Combination for the treatment of benzodiazepine use disorder

Abstract

A combination of a first and second pharmaceutically active agent, wherein the first pharmaceutically active agent is GABA agonist and the second pharmaceutically active agent is a GABA antagonist is disclosed. An oral thin film comprising a combination of pharmaceutically active agent and a permeation enhancer, preferably wherein the pharmaceutically active agent is a benzodiazepine agonist is also disclosed.

Description

TREATMENT OF DRUG USE FIELD OF THE INVENTION

[0001] The present invention relates to a combination of a benzodiazepine agent and a benzodiazepine antagonist. Also provided is a method of treating a benzodiazepine use disorder for example overuse or misuse, or preventing or reversing an effect of a benzodiazepine use disorder. BACKGROUND OF THE INVENTION

[0002] Benzodiazepines are commonly prescribed for the treatment of anxiety, seizures and insomnia. Benzodiazepines are one of the most highly prescribed drugs and considered a safe treatment option for short-term use. Many benzodiazepines bind to a GABA receptor found in normal human brain neurones, this causes the nerve to become less reactive, and induces a sedative effect. Benzodiazepines provide feelings of relaxation and euphoric effects in the patient, and can lead to the development of tolerance and addiction.

[0003] Misuse of prescription drugs is a major health concern worldwide, with health services seeing increasing addiction to medically prescribed drugs, including benzodiazepines. It is estimated that misuse of benzodiazepines accounts for approximately 20% of the use of benzodiazepines worldwide. Long-term overuse and misuse of benzodiazepines lead to dependence and can become lethal when the respiratory system becomes overly suppressed, and results in hypoxic respiratory failure.

[0004] However, there remains a continuing upward trend in international drug-related deaths which represents a deepening public health crisis that needs to be urgently addressed. The availability of additional safe and effective medicines remains a central component part of a solution. Drug substitution therapy can be used to manage dependence in people with substance use disorder related to benzodiazepine. Drug substitution therapy may involve gradual reduction of the misused agent, and / or a maintenance program which may involve providing safer forms of a drug, or agents which minimize the drugs effects.

[0005] Flumazenil is the first and only benzodiazepine antagonist in clinical practice for the complete or partial reversal of the central sedative effects of benzodiazepines during surgical procedures. Diazepam is a long action benzodiazepine which is routinely used for as a drug substitution agent for the management of benzodiazepine withdrawal symptoms in reduction or maintenance treatment.

[0006] However, there remains a need to effectively manage dependence arising from benzodiazepine use disorders and associated withdrawal symptoms, and / or to mitigate overuse or misuse of drug substitution agents. BRIEF SUMMARY OF THE DISCLOSURE

[0007] In a first aspect, the present invention provides a pharmaceutical composition comprising a first and second pharmaceutically active agent, wherein the first pharmaceutically active agent is a GABA receptor antagonist, and the second pharmaceutically active agent is a GABA receptor agonist. Suitably the first pharmaceutically active agent is a benzodiazepine antagonist. Suitably the first pharmaceutically active agent is flumazenil. Suitably the second pharmaceutically active agent is a benzodiazepine agent. Suitably the second pharmaceutically active agent is a long action benzodiazepine agent. Suitably the second pharmaceutically active agent is diazepam. Suitably the pharmaceutical composition is suitable for oral delivery. Suitably, the pharmaceutical composition is a mucosal drug delivery system. Suitably, the pharmaceutical composition is suitable for oral preferably buccal or sublingual, delivery. Suitably, the pharmaceutical composition is dissolvable, for example an oral thin film.

[0008] In a second aspect, the present invention provides a combination of a first and second pharmaceutically active agent, wherein the first pharmaceutically active agent is an is a GABA receptor antagonist, and the second pharmaceutically active agent is a GABA receptor agonist. Suitably the first pharmaceutically active agent is a benzodiazepine antagonist. Suitably the first pharmaceutically active agent is flumazenil. Suitably the second pharmaceutically active agent is a benzodiazepine agent. Suitably the second pharmaceutically active agent is a long action benzodiazepine agent. Suitably the second pharmaceutically active agent is diazepam. Suitably, the combination of the a first and second pharmaceutically active agents are provided as a pharmaceutical composition. Suitably, the pharmaceutical composition is mucosal drug delivery system. Suitably, the pharmaceutical composition is suitable for oral, preferably buccal or sublingual, delivery. Suitably, the pharmaceutical composition is dissolvable, for example an oral thin film.

