Method for treating epilepsy

Abstract

To provide methods for treating epilepsy and / or seizures in a mammal subject.SOLUTION: The present invention provides methods 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 aerosol, e.g., condensation aerosol, through an oral inhalation route.SELECTED DRAWING: None

Description

Technical Field

[0001] Copyright Notice Part of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner does not object to the reproduction by anyone of a patent document or patent disclosure that is considered to be a patent application or record in the Patent and Trademark Office, but retains all rights in all other copyrights whatsoever.

[0002] The present invention generally relates to a method for treating epilepsy and / or seizures in a subject, the method comprising administering to the subject in need of a therapeutic dose of alprazolam via inhalation. More specifically, the present invention relates to a method for treating epilepsy and / or seizures by administering a condensed alprazolam aerosol.

Background Art

[0003] There are approximately 3 million epileptic patients in the United States. Seizures are of two types: partial seizures and generalized seizures. When a patient is diagnosed, they are prescribed an anti-epileptic drug (AED). If two AEDs are ineffective, the disease is considered refractory or uncontrolled. One million patients live with uncontrolled seizures because there is no available treatment that works for them. Approximately 200,000 or 20% of the uncontrolled people have a premonitory system or predictive pattern that warns the patient of the onset of seizure activity. The premonitory signals can occur minutes or days before and can include changes in behavior such as muscle jerks, déjà vu, a "mean streak", hallucinations or illusions, bad odors, anxiety, or flashes of light.

[0004] Seizures can be defined as abnormal and uncontrolled electrical activity in brain cells. Seizures can progress through four stages: premonitory symptoms, aura, seizure, and postictal. An aura is a small partial seizure, often followed later by a larger event. Predictive patterns can occur during the premonitory symptoms and aura phases, and drugs that improve or halt seizure activity can be administered to patients with such predictive patterns. To date, there are no out-of-office treatments applied to treat seizures during these periods. The seizure or ictal phase is the main generalized seizure stage. What happens to a person during a seizure depends on the area of the brain where the breakdown of neural activity occurs. Certain areas of the brain may be more involved in seizure activity than others. The motor cortex, which is responsible for body movement, and the temporal lobe, including the hippocampus involved in memory, are particularly sensitive to biochemical fluctuations (e.g., decreased oxygen levels, metabolic imbalances, infections) that stimulate abnormal brain cell activity. Following a seizure, a person enters the postictal state. This period is commonly characterized by drowsiness and confusion. The postictal state is a period during which the brain recovers from the damage it has sustained.

[0005] Episodes of recurrent seizures are different from the normal seizure pattern. Recurrent seizures include multiple seizures, such as three or more times within 24 hours in adults (or within 12 hours in children). An episode may last from a few minutes to several hours. These seizures carry a significantly higher risk of status epilepticus.

[0006] Benzodiazepines are recognized as a treatment option for seizures. Drugs in this family have been observed to have sedative, anxiolytic, and muscle relaxant properties. Benzodiazepines are often classified as anxiolytics and skeletal muscle relaxants. They are thought to be useful in preventing, treating, or improving anxiety, insomnia, agitation, seizures (such as those induced by epilepsy), muscle cramps and rigidity, withdrawal symptoms associated with the continuous abuse of central depressants, and symptoms of exposure to neuroleptics. Benzodiazepines act on the GABA of nerve cells AIt acts by binding to the receptor, and according to this, it is thought to cause a conformational change in the receptor, making the receptor more accessible to gamma-aminobutyric acid (GABA).

[0007] Rectal diazepam (DZ) gel (Diastat®) is approved for the treatment of acute repetitive seizures (ARS). This gel is administered only by trained caregivers or healthcare professionals, and multiple steps are taken to administer this gel. This gel is only likely to be used in pediatric patients. The onset of the therapeutic effect is 30 - 40 minutes after administration, and the bioavailability of the dose is 70 - 90%. The peak plasma concentration occurs 1.5 hours after administration. Diazepam has a long half-life of 46 hours, and the active metabolite desmethyldiazepam has a half-life of 71 hours. Sedation and drowsiness are known side effects.

[0008] A pharmaceutical composition containing one or more benzodiazepine drugs for nasal administration is disclosed in U.S. Patent No. 8,895,546. Intranasal and intramuscular administration of benzodiazepines such as midazolam or diazepam are not yet approved for the treatment of ARS. There may be four steps to administer a benzodiazepine intranasally. The onset of action may take 15 - 40 minutes, and the bioavailability of the dose is only 40 - 80%. Side effects can include nasal irritation, memory loss, and black box respiratory depression.

[0009] Once the initial seizure has ended, rectal, intranasal, and intramuscular administration of benzodiazepine drugs are administered in the late stage of the seizure to address the prevention of the next seizure. It is desirable to identify and develop a treatment that can be administered during the prodromal or premonitory phase of seizure activity to reduce the severity of the seizures that occur or stop them. The present invention is directed to overcoming or improving one or more of the problems discussed above.

Summary of the Invention

[0010] The present invention provides a method for treating epilepsy and / or seizures in a mammalian subject, which comprises administering a therapeutically effective dose of alprazolam via oral inhalation. The alprazolam is delivered through the oral inhalation route in the form of an aerosol, such as a condensed aerosol. In some embodiments, the patient is a human.

[0011] The alprazolam aerosol comprises particles of alprazolam having a particle size distribution. In one embodiment, at least 80% by weight of the alprazolam particles have a size of less than 5 microns. In another embodiment, at least 90% by weight of the alprazolam particles have a size of less than 5 microns. In another embodiment, at least 50% by weight of the alprazolam particles have a size of less than 2 microns. In another embodiment, at least 50% by weight of the alprazolam aerosol particles have a size of less than 1 micron. The alprazolam may be substantially excipient-free or excipient-free in some embodiments.

