilepsy and/or seizure in a mammal subject comprising administering a therapeutically ive dose of alprazolam. The alprazolam is delivered in the form of a condensation aerosol through an oral inhalation route. A therapeutically effective amount of alprazolam in some embodiments is from about 0.1 mg to about 2 mg. In some embodiments, the mammal is human.

The ent of epilepsy and/or seizure includes protecting against seizure, ng or rating the intensity of seizure, reducing or ameliorating the frequency of seizure, interrupting the seizure cycle and/or preventing occurrence or re-occurrence of seizure. A particular embodiment is the method for acute treatment of seizures.

Epileptic ts can ence partial (focal) or generalized seizures. The current International League Against Epilepsy (ILAE) classification bes focal seizures as including seizures with or without impairment of consciousness and with specific autonomic, motor, psychic, sensory, or other phenomena. Focal seizures originate within neural networks limited to one brain hemisphere. A focal seizure can be consciousness (or awareness)-impaired (complex partial seizure), or be t ment (simple partial seizure). Focal seizures can also evolve into a generalized seizure (focal to bilateral tonicclonic ). Generalized seizures ate at some point within, and rapidly engage bilaterally distributed neural networks.

The onset of both types of es can be preceded by an “aura” or a “warning”. Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or to those familiar with the patient. An aura is defined as a subjective experience of a focal seizure that usually, or typically, precedes a patient's experiencing a seizure. These auras are practically sui generis for each patient. Each patient will generally experience a ent type of aura that is unique to the patient. An aura can be classified as sensory (somatosensory, tactile, visual, auditory, olfactory, gustatory, epigastric or cephalic sensations) or experiential (affective, mnemonic, hallucinatory, or illusory). Not all patients who suffer seizures ence aura; however auras are not uncommon amongst those who suffer the worst type of seizures, especially tonicclonic seizures.

In addition to subjects experiencing aura and/or secondarily generalized seizures, additional seizure events include cluster (acute repetitive) seizures, prolonged focal (partial) seizures, and juvenile myoclonic sy.

The indication of “acute treatment of es” is directed to possible patient types in which rescue treatment with a rapid acting benzodiazepine such as olam is warranted. It es physicians the opportunity to identify their patients who can use and would most benefit from the rapid anti-epileptic activity.

Patients that can be treated with the ion include those who have a cluster of seizures or e events that e a predictable prodrome, aura, or evolution of their seizures, such that a change in that pattern of evolution can be detected. Examples of the latter are ts with aura, focal seizures that secondarily generalize, or patients with juvenile nic epilepsy whereby the seizure typically manifests over a period of minutes. ts who can recognize aura as a precursor to a seizure would be candidates for self-administration. Patients with a focal seizure without ment of consciousness/awareness would have the mental and motor capacity to be candidates for selfadministration the invention. Patients with some impairment of awareness may be assisted by a caregiver for drug administration.

In addition to patients with aura and patients with secondarily generalized seizures, additional seizure events being considered include patients with cluster (acute tive) seizures, prolonged focal (partial) seizures, or juvenile myoclonic epilepsy. These patient types share the key characteristics of having the need for acute treatment but with the capacity for self-administration. In st, treatment of patients with status epilepticus would not be appropriate given that inhalation is required.

In some embodiments, the alprazolam condensation aerosol is administrated by inhalation at any time before or after onset of symptoms of sy and/or e. In some ments of the ion, the method includes prompt administration of a preparation of alprazolam according to the invention during the aura. In some embodiments, such inhalation administration of alprazolam, will prevent or at least ameliorate the s (intensity, on or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of e, either with or without the benefit of a warning aura.

Administration may occur when the t is in the prodrome or aura phase of seizure. For example, the alprazolam may be administered when the subject experiences sensory aura, such as somatosensory, visual, auditory, ory, gustatory, epigastric or cephalic, experiential aura, such as affective, mnemonic, hallucinatory, or illusory auras.

The methods of the invention provide fast onset of therapeutic benefit. The present method may provide a rapidly effective rescue tion because in some instances the therapeutic effect is maximal within 15 minutes, or within 5 minutes, or within 2 minutes of inhalation of alprazolam. For example, epileptiform activity may be absent within 15 minutes, or within 5 minutes, or within 2 minutes of inhalation of alprazolam in accordance with the invention. Further, epileptiform activity may be absent for at least six hours after inhalation of olam.