[0009] In a third aspect, the present invention provides a pharmaceutical composition comprising a first and second pharmaceutically active agent, wherein the first pharmaceutically active agent is an GABA receptor antagonist and the second pharmaceutically active agent is a GABA receptor agonist, for use in treating a benzodiazepine use disorder. Suitably, the GABA receptor antagonist is a benzodiazepine antagonist. Suitably, the benzodiazepineantagonist is flumazenil. Suitably, the GABA receptor agonist is a benzodiazepine agent. Suitably, the GABA receptor agonist is a long action benzodiazepine agent. Suitably, the benzodiazepine agent is diazepam. Suitably, the pharmaceutical composition is as described in the first aspect of the present invention.

[0010] In a fourth aspect, the present invention provides a dissolvable film, in particular an oral thin film (OTF), comprising a combination of pharmaceutically active agent and a permeation enhancer. Suitably, the permeation enhancer may be selected from the group consisting of a surfactant, for example Tween 80, a polymeric stabiliser, for example Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer), a detergent for example sucrose monolaurate, and vitamin E, suitably vitamin E TPGS (a water miscible form of vitamin E composed of a hydrophobic vitamin E part and a hydrophilic PEG chain). Suitably, the film may further comprise a non-ionic solubilizer. Suitably, the film may comprise a disintegrator, a plasticiser, a sweetener, a flavouring agent, and / or a saliva stimulant, or any combination thereof. Suitably, the film may comprise one or more layers. Suitably, the film is a single-layered film, such that it consists of one layer. Suitably, the pharmaceutically active agent is a benzodiazepine antagonist, suitably flumazenil. Suitably, the pharmaceutically active agent is a combination of a GABA receptor antagonist and a GABA receptor agonist as defined in the first aspect of the invention. Suitably, the pharmaceutically active agent is a combination of flumazenil and a long action benzodiazepine agent as defined in the first aspect of the invention. Suitably, the pharmaceutically active agent is a combination of flumazenil and diazepam. Suitably, the dissolvable film is for use in the treatment of benzodiazepine use disorder. The film may facilitate rapid drug absorption directly to the systemic circulation. It may be suitable for sub-lingual, buccal, nasal, rectal or vaginal delivery.

[0011] In a fifth aspect, the present invention provides a method of treating a benzodiazepine misuse disorder, or preventing or reversing an effect of a benzodiazepine use disorder, wherein the method comprises administering to a subject in need thereof a combination of a first and second pharmaceutically active agents, wherein the first pharmaceutically active agent is a GABA receptor antagonist and the second pharmaceutically active agent is a GABA receptor agonist. Suitably, the GABA receptor antagonist is a benzodiazepine antagonist. Suitably, the benzodiazepine antagonist is flumazenil. Suitably the GABA receptor agonist is a benzodiazepine agent. Suitably the GABA receptor agonist is a long action benzodiazepine agent. Suitably the benzodiazepine is diazepam. Suitably, the subject has been diagnosed ashaving a benzodiazepine misuse disorder. Suitably, the subject may have one or more symptoms of benzodiazepine overuse or misuse, for example dependence or respiratory depression.

[0012] In a sixth aspect, the present invention provides the use of a first and second pharmaceutically active agents, wherein the first pharmaceutically active agents is a GABA receptor antagonist and the second pharmaceutically active agents is a GABA receptor agonist, in the manufacture of medicament for the treatment of benzodiazepine use disorder, or for the prevention or reversal of an effect of benzodiazepine use disorder. Suitably, the GABA antagonist is a benzodiazepine antagonist. Suitably the benzodiazepine antagonist is flumazenil. Suitably, the GABA receptor agonist is a benzodiazepine agent. Suitably, the GABA receptor agonist is a long action benzodiazepine agent. Suitably, the benzodiazepine is diazepam.