[0012] The dose of alprazolam administered to the subject exhibits specific C max and T max characteristics. For example, the alprazolam exhibits a plasma T of about 2 minutes to about 15 minutes after administration max . In some embodiments, the T max is less than 15 minutes after administration, preferably less than 5 minutes after administration, or more preferably less than 2 minutes after administration. The C max is at least 5 ng / mL after oral administration. For example, the C max is at least 12 ng / mL after oral administration, or at least 30 ng / mL after oral administration.

[0013] Alprazolam administered orally exhibits a bioavailability similar to that of alprazolam administered intravenously. For example, the administered alprazolam aerosol exhibits a bioavailability of about 80 - 125% of the bioavailability achieved with alprazolam administered intravenously.

[0014] The alprazolam may be self-administered at the onset of one or more symptoms of a seizure, or the alprazolam may be self-administered before the onset of one or more symptoms of a seizure, or the alprazolam may be self-administered after the onset of one or more symptoms of a seizure. One or more symptoms of epilepsy include seizures; and / or the treatment defends against seizures, reduces or improves the intensity of seizures, reduces or improves the frequency of seizures, interrupts the seizure cycle, and / or prevents the occurrence or recurrence of seizures.

[0015] In other embodiments, the seizure includes an epileptic seizure, a breakthrough seizure, or other seizures; the seizure includes a partial (focal) seizure or a generalized seizure; the partial seizure includes a complex partial seizure, a simple partial seizure, or a seizure originating within a neural network limited to one cerebral hemisphere; or the generalized seizure originates at several points within a bilaterally distributed neural network or progresses from a partial seizure.

[0016] If the subject is a patient in the prodromal or premonitory phase of a seizure, for example, if the patient subjectively feels a sensory or experiential aura, and the sensory aura includes somatosensory, visual, auditory, olfactory, gustatory, gastric or head auras, or the experiential aura includes emotional, memory, hallucinatory, or illusory auras, the method also includes administration of an alprazolam condensed aerosol. Another embodiment of the method is an embodiment where the subject is a patient with cluster or acute repetitive seizures, long-term focal partial seizures, or juvenile myoclonic epilepsy.

[0017] The present invention may be an emergency medicine for the treatment of epilepsy and / or seizures. During the operation of the device described herein, the patient obtains an alprazolam dose that provides immediate symptom relief.

[0018] The effect of the administered alprazolam may be maximal within 2 to 15 minutes of alprazolam inhalation. For example, the maximal effect may occur within 5 minutes of alprazolam inhalation, or within 2 minutes of alprazolam inhalation.

[0019] As an embodiment, there is an embodiment in which epileptiform activity is not present within 15 minutes of alprazolam inhalation; and / or an embodiment in which epileptiform activity is not present for at least 6 hours after alprazolam inhalation.

[0020] Various modifications and additions can be made to the described embodiments without departing from the scope of the invention. For example, while the foregoing embodiments refer to specific features, the scope of the invention also encompasses embodiments having different combinations of features and embodiments that do not include all of the features described above.

[0021] A further understanding of the nature and advantages of particular embodiments may be realized by reference to the remainder of the specification and drawings, in which like reference numerals are used to refer to like components.

Brief Description of the Drawings

[0022]

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DETAILED DESCRIPTION OF THE INVENTION

[0023] Although various aspects and features of specific embodiments have been summarized above, the following detailed description shows some embodiments in more detail and enables those skilled in the art to practice such embodiments. The described examples are provided for illustrative purposes and do not limit the scope of the present invention.

[0024] In the following description, for the purpose of explanation, numerous specific details are presented in order to provide a complete understanding of the described embodiments. However, it will be apparent to those skilled in the art that the embodiments of the present invention can be practiced without some of these specific details. Some embodiments are described and claimed herein, and various features result from different embodiments, and it must be noted that the features described with respect to one embodiment can be utilized with other embodiments. However, since another embodiment of the present invention can omit one or more features of any described or claimed embodiment, by the same evidence, none of such features should be considered essential to each embodiment of the present invention.

[0025] Unless otherwise noted, all numbers used herein to express amounts, dimensions, and the like are to be understood as being modified in all instances by the term "about". The modifier "about" shall generally have the meaning of recognized approximation. In some embodiments, the term may be interpreted more precisely as meaning within a certain percentage of the modified value. For example, "about" may mean ±20%, ±10%, ±5%, ±2%, ±1%, or less in some embodiments.

[0026] In this application, the use of the singular includes the plural unless specifically stated otherwise, and the use of the terms "and" and "or" means "and / or" unless stated otherwise. Further, the use of the term "comprising" and other forms, such as "comprises" and "comprised of", must be regarded as non-exclusive. Similarly, terms such as "element" or "component" include both elements and components that contain one unit and elements and components that contain more than one unit, unless specifically stated otherwise.

[0027] The "aerodynamic diameter" of a given particle refers to the diameter of a spherical droplet having a specific gravity of 1 g / mL (the specific gravity of water) and the same sedimentation rate as the given particle.

[0028] "Aerosol" refers to a collection of solid or liquid particles suspended in a gas.

[0029] "Aerosol mass concentration" refers to the mass of particulate matter per unit volume of aerosol.

[0030] "Condensed aerosol" refers to an aerosol formed by the evaporation of a composition and subsequent cooling of the vapor such that the vapor condenses to form particles.