The alprazolam formulations of this ion also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.

The method described herein can provide for improved bioavailability of alprazolam, delivery of higher concentrations of alprazolam via the oral inhalation route, faster attainment of therapeutic levels of alprazolam in the blood plasma, avoidance of the liver portal vein and concomitant avoidance of first pass effects and/or faster presentation of alprazolam to the brain. The method described and embodied herein achieves bioavailability that is from about 80-125% (e.g. about 90-110%, or more particularly about 92.5-107.5%) of that achieved with olam administered intravenously. In some embodiments, the alprazolam and treatment with alprazolam are substantially ritating and well-tolerated.

In one embodiment, the loaded alprazolam is an inhalation powder supplied in a single-use, disposable inhaler for oral inhalation. Doses may range from 0.125 mg to 4 mg of alprazolam. In some embodiments, the therapeutic dose is in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, as needed to treat seizures. As aerosols, 0.5 mg to 4 mg, preferably 0.5 to 2 mg, alprazolam are generally provided per ation for the ent of seizures. Dosages administered may be dependent on such factors as body weight, age and sensitivity to side effects of the patient to which the alprazolam is administered. Consideration of such factors may be used by a health care professional to ine the desired dosage for an individual.

In some cases, administration of alprazolam condensation aerosols may be up to eight times a day when a patient is experiencing seizure activity, such as from 1 to 8, or 2 to 8, or 1 to 4, or about 4 to about 6 times per day. olam formulated as an inhaled preparation as described herein is a rapidly effective rescue medication for epilepsy patients. Time to effect is assessed in patients with photosensitive epilepsy, in whom epileptiform activity can be ed at will. It has been found that inhaled alprazolam strongly suppresses epileptic activity within 2 minutes.

Duration of effect was dose related, as was sedation. Inhaled alprazolam has utility in stopping a seizure within 2 minutes of use.

The condensation aerosols of the various embodiments may be formed by preparing a film containing a drug composition of a desired thickness on a heat-conductive and eable substrate and heating said substrate to vaporize said film, and cooling said vapor thereby producing aerosol particles ning said drug composition. Rapid heating in ation with the gas flow helps reduce the amount of decomposition. Thus, a heat source is used that typically heats the substrate to a temperature of greater than 200 °C, ably at least 250 °C, more preferably at least 300 °C or 350 °C, or to 390 °C ± 50 °C and produces ntially complete volatilization (vaporization) of the drug composition from the substrate within a period of 2 seconds, preferably, within 1 second, and more preferably, within 0.5 seconds. lly, the gas flow rate over the vaporizing compound is between about 4 and 50 L/minute. The heating of the alprazolam composition is performed using any suitable method. Examples of methods by which heat can be generated include the following: passage of current through an electrical resistance element; absorption of electromagnetic radiation, such as ave or laser light; and, exothermic chemical reactions, such as rmic solvation, hydration of pyrophoric materials and oxidation of combustible als. Heat sources or devices that contain a chemically reactive al which undergoes an exothermic reaction upon ion, e.g., by a spark or heat element, such as flashbulb type heaters are also suitable. In ular, heat sources that generate heat by exothermic reaction, where the chemical "load" of the source is consumed in a period of between 50-500 msec or less are generally suitable, assuming good l coupling n the heat source and substrate.

The film ess is such that an aerosol formed by vaporizing the compound by heating the substrate and condensing the vaporized compound contains 10% by weight or less of drug-degradation product(s). The use of thin films allows a more rapid rate of vaporization and hence, generally, less thermal drug degradation. Typically, the film has a ess between 0.05 and 20 microns, such as between 0.1 and 10 microns. In some ions, the film has a thickness between 0.5 and 5 microns. The selected area of the substrate surface expanse is such as to yield an effective human therapeutic dose of the drug aerosol.

Alprazolam aerosols of the invention are delivered to a mammal using an inhalation device. A photograph of one embodiment of the inhalation device is shown in Fig. 1. The delivery device comprises an element for heating the composition to form a vapor and an element allowing the vapor to cool, thereby forming a condensation aerosol. Referring to Fig. 2 schematic cut-away views of the device are depicted before and after vaporization is initiated. The resultant aerosol from the vaporization is generally red via inhalation from the device to the lungs of a subject, for local or systemic treatment.