[0013] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the in vitro drug release of thin films according to the Example, in pH 7.4 buffer media. DETAILED DESCRIPTION

[0014] Withdrawal symptoms are common in subjects who have abused or misused a benzodiazepine. Typically, a benzodiazepine substitution agent is administered to the subject, to effectively maintain or reduce withdrawal symptoms while treating dependence. The current treatments for overuse or misuse disorder however do not address the effect of the possible withdrawal symptoms or the risk of overuse or misuse of drug substitution agents. The present invention is based upon the novel identification of a benzodiazepine agonist provided in a dissolvable composition suitable for mucosal delivery, for example as an oral thin film. The benzodiazepine agonist may be provided in combination with a benzodiazepine antagonist. The invention may be provided for use in treating a subject who is suffering from a benzodiazepine use disorder. The present invention may have the advantage of reducing or preventing the possibility of re-occurrence of respiratory depression. The present invention may relieve one or more symptoms of benzodiazepine misuse. The present invention may relieve one or more symptoms of benzodiazepine withdrawal. Aspects of the present invention also have the advantage of being suitable for oral administration. The present invention maybe suitable for administration to a subject who has been diagnosed as suffering from a benzodiazepine misuse disorder.

[0015] Definitions

[0016] An “oral thin film” is a thin, flexible film based on a polymer matrix and loaded with one or more active ingredient for drug delivery to a subject.

[0017] An “opioid” is a natural, synthetic or semi-synthetic chemical which interacts with an opioid receptor on nerve cells in the body and brain to reduce feelings of pain, and which can produce feelings of euphoria.

[0018] A “benzodiazepine” enhances the effect of the neurotransmitter, gamma-aminobutyric acid (GABA). A benzodiazepine may be a substituted 1,4-benzodiazepine, having a core chemical structure derived from the fusion of a benzene ring and a diazepine ring, or may be a 1,5-benzodiazepine such as clobazam. A benzodiazepine may have a sedative, hypnotic, anxiolytic, anticonvulsant, and / or muscle relaxing effect in a subject.

[0019] A “benzodiazepine antagonist” is an agent which inhibits or blocks a benzodiazepine receptor in the peripheral or central nervous system. An benzodiazepine antagonist inhibits, reduces or reverses the effect of a benzodiazepine on the nervous system in a subject.

[0020] A “pharmaceutically active agent” as used herein is any natural or synthetic or semi synthetic compound or combination of compounds which are provided to a subject with the aim of obtaining a beneficial clinical outcome.

[0021] A “pharmaceutically effective amount” means the amount of a therapeutic agent (alone or in combination) that, when administered to a subject or patient for treating a condition or symptom, is sufficient to effect a treatment for the condition or symptom, as defined herein.

[0022] The term “half-life” or “elimination half life” as used herein refers to the period of time required for one-half of an amount of a substance to be lost through biological processes, i.e for its concentration in the body to be reduced to half of its starting dose in the body.

[0023] The term “bioavailability” as used herein refers to the physiological availability of a given amount of a drug, as distinct from its chemical potency. The term may also refer to the proportion of the administered dose which is absorbed into the bloodstream.

[0024] A GABA derivative is a compound derived from gamma-aminobutyric acid, an inhibitory neurotransmitter, which exhibits the same or similar activity to native GABA.

[0025] “Treating” or "treatment" is an approach for obtaining beneficial or desired results by providing to the subject a pharmaceutically effective amount of an agent, for example a combination or composition as described herein. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of a symptom, affliction or condition, diminishment of any direct or indirect pathological consequences of a condition, affliction or symptom, stabilisation (i.e., not worsening) of a affliction or symptom, a delay or slowing of the progression of the condition, affliction or symptom, an amelioration or palliation of the condition, affliction or symptom, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0026] “Prevention” may additionally refer to avoiding an undesirable or harmful clinical condition, affliction or symptom of a condition. Prevention as used herein may include diminish the likelihood or seriousness of a condition, affliction or symptom, and / or delaying the onset of a condition or symptom for a period of time.

[0027] “Condition”, “affliction” or “symptom” as referred to herein may be any pathological consequence of a drug misuse or overuse, adverse reaction or overdose. A symptom may include a combination or two or more symptoms.

[0028] Drug misuse as referred to herein may be the use of a drug in a manner which not in line with the drug label or the advice of a medical professional. For example, a drug use disorder may the use of a prescription drug in amounts higher than prescribed by a medical professional or the use of a prescription drug for longer periods than prescribed by a medical professional. A dug use disorder may include a dependency or an addiction.

[0029] A “drug substitution agent” as referred to herein may be an agent prescribed by a medical professional to effectively manage, maintain or reduce withdrawal symptoms arising from drug misuse or overuse.

[0030] As used herein, “pharmaceutically acceptable” refers to materials that are generally chemically and / or physically compatible with other ingredients (such as, for example, with reference to a formulation), and / or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.