[0031] "Tidal volume of a typical patient" refers to 1 L for an adult patient and 15 mL / kg for a pediatric patient.

[0032] As used herein, the phrase "therapeutically effective amount" (or more simply "effective amount") includes an amount sufficient to provide a specific therapeutic response when a drug is administered to a patient in need of a particular treatment. The therapeutic effect can be any therapeutic effect within the range from prevention, amelioration, treatment of symptoms to arrest or cure of the disease. A skilled clinician will recognize that the therapeutically effective amount of a drug depends on the patient, the indication, and the particular drug being administered.

[0033] As used herein, the term "seizure" encompasses generally recognized types of seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures.

[0034] As used herein, the term "prevention" refers to preventing the onset of a disorder (including temporarily preventing it). In the case of seizures, prevention can occur with or without the benefit of a warning aura.

[0035] The term "anticonvulsant" encompasses the treatment of seizures, protection against seizures, reduction or improvement in the intensity of seizures, reduction or improvement in the frequency of seizures, and / or prevention of the occurrence or recurrence of seizures. In this regard, the treatment of seizures includes stopping ongoing seizures, reducing the severity of ongoing seizures, or reducing the duration of ongoing seizures. Protection against seizures includes preventing future seizures from occurring.

[0036] As used herein, the term "pharmacokinetics" (PK) refers to the chemical metabolism of a drug, i.e., the fate of the drug from the moment of administration until it is completely eliminated from the body. Pharmacokinetics explains how the body affects a particular drug after administration through the mechanisms of absorption and distribution of substances in the body, metabolic variations, and the effects and excretion pathways of the drug's metabolites. The pharmacokinetic properties of a chemical drug are affected by the route of administration and the dose of the drug administered. Pharmacokinetic properties may affect the absorption rate. "Pharmacodynamics" (PD) is the study of how a drug affects an organism, such as the onset and duration of the response to the drug. As recognized in PK / PD models, both affect each other with respect to administration, benefit, and adverse effects.

[0037] Alprazolam (API) is the compound 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-α][1,4]-benzodiazepine or 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepine (CAS number 28981-97-7), molecular formula C 17 H13 ClN 4 This is the international common name of alprazolam. Alprazolam is substantially insoluble in water, soluble in ethanol and methanol, and easily soluble in chloroform. It is an odorless white crystalline powder. The structure of alprazolam is shown as Formula I.

Chemical formula

[0038] The trade name of alprazolam is Xanax (registered trademark). Alprazolam may be manufactured using the process disclosed in U.S. Patent No. 3,987,052. As used herein, the term "inhaled alprazolam" refers to a dose of alprazolam delivered by oral inhalation of a condensed aerosol from a device, as described herein.

[0039] In one aspect, the present invention provides a method for treating epilepsy and / or seizures in a mammalian subject, comprising administering a therapeutically effective dose of alprazolam. The alprazolam is delivered in the form of a condensed aerosol through an oral inhalation route. The therapeutically effective amount of alprazolam in some embodiments is from about 0.1 mg to about 2 mg. In some embodiments, the mammal is a human.

[0040] Treatment of epilepsy and / or seizures includes protection against seizures, reduction or improvement in seizure intensity, reduction or improvement in seizure frequency, interruption of seizure cycles, and / or prevention of seizure occurrence or recurrence. Certain embodiments are methods for acute treatment of seizures.

[0041] Epileptic patients may be affected by partial (focal) or generalized seizures. In the current International League Against Epilepsy (ILAE) classification, focal seizures are described as including seizures with or without impairment of consciousness and with specific autonomic, motor, psychic, sensory, or other phenomena. Focal seizures originate within a neural network limited to one cerebral hemisphere. Focal seizures may be associated with an impairment of consciousness (or awareness) (complex partial seizures) or may occur without impairment (simple partial seizures). Focal seizures can also progress to generalized seizures (focal to bilateral tonic-clonic). Generalized seizures originate at several points within a bilaterally distributed neural network and rapidly involve that neural network.

[0042] The onset of both types of seizures may be preceded by an "aura" or "warning". Many seizures, especially severe tonic or tonic-clonic seizures, will be heralded by one or more premonitory events well known to the patient or to someone familiar with the patient. An aura is usually or typically defined as the subjective experience of a focal seizure that precedes the seizure the patient experiences. These auras are in fact unique to each patient. Each patient will generally be affected by different types of auras specific to that patient. Auras can be classified as sensory (somatosensory, tactile, visual, auditory, olfactory, gustatory, sensations in the stomach or head) or experiential (emotional, mnemonic, hallucinatory, or illusory). Not all patients who have seizures experience an aura, but auras are not uncommon among patients who have the worst types of seizures, especially tonic-clonic seizures.

[0043] In addition to subjects who experience auras and / or secondary generalized seizures, additional seizure events include cluster (acute repetitive) seizures, long-term focal (partial) seizures, and juvenile myoclonic epilepsy.

[0044] The application of "acute seizure treatment" is for possible patient types where emergency treatment with an immediate-acting benzodiazepine such as alprazolam is guaranteed. It provides the physician with the opportunity to identify patients who can use it and who will most benefit from rapid antiepileptic activity.

[0045] Patients who can be treated by the present invention include those having a cluster of seizures or seizure events including predictable prodromal symptoms, auras, or seizure progression such that a change in the progression pattern can be detected. Examples of the latter are patients with an aura, focal seizures that secondarily generalize, or juvenile myoclonic epilepsy where seizures typically manifest symptoms over several minutes.