In one embodiment the aerosol is a condensation aerosol. With regard to the condensation aerosol, the delivery device as depicted in Fig. 1 and Fig. 2 es a first element for heating an alprazolam composition to form a vapor; a second element allowing the vapor to cool, thereby providing a condensation aerosol; and, a third element permitting inhalation of the aerosol.

Various suitable first heating elements are described above, and involve a heatable substrate coated with a film of alprazolam. Typically, the substrate or support is heated to a ature sufficient to vaporize all or a portion of the alprazolam film, so that the composition forms a vapor that becomes entrained in a stream of air during inhalation.

The second element that allows cooling is, in its simplest form, an inert passageway g the heating element to the inhalation element. The third element permitting inhalation is an aerosol exit portal that defines a connection between the g element and the mammal's respiratory system, such as a mouthpiece.

Fig. 3 shows high speed photographs showing the generation of aerosol particles from a device similar to the device of Fig. 1. The device has a heat-conductive ate about 2 cm in length coated with a film of drug. The drug-coated substrate was placed in a chamber through which a stream of air was g in an upstream-to-downstream ion (from left to right in at rate of about 15 L/min. The substrate was electrically heated and the progression of drug vaporization monitored by ime photography. The raphs show the sequence of drug vaporization and aerosol generation at time intervals of 30 milliseconds (msec), 50 msec, and 200 msec, respectively after initiation of heating (time =0). The white cloud of drug-aerosol les formed from the drug vapor entrained in the flowing air is visible in the raphs. Complete vaporization of the drug film was achieved by 500 msec and the vapor can be seen exiting the device at the right.

Inhalation h the device is detected by the breath sensor, which tes an electrical signal that activates the starter to initiate the redox reaction. This leads to rapid heating of the exterior surface of the hermetically sealed heat package to approximately 390°C ± 50°C, which is also accompanied by a clicking sound associated with the thermal expansion of the stainless steel. Heat then transfers into the alprazolam coated as a thin film on the heat package exterior. Because the thin film of alprazolam has a high surface area, vaporization of the alprazolam is very rapid, occurring in less than 1 second and before substantial thermal decomposition can occur.

The alprazolam aerosol of the invention has a mass median namic er (MMAD) of about 0.5 μm to 3.0 μm. The aerosol particle size diameter preferably is from 0.5 to 3 s, which is optimal for deep lung delivery. The pharmacokinetics of the administered alprazolam dose is similar to an IV injection. Achievement of peak plasma levels within minutes via a simple, user-friendly ry system makes the ion ideal for the acute treatment of seizures.

As shown in Figure 4, the particle size distribution of the alprazolam aerosol in one embodiment has alprazolam les having a MMAD of 1.2 to 1.8 microns. At least 80% by weight of the olam aerosol particles have a size less than 5 microns, preferably at least 90% by weight of the alprazolam aerosol particles have a size less than 5 microns. At least 50% by weight of the alprazolam aerosol particles have a size less than 2 microns, preferably at least 50% by weight of the alprazolam aerosol particles have a size less than 1 micron. The Next Generation Pharmaceutical Impactor (NGI) was used to determine the particle size distribution.

In some embodiments, the alprazolam is administered from a hand-held, single-dose, single-use inhalation device. The drug is stered in a single, normal breath, which is sufficient at typical patient tidal volumes to provide complete delivery of a dose of the alprazolam vapor. The single dose device may include a pull-tab that when pulled from the device renders it ready for use, which is indicated by illumination of a colored light located in the device g. The device may remain active to facilitate delivery for a minimum of 15minutes. To use, the patient simply exhales and then seals his or her lips around the mouthpiece of the product and inhales deeply, leading to generation and delivery of the drug aerosol. When the heat package is actuated, the green light turns off, indicating that the drug has been discharged. After use, the device is discarded. Since the heat package redox reaction occurs in an all-or-none fashion, the device contains no active reactants after use, nor can the product be reused.