[0031] As used herein by itself or in conjunction with another term or terms, “pharmaceutical composition” refers to a composition that can be used to treat a condition, affliction or symptom in a subject.

[0032] A “functional equivalent” is any compound which is capable of, or which does perform, the same function as the specified chemical performs in vivo.

[0033] The term "pharmaceutically acceptable salt" is intended to include salts derived from inorganic or organic acids including, for example hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluroacetic, trichloroacetic, naphthalene-2 sulfonic and other acids; and salts derived from inorganic or organic bases including, for example sodium, potassium, calcium, ammonium or tetrafluoroborate. Exemplary pharmaceutically acceptable salts are found, for example, in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; hereby incorporated by reference in its entirety). Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2: 1. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi- salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate.

[0034] A “permeation enhancer” is an agent or combination of agents which enhance penetration of a therapeutic agent into the circulatory system of a subject. A permeation enhancer may also be referred to as a penetration enhancer.

[0035] The term "solvate" as used herein means a compound, or a pharmaceutically acceptable salt thereof, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate."

[0036] By "subject" or "individual" or "animal" or "patient" or "mammal," is meant any subject for whom treatment or prevention of a harmful effect is desired. A subject may also be referred to herein as an “individual,” “patient,” or “host.

[0037] Unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or more than one.

[0038] The term “and / or” means one or all of the listed elements or a combination of any two or more of the listed elements.

[0039] GABA agonists and Benzodiazepines

[0040] A GABA agonist as referred to herein may include any agent which acts on a neurotransmitter gamma-aminobutyric acid (GABA) receptor, either competitively or non- competitively. A GABA agonist may bind a GABA receptor, thereby increasing the effect of GABA. A GABA agonist may bind a GABA receptor either at the GABA active site or at a different site. Suitably, a GABA agonist may activate the receptor, partially or fully. Suitably, a GABA agonist for use in the present invention is a full or partial agonist at the GABAAreceptor and / or the GABAB receptor. Suitably, a GABA agonist may be a benzodiazepine agent.

[0041] A benzodiazepine agent as referred to herein may include any agent having a chemical structure which is the fusion of a benzene ring and a diazepine ring, and which is capable of enhancing the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor or at the GABAB receptor. A suitable benzodiazepine agent may be a depressant, a sedative, an anxiolytic, an anticonvulsant, or a muscle relaxant. A benzodiazepine agent may be short acting or long acting benzodiazepine.

[0042] GABA controls the excitability of neurons by binding to the GABAA receptor, an ion channel, which is located in the synapses between neurones. The GABA receptors contains two binding sites for GABA. Some GABAAreceptors (BzR’s) also contain a site to which a benzodiazepine can bind, without affecting the binding of GABA to the receptor. The binding of benzodiazepine to the receptor therefore acts as a positive allosteric modulator, serving to increase the total conduction of chloride ions across the synapse. The inhibitory effect of the available GABA is potentiated, leading to sedative and anxiolytic effects. There are many different GABAA receptor subtypes, which are distributed within different regions of the brain and so control distinct neuronal circuits. Therefore, depending on binding preference, different benzodiazepines may mediate differing pharmacological effects.

[0043] These properties make benzodiazepines useful in treating anxiety, panic disorder, insomnia, agitation, seizures, muscle spasms, and drug and / or alcohol withdrawal.

[0044] The present invention may be useful in the treatment or prevention of overuse or misuse of any one or more benzodiazepines, for example (but not limited to) one or more benzodiazepines selected from adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, bromazolam, brotizolam, camazepam, chlordiazepoxide, cinezepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam,deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, etizolam, ethyl loflazepate, flualprazolam, flubromazepam, flubromazolam, flubortizolam, fluclotizolam, flunitrazepam, flunitrazolam, flurazepam, flutazolam, flutemazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, meclanazepam, medazepam, metizolam, mexazolam, midazolam, nifoxipam, nimetazepam, nitrazepam, nitrazolam, nordazepam, norflurazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, rilmazafone, temazepam, tetrazepam, or triazolam.

[0045] Suitably, the present invention may be useful in the treatment or prevention of misuse or overuse of one or more benzodiazepines. Such a benzodiazepine may include, but is not limited to, alprazolam (e.g., Xanax), bretazenil, bromam, bromazepam, brotizolam, cinolazepam, chlordiazepoxide, clonazepam (e.g., Klonopin), clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam (e.g., Valium), diclazepam, estazolam, etizolam, ethyl loflazepate, flubromazepam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, lectopam, lexaurin, lexotanil, lexotan, loprazolam, lorazepam (e.g., Ativan), lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, temazepam, tetrazepam, triazolam, and derivatives or analogues thereof.