[0046] Patients who can recognize an aura as a premonition of a seizure would be candidates for self-administration. Patients with focal seizures without impairment of consciousness / awareness have the mental and motor abilities to be candidates for self-administration of the present invention. Patients with any impairment of awareness may be assisted by a caregiver for drug administration.

[0047] In addition to patients with an aura and patients with secondarily generalized seizures, additional seizure events to be considered include patients with cluster (acute repetitive) seizures, long-lasting focal (partial) seizures, or juvenile myoclonic epilepsy. These patient types share the important feature of having a need for acute treatment but having the ability for self-administration. In contrast, the treatment of patients in status epilepticus would not be appropriate if inhalation is required.

[0048] In some embodiments, the alprazolam condensed aerosol is administered by inhalation at any time before or after the onset of symptoms of epilepsy and / or seizures. In some embodiments of the present invention, the method includes the rapid administration of a preparation of alprazolam according to the present invention during a prodrome. In some embodiments, such inhaled administration of alprazolam will prevent, or at least ameliorate, the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, prevention of a seizure refers to temporarily preventing the onset of a seizure, with or without the benefit of an aura prodrome.

[0049] Administration may be performed when the subject is in the prodromal symptoms or prodromal phase of a seizure. For example, alprazolam may be administered when the subject experiences sensory prodromes such as somatosensory, visual, auditory, olfactory, gustatory, gastric or head auras, or experiential prodromes such as emotional, memory, hallucinatory, or illusory auras.

[0050] The method of the present invention provides a rapid onset of therapeutic benefit. In some examples, since the therapeutic effect is maximized within 15 minutes, or within 5 minutes, or within 2 minutes of alprazolam inhalation, the method of the present invention may provide a rapidly effective rescue medication. For example, epileptiform activity may cease within 15 minutes, or within 5 minutes, or within 2 minutes of alprazolam inhalation according to the present invention. Furthermore, epileptiform activity may cease for at least 6 hours after alprazolam inhalation.

[0051] The alprazolam formulation of the present invention also provides a convenient administration of a therapeutically beneficial drug to patients who do not require intravenous or rectal drug administration.

[0052] The methods described herein can provide improved bioavailability of alprazolam, delivery of higher concentrations of alprazolam via the oral inhalation route, more rapid achievement of therapeutic levels of alprazolam in plasma, avoidance of the hepatic portal vein and concomitant avoidance of the first-pass effect, and / or more rapid presentation of alprazolam to the brain. The methods described and embodied herein achieve a bioavailability of about 80-125% (e.g., about 90-110%, or more particularly about 92.5-107.5%) of the bioavailability achieved with intravenously administered alprazolam. In some embodiments, the alprazolam, and treatment with alprazolam, are substantially non-irritating and well tolerated.

[0053] In one embodiment, the loaded alprazolam is an inhaled powder supplied in a single-use disposable inhaler for oral inhalation. The dosage may be in the range of 0.125 mg to 4 mg of alprazolam. In some embodiments, the therapeutic dosage is in the range of about 0.5 to about 4 mg / dose, preferably about 1 to about 2 mg / dose, required to treat an episode. As an aerosol, 0.5 mg to 4 mg, preferably 0.5 to 2 mg of alprazolam is generally provided by inspiration for the treatment of an episode. The dosage administered may depend on factors such as the weight, age and sensitivity to side effects of the patient to whom alprazolam is administered. Consideration of such factors may be used by a healthcare professional to determine the desired dosage for an individual.

[0054] In some instances, administration of the alprazolam condensed aerosol may be up to 8 times a day, such as 1-8 times a day, or 2-8 times a day, or 1-4 times a day, or about 2-about 6 times, when the patient is experiencing seizure activity.

[0055] Alprazolam formulated as an inhalation preparation as described herein is a rapidly effective rescue medicine for epileptic patients. The time to effect is evaluated in patients with photosensitive epilepsy in which epileptic activity can be voluntarily induced. It has been found that inhaled alprazolam strongly suppresses epileptic activity within 2 minutes. Similar to the sedative effect, the duration of effect was dose-related. Inhaled alprazolam is useful for stopping seizures within 2 minutes of use.

[0056] The condensed aerosols of various embodiments may be formed by preparing a coating containing a drug composition of a desired thickness on a thermally conductive and impermeable substrate, heating the substrate to evaporate the coating, and cooling the vapor, thereby generating aerosol particles containing the drug composition. Rapid heating combined with an air stream aids in reducing the amount of decomposition. Thus, typically the substrate is heated to a temperature above 200 °C, preferably at least 250 °C, more preferably at least 300 °C or 350 °C, or 390 ± 50 °C, and a heat source is utilized that causes substantially complete volatilization (evaporation) of the drug composition from the substrate within 2 seconds, preferably within 1 second, more preferably within 0.5 second. Typically, the air flow rate of the evaporating compound is between about 4 and 50 L / min. Heating of the alprazolam composition is carried out using any suitable method. Examples of methods by which heat can be generated include: passage of an electric current through an electrical resistance element; absorption of electromagnetic radiation such as microwave or laser light; and exothermic chemical reactions such as exothermic solvation, hydration of pyrophoric materials, and oxidation of combustible materials. Also suitable is a heat source or heating device containing a chemical reaction material that undergoes an exothermic reaction upon activation, such as a spark or heating element, for example a flash bulb type heater. Assuming good thermal coupling between the heat source and the substrate, in particular, a heat source that generates heat by an exothermic reaction and consumes the chemical "load" of the heat source in a period between 50 and 500 msec, or less, is generally suitable.