The t invention delivers drugs non-invasively to the deep lung producing reliable IV-like pharmacokinetics. The -activated device rs the drug while the patient simply takes a single inspiration through the mouthpiece without any other coordination needed. The drug delivery device and method for using it allows for self- administration and high reliability of delivery, producing rapid drug delivery and faster onset of action. Delivery of alprazolam in accordance with the invention can provide clear advantages over routes of administration currently available or in development, i.e., rectal and nasal administration.

Studies conducted ed safety pharmacology as well as acute and repeatdose toxicity studies in dogs and rats. Aerosolized alprazolam was used in these s as it is the intended route of administration in clinical trials. The lone exception (as noted below) was the use of intravenous (IV) bolus administration in the safety pharmacology study. Safety studies are summarized y below.

In a pharmacokinetic (PK) study in dogs, alprazolam PK was profiled ing either intravenous or inhalation administration. Mean bioavailability was estimated to be 85-96% with an inhalation Tmax of less than 1 minute.

In a 5-day exploratory inhalation toxicity study in dogs, the no-observedadverse-effect level was 1.5 mg/kg/day for ent-related histopathological findings.

In a 28-day GLP tion toxicity study with a 14-day recovery period in dogs, the no-observed-effect level for the histopathological finds was 2.8 and 4.4 mg/kg/day for males and females, respectively. There were no deaths during the course of the study. The immunogenic potential of olam was ed and there were no immunoglobulin or hypersensitivity response.

In a cardiovascular and respiratory safety study in dogs intravenously dosed with alprazolam over 5 sec, a transient se in respiratory rate and transient increase in heart rate were found. However, these s were within normal ranges and not considered biologically significant. The plasma concentration of alprazolam associated with modest cardiovascular or respiratory effects exceeded 900 ng/mL and would not be expected to induce any significant changes at the range of doses d considered for clinical studies (0.5 to 2.0 In a rat inhalation MTD study, a single dose of inhaled alprazolam was well tolerated up to 10.8 mg/kg and did not result in any adverse signs of toxicity. In the 14-day inhalation toxicity study in rats, the no-adverse-effect level was considered to be 10.3 mg/kg/day.

In vitro drug transporter and cytochrome P450 inhibition potential were also studied. No inhibition was ed at the maximum alprazolam concentration tested.

A Phase 2a proof-of concept study to investigate the potential of inhaled alprazolam in patients with photosensitive epilepsy was recently completed (See Example 1).

Oral inhalation treatment using inhaled alprazolam will focus on subtypes of patients diagnosed with partial onset (focal) or generalized seizure disorder in which acute treatment with a benzodiazepine for a rapid anti-seizure activity could be beneficial. d alprazolam has been shown to produce a rapid rise in alprazolam plasma levels (less than 2 min) and effects on EEG in patients with photosensitive epilepsy within 2 minutes. Patient es under eration include patients with cluster es; patients with e events that e a predictable prodrome, aura, or evolution of their seizures, such that a change in that pattern of evolution can be detected; and patients with juvenile myoclonic epilepsy. e epilepsy is commonly found in individuals under the age of 18, adolescent patients represent a significant subpopulation that might t from inhaled alprazolam. cy and tolerability data from adults, such as age 18-60, or older, can be informative for dose selection in the younger population. Studies on cent subjects (ages 13-17) assessing PK, safety and tolerability prior to Phase 3 could be used to inform the doses for this age range. Modeling and simulation of clinical study data in adults and adolescents may be used to support the dose selection for those age groups and may also inform dose selection for children less than 13 years old.

Other indications where the invention may be used include acute panic attack, severe dental anxiety, post-traumatic stress disorder (PTSD), autism with intermittent aggressive behavior, or for n ophthalmic procedures.

EXAMPLES The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

Example 1 evaluated the ability of inhaled alprazolam to y suppress photosensitivity in a double blind placebo-controlled crossover proof of concept study. This study was an in-clinic, randomized, placebo-controlled, double-blind , 5-way crossover study design, which allowed for small patient size. Epilepsy patients were evaluated using an Intermittent Photic Stimulation model, allowing for screening for antiepileptic effects without triggering seizures or convulsive responses. Three doses of alprazolam were investigated along with placebo (twice) in 5 subjects.

In patients with photosensitive epilepsy, intermittent photic stimulation was used to elicit generalized tiform EEG activity. The t is exposed to certain frequency of light ation (flash frequencies), and photosensitivity range measured. The model has been used to identify antiepileptic effects on a number of drugs. The model is specific ive drugs did not show photosensitivity).