[0046] Suitably, the present invention may be useful in the treatment or prevention of polydrug misuse or overuse. Suitably the present invention may be useful in the treatment or prevention of misuse or overuse of benzodiazepine and one or more additional drugs, such as an opioid. An opioid may include but is not limited to bromadol, buprenorphine, carfentanil, clonitazene, codeine, dextropropoxyphene, diamorphine (heroin), dihydrocodeine, dihydroetorphine, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, pentazocine, pethidine (meperidine hydrochloride), propoxyphene, sufentanil, tapentadol, tramadol, and derivatives or analogues thereof. Therefore, a composition or combination of the present invention as described herein may comprise one or more further active ingredients, for example an opioid antagonist. An opioid antagonist may include a centrally active antagonist, for example but not limited to: naloxone, naltrexone, nalmefene, samidorphan, nalophine, nalorphine dinicotinate, levallorphan; and / or a peripherally active antagonist, for example but not limited to 6β naltrexol, axelopran, bevenopran, methylsamidorphan, or naldemedine.

[0047] An effect of, an adverse effect of, a symptom of misuse or overuse of a benzodiazepine may result in one or more of symptoms including, but not limited to, one or more of drowsiness,weakness, blurred vision, slurred speech, nystagmus, hypotension, ataxia, cognitive decline, coma, respiratory depression, and cardiorespiratory arrest.

[0048] An effect of, an adverse effect of, a symptom of misuse or overuse of an opioid may result in one or more of symptoms including, but not limited to, one or more of drowsiness, sedation, hypotension, confusion, unconsciousness, difficulty breathing, respiratory depression, and pinpoint pupils.

[0049] The use of a benzodiazepine with alcohol, an opioid and / or another central nervous system depressants potentiates their action. An effect of, an adverse effect of, a symptom of misuse or overuse of a benzodiazepine and alcohol, an opioid and / or a central nervous system depressants may result in one or more symptoms including, but not limited to, increased sedation, impaired motor coordination, coma, respiratory depression, suppressed breathing, cardiorespiratory arrest.

[0050] The present invention may be useful in the treatment of a subject who has taken, or is experiencing the effect of, or is experiencing an adverse effect of, or is experiencing a symptom of misuse or overuse of, or has misused or overused a benzodiazepine. The subject may have been diagnosed as having or suffering from a benzodiazepine use disorder. The subject may not have, or may have recovered from, a condition typically treated with a benzodiazepine.

[0051] The present invention may be useful in the treatment of a subject who has taken, or is experiencing the effect of, or is experiencing an adverse effect of, or is experiencing a symptom of benzodiazepine withdrawal.

[0052] GABA or Benzodiazepine antagonist

[0053] A GABA antagonist as referred to herein may include any agent which inhibits a response or activity from a neurotransmitter gamma-aminobutyric acid (GABA) receptor. Such an antagonist may act directly on the receptor, either competitively or non-competitively, or may function downstream in the signalling pathway. A GABA antagonist may bind a GABA receptor, thereby inhibiting the effect of GABA. A GABA antagonist may bind a GABA receptor either at the GABA active site or at a different site. Suitably, a GABA antagonist may inhibit the receptor, partially or fully. Suitably, a GABA antagonist for use in the present invention is a full or partial antagonist at the GABAA receptor and / or the GABAB receptor. Any suitable GABA antagonist may be useful in the present invention. Suitably, a GABA antagonist is a benzodiazepine antagonist.

[0054] Any suitable benzodiazepine antagonist may be used in the present invention. A benzodiazepine antagonist may also be known as a drug reversal agent. A benzodiazepine antagonist for use in the present invention may be a selective GABAA receptor antagonist, and may be a competitive or non-competitive antagonist. Suitably, a benzodiazepine antagonist for use in the present invention may be flumazenil (ethyl 8-fluoro- 5,6-dihydro- 5-methyl- 6-oxo- 4H-imidazo [1, 5-a][1,4] benzodiazepine- 3 carboxylate, which may also be referred to as flumazepil, anexate, lanexate, maxicon, romazicon, code name Ro151788). Flumazenil is a competitive antagonist of the benzodiazepine (BZ) recognition site on the GABA / benzodiazepine receptor complex. Flumazenil may be used to fully or partially reverse the effect of a benzodiazepine in a subject.