[0057] The film thickness is such that the aerosol formed by evaporating the compound by heating the substrate and condensing the evaporated compound contains 10% by weight or less of the drug degradation product(s). The use of a thin film allows for more rapid evaporation, i.e., generally less thermal degradation of the drug. Typically, the coating has a thickness between 0.05 and 20 microns, for example between 0.1 and 10 microns. In some variations, the coating has a thickness between 0.5 and 5 microns. The selected area of the substrate surface is such that it produces an effective human therapeutic dose of the drug aerosol.

[0058] The alprazolam aerosol of the present invention is 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 includes an element that heats the composition to form a vapor and an element that cools the vapor, thereby forming a condensed aerosol. Referring to FIG. 2, cross-sectional views of the device before and after the start of evaporation are depicted. The aerosol obtained from evaporation is delivered from the device to the lungs of the subject, generally via inhalation, for local or systemic treatment.

[0059] In one embodiment, the aerosol is a condensed aerosol. In connection with the condensed aerosol, the delivery device depicted in FIGS. 1 and 2 includes a first element for heating the alprazolam composition to form a vapor; a second element for cooling the vapor, thereby providing a condensed aerosol; and a third element for enabling inhalation of the aerosol.

[0060] Various suitable first heating elements have been described above and include a heatable substrate coated with a film of alprazolam. Typically, the substrate or support is heated to a temperature sufficient to evaporate all or part of the alprazolam coating, whereby the composition forms a vapor that is entrained in an air stream upon inhalation.

[0061] The second element for cooling, in its simplest form, is an internal passage connecting the heating element to the inhalation element. The third element enabling inhalation is an aerosol inlet / outlet defining the connection between the cooling element and the respiratory system of a mammal, such as a mouthpiece.

[0062] Figure 3 shows a high-speed photograph demonstrating the generation of aerosol particles from a device similar to the device of Figure 1. The device has a thermally conductive substrate approximately 2 cm in length coated with a drug film. The drug-coated substrate was placed in a chamber and an air flow was passed through it at a rate of approximately 15 L / min in the upstream to downstream (left to right in Figure 3) direction. The substrate was electrically heated and the progress of drug evaporation was monitored by real-time photography. The photographs show a series of drug evaporation and aerosol generation at time intervals of 30 milliseconds (msec), 50 msec, and 200 msec respectively after the start of heating (time = 0). The white cloud-like drug aerosol particles formed from the drug vapor mixed in the flowing air are visualized in the photographs. Complete evaporation of the drug film was achieved at 500 msec and the vapor discharging from the device on the right can be seen.

[0063] Inhalation through the device is detected by a respiratory sensor, generating an electrical signal that activates a starter to initiate a redox reaction. As a result, the outer surface of the sealed heat package is rapidly heated to approximately 390°C ± 50°C, which is accompanied by a clicking sound related to the thermal expansion of stainless steel. Subsequently, heat is transferred to alprazolam coated as a thin film on the outside of the heat package. Since the thin film of alprazolam has a high surface area, the evaporation of alprazolam is very rapid, occurring in less than 1 second and before substantial thermal decomposition can occur.

[0064] The alprazolam aerosol of the present invention has an aerodynamic median particle diameter (MMAD) of about 0.5 μm to 3.0 μm. The aerosol particle size is 0.5 to 3 microns, which is optimal for deep lung delivery. The pharmacokinetics of the administered alprazolam dose is similar to that of IV injection. Since the peak plasma level is reached within minutes via a simple and user-friendly delivery system, the present invention is ideal for the acute treatment of seizures.

[0065] As shown in Figure 4, the particle size distribution of the alprazolam aerosol in one embodiment has alprazolam particles with an MMAD of 1.2 to 1.8 microns. At least 80% by weight of the alprazolam aerosol particles have a size of less than 5 microns, preferably at least 90% by weight of the alprazolam aerosol particles have a size of less than 5 microns. At least 50% by weight of the alprazolam aerosol particles have a size of less than 2 microns, preferably at least 50% by weight of the alprazolam aerosol particles have a size of less than 1 micron. The particle size distribution was measured using a Next Generation Pharmaceutical Impactor (NGI).

[0066] In some embodiments, the alprazolam is administered from a portable, single-dose, single-use inhalation device. An amount of drug sufficient to provide complete delivery of the alprazolam vapor at the tidal volume of a typical patient is administered in a single normal breath. The single-dose device may include a pull tab that readies the device for use when pulled from the device, and being ready for use is indicated by illumination of a colored light disposed on the housing of the device. The device may remain active for at least 15 minutes to facilitate delivery. For use, the patient simply exhales and then seals the lips around the mouthpiece of the product and inhales deeply to generate and deliver the drug aerosol. When the heat pack activates, the green light turns off, indicating that the drug has been discharged. The device is discarded after use. Since the redox reaction of the heat pack occurs in an all-or-nothing manner, the device does not contain reactive species after use or the product cannot be reused.

[0067] The present invention non-invasively delivers drugs deep into the lungs, resulting in reliable IV-like pharmacokinetics. If a patient simply inhales once through a mouthpiece, the respiratory-actuated device delivers the drug without any other co-action being required. The drug delivery device and the method for using the same enable self-administration and reliable delivery, resulting in rapid drug delivery and a more rapid onset of action. The delivery of alprazolam according to the present invention can provide distinct advantages over currently available or developing routes of administration, namely rectal and nasal administration.

[0068] The tests conducted included safety pharmacology tests, as well as acute and repeated-dose toxicity tests in dogs and rats. Aerosolized alprazolam was used in these tests because it is the route of administration planned in the clinical trials. The only exception (as described below) was the use of intravenous (IV) bolus administration in the safety pharmacology tests. The safety tests are briefly summarized below.