The primary objectives of the study were to assess 1) the effects of inhaled alprazolam on the IPS-induced photoparoxysmal EEG response in patients with sy, 2) the sedative properties of these doses in order to select maximally-effective dose with the least sedation for further clinical studies, and 3) overall safety. The primary nt was the change in the Standard Photosensitivity Range (SPR) in subjects receiving each dose of d alprazolam.

Patients at least 18 years old with photosensitive epilepsy at 3 sites were tested on a baseline day, and then received in ized order either inhaled placebo (on 2 days) or 0.5, 1 or 2 mg inhaled alprazolam red using a hand-held inhaled alprazolam device. Study days were separated by at least 1 week. Presence (and degree) of photosensitivity was measured e, then at 2 min, 10 min, 30 min, 1,2, 4 and 6 hours postdose.

Plasma concentration of study drug was measured at each time point. Sedation was assessed at each time point using the 100-mm linear visual analogue scale (VAS).

The test subjects were exposed to ittent photic stimulation (14 frequencies, from 2 to 60 Hz), starting with lowest frequency and increasing frequency stepwise until a photosensitivity response was elicited. The test was repeated with the highest frequency and decreased frequency. The results can be summarized in a quantitative measure known as the Standardized Photosensitive Range (SPR). The Maximum SPR is 14. In the example shown, SPR is 8. The Primary endpoint is reduction in mean SPR, which is an indication of izure activity. Patients that have a vely stable SPR were enrolled in the study to allow for small study size.

Secondary study endpoints included assessment of sedation using two visual analogue scales (VAS); correlation of plasma concentrations of inhaled alprazolam with PD effects on the SPR range; correlation of plasma concentrations of inhaled alprazolam with PD effects on sedation; and assessment of adverse events and changes in the neurological examination.

Five patients were enrolled and completed all ent arms. All doses decreased the mean standardized photosensitivity range (SPR), with maximal or near-maximal effect ing by 2 minutes post dose. Higher doses produced effects on SPR out to 4 hours.

Sedation was dose related, but separated from SPR effects at later time points. Treatment was well ted with no serious adverse events.

The effects of inhaled alprazolam were assessed on the IPS-induced photoparoxysmal EEG response in patients with epilepsy. The plasma concentrations of inhaled alprazolam were correlated with pharmacodynamic effects on IPS and sedation (PK/PD correlation). The sedative properties of these doses were assessed in order to select lly effective dose with the least sedation for further clinical studies. The safety of a single dose of inhaled alprazolam was assessed in ts with photosensitive epilepsy.

Figures 5A and 5B show graphs of the mean plasma concentration of alprazolam in phase 1 and phase 2a al trials respectively. The graphs indicate a rapid uptake of alprazolam into the plasma after oral administration of the condensation aerosol.

Notably, oral administration as described herein es plasma uptake of alprazolam wherein the Tmax is less than 15 minutes post administration, or wherein the Tmax is less than 5 minutes post administration or wherein the Tmax is less than 2 minutes post administration.

Mean peak plasma concentration occurred one to two minutes after administration of the alprazolam concentration aerosol. Delivery of the olam via inhalation of a sation aerosol resulted in a Cmax of at least 5 ng/ml, or at least 12 ng/ml or at least 30 ng/ml less than s after administration, when administered in doses of at least 0.5 mg.

The change in the SPR range in subjects receiving each dose of inhaled alprazolam was compared to placebo. A correlation of plasma concentrations of inhaled alprazolam with pharmacodynamic effects on the SPR range was made. Figure 6 shows a graph of the mean rdized photosensitivity rage (SPR) over time for the three dose rates used in the study. All three inhaled alprazolam doses produced a decrease in mean SPR (primary study endpoint). For all doses, maximal or near-maximal effect ed by about 2 s. The maximal decrease in epileptic response compared to placebo for all three doses at two s suggest rapid anti-epileptic activity.