[0069] In the pharmacokinetics (PK) test in dogs, alprazolam PK was profiled following intravenous or inhalation administration. The mean bioavailability was estimated to be 85 - 96%, and the inhalation T max was less than 1 minute.

[0070] In the 5-day exploratory inhalation toxicity test in dogs, the non-toxic dose was 1.5 mg / kg / day with treatment-related histopathological findings.

[0071] In the 28-day GLP inhalation toxicity test in dogs including a 14-day recovery period, the non-toxic doses based on histopathological findings were 2.8 and 4.4 mg / kg / day for males and females, respectively. No deaths were observed during the test period. The immunogenicity of alprazolam was evaluated, and no immunoglobulins or hypersensitivity responses were observed.

[0072] In a cardiovascular and respiratory safety study in dogs administered alprazolam intravenously over 5 seconds, a transient decrease in respiratory rate and a transient increase in heart rate were found. However, these changes were within the normal range and were not considered biologically significant. Plasma concentrations of alprazolam associated with mild cardiovascular or respiratory effects exceeded 900 ng / mL and were not predicted to induce any significant changes within the planned dose range (0.5 - 2.0 mg) under investigation in clinical trials.

[0073] In the rat inhalation MTD study, a single administration of inhaled alprazolam was well tolerated up to 10.8 mg / kg and produced no harmful signs of toxicity. In a 14-day inhalation toxicity study in rats, the no-observed-adverse-effect level was determined to be 10.3 mg / kg / day.

[0074] In vitro drug transporter and cytochrome P450 inhibitory potential was also tested. Inhibition was not observed at the maximum alprazolam concentration tested.

[0075] A Phase 2a proof-of-concept study examining the ability of inhaled alprazolam in patients with photosensitive epilepsy was recently completed (see Example 1).

[0076] Oral inhalation treatment with inhaled alprazolam would target subtypes of patients diagnosed with partial-onset (focal) or generalized seizure disorders for whom acute treatment with benzodiazepines for rapid antiseizure activity may be beneficial. Inhaled alprazolam has been shown to produce a rapid increase in alprazolam plasma levels (within 2 minutes) and an effect on EEG in patients with photosensitive epilepsy within 2 minutes. Subtypes of patients under investigation include patients with generalized seizures; patients with seizure events that include predictable prodromal symptoms, auras, or progression of the seizure and in whom fluctuations in the progression pattern can be detected; and patients with juvenile myoclonic epilepsy.

[0077] Since epilepsy is generally found in individuals under 18 years of age, adolescent patients represent a meaningful subset who may benefit from inhaled alprazolam. Efficacy and tolerability data from adults aged 18 - 60 years or older may provide information for dose selection in the younger population. Studies in adolescent subjects (13 - 17 years of age) evaluating PK, safety, and tolerability prior to phase III trials can be used to determine doses in this age range. Modeling and simulation of clinical trial data in adults and adolescents may be used to assist in dose selection for those age groups and may also provide information for dose selection in pediatric patients under 13 years of age.

[0078] Other indications for which the present invention may be used include acute panic attacks, severe dental phobia, post - traumatic stress disorder (PTSD), autism with intermittent aggressive behavior, or for certain ophthalmic procedures, etc.

Examples

[0079] The following examples are provided for illustrative purposes only and do not limit the scope of the present invention.

[0080] In Example 1, the ability of inhaled alprazolam to rapidly suppress photosensitivity was evaluated in a double - blind placebo - controlled crossover proof - of - concept trial. This trial was a randomized placebo - controlled double - blind phase 5 crossover trial design in a hospital setting feasible for a small number of patients. Epilepsy patients were evaluated using an intermittent light stimulation model and could be screened for anti - epileptic effects that did not induce seizure or convulsive responses. Three doses of alprazolam were examined in 5 subjects along with placebo (double).

[0081] In patients with photosensitive epilepsy, intermittent light stimulation was used to induce general epileptiform EEG activity. Subjects were exposed to light stimulation at a specific frequency (flash frequency) to measure the photosensitive range. This model has been used to identify the anti - epileptic effects of multiple drugs. This model is specific (sedatives did not show photosensitivity).

[0082] The primary objectives of the trial were to: 1) assess the effect of inhaled alprazolam on IPS-induced photoparoxysmal EEG responses in epileptic patients; 2) select the maximum effective dose with minimal sedation for further clinical trials, evaluating the sedative properties of these doses; and 3) assess overall safety. The primary endpoint was the variation in the standard photoresponsive range (SPR) in subjects receiving each dose of inhaled alprazolam.

[0083] Patients at least 18 years of age with photosensitive epilepsy at three sites were tested on the baseline day and then received inhaled placebo (day 2) or one of inhaled alprazolam 0.5, 1, or 2 mg in random order using a portable inhaled alprazolam device. The test days were separated by at least one week. The presence (and degree) of photosensitivity was measured before dosing and then at 2, 10, 30 minutes, 1, 2, 4, and 6 hours after dosing. Plasma concentrations of the investigational drug were measured at each time point. Sedation was evaluated at each time point using a 100-mm linear visual analog scale (VAS).

[0084] Subjects were exposed to intermittent light stimulation (14 frequencies from 2 - 60 Hz), starting at the lowest frequency and increasing the frequency stepwise until a photosensitive response was induced. This test was repeated at the highest frequency and the frequency was decreased. The results can be summarized by a quantitative measurement known as the standard photoresponsive range (SPR). The maximum SPR is 14. In the example shown, the SPR is 8. The primary endpoint is the decrease in the mean SPR, which is an indicator of anti-seizure activity. Enrolling patients with a relatively stable SPR in this trial enabled a small-scale study.

[0085] Secondary trial endpoints included: assessment of sedation using two visual analog scales (VAS); correlation of the plasma concentration of inhaled alprazolam with the PD effect on the SPR range; correlation of the plasma concentration of inhaled alprazolam with the PD effect on sedation; and assessment of adverse events and variations in neurological examinations.

[0086] Five patients were enrolled and all treatment groups were completed. At all doses, the mean standard photoresponsive range (SPR) decreased and maximum or near-maximum effect occurred by 2 minutes after dosing. The high dose produced an effect on SPR up to 4 hours. Sedation was dose-related but different from the effect on SPR at later time points. The treatment had good tolerability and there were no serious adverse events.

[0087] The effects of inhaled alprazolam were evaluated on IPS-induced photoparoxysmal EEG responses in epileptic patients. The plasma concentration of inhaled alprazolam was correlated with the pharmacodynamic effects on IPS and sedation (PK / PD correlation). The sedative properties of these doses were evaluated to select the maximum effective dose with minimal sedation for further clinical trials. The safety of single-dose inhaled alprazolam was evaluated in patients with photosensitive epilepsy.

[0088] Figures 5A and 5B show graphs of the mean plasma concentration of alprazolam in the first-phase and second-a-phase clinical trials, respectively. The graphs show the rapid uptake of alprazolam into the plasma after oral administration of the condensed aerosol. Notably, the oral administration described herein provides plasma uptake of alprazolam where T max is less than 15 minutes after dosing, or T max is less than 5 minutes after dosing, or T max is less than 2 minutes after dosing. The mean peak plasma concentration occurred 1 - 2 minutes after administration of the alprazolam concentrated aerosol. Delivery of alprazolam via inhalation of the condensed aerosol resulted in a C max of at least 5 ng / ml, or at least 12 ng / ml, or at least 30 ng / ml within less than 5 minutes after dosing when administered at a dose of at least 0.5 mg.

[0089] The variability in the SPR range in subjects receiving each dose of inhaled alprazolam was compared to placebo. The pharmacodynamic effects on the plasma concentration of inhaled alprazolam and the SPR range were correlated. Figure 6 shows a graph of the mean standard light sensitivity range (SPR) over time for the three dose rates used in the study. A decrease in mean SPR (primary study endpoint) occurred with all three inhaled alprazolam doses. At all doses, the maximum or nearly maximum effect occurred by about 2 minutes. A rapid antiepileptic activity is suggested from the maximum decrease in seizure response compared to placebo at 2 minutes for all three doses.

[0090] Regarding the magnitude of the SPR variability, a maximum decrease of approximately five steps was obtained at least at the early time points. Near complete photoreceptor elimination was achieved with the 1 mg and 2 mg doses. These effects represent significant variability. For example, 90% confidence intervals were determined for the mean SPR variability from baseline at each dose at each time point. The magnitude and duration of the effect were equivalent at 1 mg and 2 mg. The results at the first time point (2 minutes) are shown, and there was no or minimal overlap in the confidence intervals.

[0091] The results demonstrated a maximum or nearly maximum decrease (primary endpoint) in seizure-like responses at all doses (0.5 mg, 1 mg, and 2 mg) by the 2-minute time point, suggesting rapid antiepileptic activity.

[0092] Figures 7A and 7B show representative patient EEG traces before and after administration of alprazolam condensed aerosol, respectively. The post-administration trace shows complete abolition of seizure-like activity. The seizure-like activity shown in Figure 7A exhibits inconsistent brain activity during the seizure. As seen in Figure 7B, after treatment, the brain activity returns to normal.

[0093] Sedation assessment was performed using two visual analog scales. Figure 8 shows a graph of the mean visual analog scale (VAS) of patients after administration of alprazolam condensed aerosol. The plasma concentration of inhaled alprazolam was correlated with the pharmacodynamic effects on sedation. Sedation was measured by VAS, and a rapid onset of activity in the brain was suggested after oral inhalation of alprazolam. Maximum sedation occurred within approximately 2 minutes of alprazolam administration. Clinical observations support an early onset of sedation at 30 seconds.

[0094] From the correlation between the SPR response and the VAS response, it was shown that both responses started within less than 2 minutes, demonstrating a rapid and predictable onset of effect. Sedation recovered to placebo - like levels within 6 hours of administration. The decrease in SPR was generally maintained for at least 6 hours after administration, demonstrating an appropriate duration of effect that was not overly long. A 1 - mg dose may be optimal for the balance between potential antiepileptic effects and sedation levels.

[0095] Assessment of adverse events and variations in neurological examinations was performed. The safety profile was consistent with oral alprazolam. As summarized in Table 1, no significant treatment - emergent adverse events were observed. The minimal adverse effects suggest that the treatment was well - tolerated.

Table 1

[0096] The biological availability can be measured by appropriate pharmacodynamic methods such as comparison of the area under the plasma concentration curve (AUC) for drugs administered by inhalation and intravenously. Further, it will be understood that the % biological availability of inhaled alprazolam can be measured by comparing the area under the plasma concentration curve obtained with one dose of alprazolam (e.g., 1 mg of inhaled alprazolam) to another dose of intravenously administered alprazolam (e.g., 0.5 mg of i.v. alprazolam), taking into account the difference in doses. Thus, by way of example, an inhaled alprazolam dose of 1 mg that achieves an AUC that is precisely half of the AUC obtained with 0.5 mg of i.v. alprazolam will have 100% biological availability.