With respect to the magnitude of the change in SPR, a maximal decrease of approximately 5 steps was obtained, at least at the earlier time points. For the 1 mg and 2 mg doses, almost complete elimination of the photosensitivity was achieved. These effects represent meaningful changes. For example, the 90% Confidence Interval was ined for the mean change in SPR from baseline for each dose at each time point. Magnitude and duration of effect was comparable for 1 mg and 2 mg. The results at the first time point (2 minutes) is illustrated where there is no or minimal overlap in the Confidence Interval.

The results demonstrated a maximal or near-maximal decrease in epileptiform response (primary nt) for all doses (0.5 mg, 1 mg and 2 mg) by the 2 minute timepoint, suggesting rapid anti-epileptic activity.

Figures 7A and 7B show EEG traces of a representative patient prior to and after dosing with alprazolam condensation aerosol tively. The post-dose traces show complete abolishment of epileptiform activity. The epileptiform activity shown in Figure 7A shows erratic brain activity during a seizure. After treatment the brain activity reverts to normal as seen in Figure 7B. ment of the sedation using 2 visual analogue scales was made. Figure 8 shows a graph of the mean Visual ue Scale (VAS) for patients after dosing with alprazolam condensation l. A ation of plasma concentrations of inhaled alprazolam with pharmacodynamic effects on sedation was made. VAS measures sedation and suggests rapid onset of action in the brain after oral inhalation administration of alprazolam.

Maximum sedation occurred within about two minutes of administration of alprazolam.

Clinical observations t early onset of sedation at 30 seconds.

] Correlation between the SPR and VAS responses showed that both responses showed onset in less than two minutes, demonstrating a rapid, predictable onset of effect.

Sedation recovered to near placebo levels within six hours of administration. Reduction of SPR was generally maintained for at least six hours after administration, demonstrating an te duration of effect, without being too long. A 1 mg dose may be optimal for balancing potential anti-epileptic effect with the level of sedation.

An assessment of adverse events and changes in the ogical examination were made. The safety profile was consistent with oral alprazolam. No significant treatment emergent adverse events were observed, as summarized in Table 1. The minimal adverse effects suggest that the treatment was well tolerated.

Table 1.

Placebo 0.5 mg 1 mg Total number of subjects Adverse Event N = 5, n N = 5, n N = 5, n experiencing an event Cough 0 2 1 2 Dizziness 0 1 0 1 Dysgeusia 1 2 2 2 Oral Dysaesthesia 0 2 0 2 Sedation/somnolence 1 1 2 2 Bioavailability can be determined by a suitable pharmacodynamics , such as comparison of area under the blood plasma concentration curve (AUC) for the inhaled and intravenously administered drug. It is further understood that the percent bioavailability of the inhalation administered alprazolam may be determined by comparing the area under the blood plasma concentration curve obtained with one dose of the alprazolam (e.g. 1 mg of inhaled alprazolam) with another dose of alprazolam stered enously (e.g. 0.5 mg of i.v. olam), taking into consideration the difference in dose. Thus, for the sake of illustration, a 1 mg inhaled alprazolam dose that achieves an AUC that is precisely half of the AUC obtained with 0.5 mg of i.v. alprazolam would have a bioavailability of 100%.

In summary, all three inhaled alprazolam doses ed a se in mean SPR (primary study endpoint). For all doses, maximal or near-maximal effect occurred by 2 minutes. Magnitude and duration of effect was comparable for 1 mg and 2 mg. Dose related changes were observed in the visual-analogue scale (VAS) for sedation and sleepiness, importants marker for potential adverse events associated with dosing. PK analysis showed dose proportionality with plasma trations. In all cases, treatment with the inhaled drug was generally well tolerated, with no reported serious adverse events (SAEs) at doses up to 2 mg. Expected CNS adverse events (primarily sedation and somnolence) showed that respiratory AEs were mild or moderate and were resolved. The effect on SPR shows rapid anti-epileptic activity.

In conclusion, the results from this study demonstrated rapid and substantive decrease in mean SPR at all three d alprazolam doses. For all doses, maximal or nearmaximal effect occurred by the 2 minute timepoint. The ude and duration of the effect was comparable for the 1 mg and 2 mg doses. Dose d changes were observed in the visual-analogue scale (VAS) for sedation and sleepiness, but over a different time frame than the observed changes in SPR. Overall, the decrease in SPR suggests the ial for rapid anti-epileptic activity.

The description of the various embodiments has been presented for purposes of illustration and description, but is not intended to be exhaustive or limiting of the invention to the form disclosed. The scope of the present invention is limited only by the scope of the following claims. Many modifications and variations will be apparent to those of ordinary skill in the art. The embodiments described and shown in the s were chosen and described in order to n the principles of the invention, the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated. All references cited herein are incorporated in their entirety by reference.

Throughout this specification and the claims that follow, unless the context requires ise, the word "comprise", and ions such as "comprises" and "comprising", will be tood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of tion that that prior publication (or ation d from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (20)

1. Use of olam for the preparation of a medicament for the cessation of an ongoing epileptic seizure in a subject in need thereof, wherein the seizure has not progressed to status epilepticus, wherein the subject is selected from patients with partial (focal) or generalized seizures, and wherein the medicament is to be administered orally in the form of a condensation aerosol.

2. The use according to claim 1, wherein the subject is selected from patients with aura, focal seizures that secondarily generalize, or patients with juvenile myoclonic epilepsy whereby the seizure typically manifests over a period of minutes.

3. The use according to claim 1 or 2, wherein the ment is produced by preparing a film containing an alprazolam composition on a onductive and impermeable substrate and heating said substrate to at least 300 °C, to at least 350°C or to 390 °C ± 50 °C, thereby substantially ting volatilization ization) of the alprazolam composition from the substrate within 2 seconds, and g the vapor produced thereby producing aerosol particles containing said alprazolam ition.

4. The use according to claim 3, wherein lization (vaporization) of the alprazolam composition is substantially completed within 1 second.

5. The use according to claim 3, wherein volatilization (vaporization) of the alprazolam composition is substantially ted within 0.5 seconds.

6. The use according to any one of claims 3 to 5, n the alprazolam film has a thickness of between 0.1 and 10 µm.

7. The use according to claim 6, wherein the alprazolam film has a thickness of between 0.5 and 5 µm.

8. The use ing to any one of claims 1 to 7, wherein the medicament is to be delivered via inhalation to the lungs of the subject to achieve an alprazolam plasma Tmax of less than 2 minutes post administration.

9. The use according to any one of claims 1 to 8, wherein the alprazolam amount provided per ation is n 1 mg and 2 mg.

10. The use according to any one of claims 1 to 9, n the medicament is ed as an inhalation powder to be administered from a single-use, disposable inhaler for oral inhalation.

11. The use according to any one of claims 1 to 10, n at least 80% by weight of the alprazolam aerosol particles have a size less than 5 µm.

12. The use according to claim 11, wherein at least 90% by weight of the alprazolam aerosol particles have a size less than 5 µm.

13. The use according to any one of claims 1 to 12, wherein at least 50% by weight of the alprazolam aerosol particles have a size less than 2 µm.

14. The use according to any one of claims 1 to 13, wherein the alprazolam condensation aerosol is substantially excipient free, preferably the alprazolam condensation aerosol is excipient free.

15. The use according to any one of claims 1 to 14, n the medicament is to be selfadministered at onset of one or more symptoms of the seizure, or after onset of one or more symptoms of the seizure.

16. The use according to any one of claims 1 to 15, wherein the medicament is to be administered when the subject experiences a sensory or experiential aura.

17. The use according to any one of claims 1 to 16, n the subject is a patient with a focal seizure without impairment of consciousness/awareness.

18. The use according to any one of claims 1 to 17, wherein the subject is a patient with prolonged focal partial seizures, or juvenile myoclonic epilepsy.

19. The use according to any one of claims 1 to 18, wherein the medicament is to be delivered via inhalation to the lungs of the t to achieve a maximal therapeutic effect within 2 s of inhalation.

20. The use according to any one of claims 1 to 19, wherein the medicament is to be administered non-invasively to the deep lung, thereby ing reliable IV-like pharmacokinetics, using a breath-activated device that delivers the alprazolam while the patient simply takes a single inspiration through the mouthpiece of said device without any other coordination needed. Time = 0, ion of heating Time = 30 ms WWII/”#4 Concentration (ng/ml) 125 mg «\\\\\\w 3.2513 mg 0.590 mg 1.0 mg “”210 mg 0.0 5.0 10.0 15.0 Time (minutes) Concentration ...... ng/ml \uu\“““m<<\)<““