[0097] In summary, all three inhaled alprazolam doses produced a decrease in mean SPR (primary study endpoint). At all doses, the maximum or nearly maximum effect occurred within 2 minutes. The magnitude and duration of the effect were equivalent at 1 mg and 2 mg. Variation in the dose relationship was observed using the Visual Analogue Scale (VAS) for sedation and drowsiness, which are important markers of potentially harmful events associated with administration. PK analysis showed dose proportionality with plasma concentration. In all cases, treatment with the inhaled drug had generally good tolerance, and no serious adverse events (SAEs) were reported at doses up to 2 mg. Respiratory AEs were shown to be mild or moderate and resolved from the predicted CNS adverse events (mainly sedation and somnolence). Rapid antiepileptic activity was demonstrated from the effect on SPR.

[0098] In conclusion, the results of this study demonstrated a rapid and substantial decrease in mean SPR with all three inhaled alprazolam doses. At all doses, the maximum or nearly maximum effect occurred by the 2-minute time point. The magnitude and duration of the effect were equivalent at the 1 mg and 2 mg doses. Variation in the dose relationship was observed in the Visual Analogue Scale (VAS) for sedation and drowsiness, but in a different time frame from the observed variation in SPR. Overall, the decrease in SPR suggests the ability for rapid antiepileptic activity.

[0099] The descriptions of the various embodiments are presented for purposes of illustration and description, but are not intended to be exhaustive or limiting of the invention to the disclosed forms. The scope of the invention is limited only by the following claims. Many modifications and variations will be apparent to those skilled in the art. The embodiments described and illustrated in the figures were selected and described in order to explain the principles of the invention, its practical application, and to enable others skilled in the art to understand the invention for various embodiments having various modifications as are suited to the particular use contemplated. All references cited herein are hereby incorporated by reference in their entirety.

Claims

**Claim 1** A pharmaceutical composition for stopping ongoing epileptic seizures in a subject in need thereof, comprising alprazolam, wherein the seizure has not progressed to status epilepticus, the subject is selected from patients with partial (focal) seizures or generalized seizures, and the pharmaceutical composition is for oral administration in the form of a condensed aerosol. **Claim 2** The pharmaceutical composition according to claim 1, wherein the subject is selected from patients with auras, secondarily generalized focal seizures, or juvenile myoclonic epilepsy in which seizures typically manifest symptoms over several minutes. **Claim 3** The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is delivered to the lungs of the subject by inhalation and achieves an alprazolam plasma Tmax of less than 2 minutes after administration. **Claim 4** The pharmaceutical composition according to any one of claims 1 to 3, wherein the amount of alprazolam provided per inhalation is 1 mg to 2 mg. **Claim 5** The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is provided as an inhalation powder supplied by a single-use disposable inhaler for oral inhalation. **Claim 6** The pharmaceutical composition according to any one of claims 1 to 5, wherein the alprazolam is provided in the form of aerosol particles, and at least 80% by weight of the alprazolam aerosol particles have a size of less than 5 microns. **Claim 7** The pharmaceutical composition according to claim 6, wherein the alprazolam is provided in the form of aerosol particles, and at least 90% by weight of the alprazolam aerosol particles have a size of less than 5 microns. **Claim 8** The pharmaceutical composition according to any one of claims 1 to 7, wherein the alprazolam is provided in the form of aerosol particles, and at least 50% by weight of the alprazolam aerosol particles have a size of less than 2 microns. **Claim 9** The pharmaceutical composition according to any one of claims 1 to 8, wherein the alprazolam condensed aerosol is excipient-free. **Claim 10** The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition is self-administered at the onset of one or more symptoms of the seizure or after the onset of one or more symptoms of the seizure. **Claim 11** The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is administered when the subject experiences a sensory or experiential aura. **Claim 12** The pharmaceutical composition according to any one of claims 1 to 11, wherein the subject is a patient with focal seizures without impairment of consciousness / awareness.

13. The pharmaceutical composition according to any one of claims 1 or 3 to 12, wherein the subject is a patient with long-term focal seizures, acute repetitive seizures (ARS) or juvenile myoclonic epilepsy.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical composition is delivered to the lungs of the subject by inhalation and achieves a maximum therapeutic effect within 2 minutes of inhalation.

15. Using the respiratory-operated device that delivers alprazolam by one inhalation through the mouthpiece of the respiratory-operated device without the need for any other co-action by the patient, the pharmaceutical composition is non-invasively delivered deep into the lungs, thereby producing reliable IV-like pharmacokinetics. The pharmaceutical composition according to any one of claims 1 to 14.

16. A device for producing the pharmaceutical composition according to any one of claims 1 to 15, comprising: (i) a drug coating containing an alprazolam composition applied on a thermally conductive and impermeable substrate; (ii) means for heating the substrate to at least 300°C, at least 350°C, or 390°C ± 50°C, thereby substantially completing the volatilization (evaporation) of the alprazolam composition from the substrate within 2 seconds; and (iii) an element for cooling the generated vapor, thereby generating aerosol particles containing the alprazolam composition. A device for producing the pharmaceutical composition according to any one of claims 1 to 15.

17. The device according to claim 16, wherein the volatilization (evaporation) of the alprazolam composition is substantially completed within 1 second.

18. The device according to claim 16, wherein the volatilization (evaporation) of the alprazolam composition is substantially completed within 0.5 second.

19. The device according to any one of claims 16 to 18, wherein the thickness of the alprazolam coating is 0.1 to 10 μm.

20. The device according to claim 19, wherein the thickness of the alprazolam coating is 0.5 to 5 μm.

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