[0055] Suitably, a benzodiazepine antagonist for use in the present invention has an elimination half life of at least 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours.

[0056] Suitably, the benzodiazepine antagonist is formulated for mucosal administration. Suitably, the benzodiazepine antagonist is formulated as a mucosal drug delivery system. A mucosal delivery system may be suitable for sub-lingual, buccal, nasal, rectal or vaginal delivery. A mucosal delivery system will suitably be dissolvable. A pharmaceutical composition according to the present invention may be an dissolvable gel, for example an oral thin film.

[0057] A benzodiazepine antagonist provided in a composition of the present invention may be formulated such that it is not be well absorbed in the gastrointestinal tract. A benzodiazepine antagonist provided in a composition of the present invention may be formulated such that it may have no, or a reduced, pharmacological effect. A composition of the present invention may be formulated such that a benzodiazepine antagonist may only have a pharmacological effect when the subject has taken a benzodiazepine which is still active in their system.

[0058] A benzodiazepine antagonist, for example flumazenil, may fully or partially reverse the effect of euphoria, drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.

[0059] A benzodiazepine antagonist may be provided in the pharmaceutical composition at any suitable concentration. A suitable concentration will be that which alleviates one or more symptoms of a benzodiazepine use disorder, suitably which prevents a patient from getting a euphoric effect. The dose will depend upon the mode of administration, and may be repeated until the adverse effect of the benzodiazepine is alleviated, for example the subject does notget a euphoric effect. A suitable dose in a mucosal delivery system may be 0.01-1% by weight based on the total weight of the composition, more suitably 0.01-0.5% by weight based on the total weight of the composition, more suitably 0.01-0.1% by weight based on the total weight of the composition.

[0060] Combined therapy

[0061] The present invention as described herein may provide the combination of a benzodiazepine antagonist and a benzodiazepine. A benzodiazepine may include any agent which mediates an effect via the GABA receptor. A benzodiazepine may be described as being short acting (having a half life of e.g 12-20 hours) or long lasting (having a half life of for example 24-200 hours). Suitably, a benzodiazepine for use in the present invention is long lasting. Each of the benzodiazepine antagonist and the benzodiazepine may be provided independently as described herein. A preferred combination may be a benzodiazepine antagonist and a long action benzodiazepine. A preferred combination may be a benzodiazepine antagonist and diazepam. A preferred combination may be a benzodiazepine and flumazenil. Suitably, the present invention as described herein may provide a combination of diazepam and flumazenil. The combination may be provided for separate, sequential or simultaneous administration. Where the pharmaceutical composition is for simultaneous administration, a benzodiazepine antagonist and a benzodiazepine may be provided in a single pharmaceutical composition, for example a mucosal delivery system, such as a dissolvable film. In a suitable embodiment, a pharmaceutical composition of the present invention may be an oral thin film comprising a benzodiazepine antagonist and a benzodiazepine agent. Where the pharmaceutical composition is a film, it may comprise one or more layers. Preferably, the film may consist of a single layer. The a benzodiazepine antagonist and a benzodiazepine agent may be provided in the same layer or in different layers. Preferably, the benzodiazepine antagonist and a benzodiazepine agent may be provided in the same layer.

[0062] Where the benzodiazepine antagonist and the benzodiazepine agent are provided in combination, the benzodiazepine antagonist may be provided at a concentration of 0.01-1% by weight based on the total weight of the composition and the benzodiazepine agent may be provided at a concentration of 0.01-10% by weight based on the total weight of the composition. Suitably, the benzodiazepine antagonist may be provided at a concentration of 0.01-0.5% by weight based on the total weight of the composition and the benzodiazepine agent may be provided at a concentration of 0.5-5% by weight based on the total weight of the composition. Suitably, the benzodiazepine antagonist may be provided at a concentration of0.0.1-0.1% by weight based on the total weight of the composition and the benzodiazepine agent may be provided at a concentration more suitably 0.5-1.5% by weight based on the total weight of the composition.

[0063] A pharmaceutical composition comprising a combination of a benzodiazepine antagonist and a benzodiazepine agent, such as mucosal delivery system for example a dissolvable film, may further comprise a permeation enhancer. A suitable permeation enhancer may be Tween, suitably Tween 80, or may be selected from the group consisting of a polymeric stabiliser, for example Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer), a detergent for example sucrose monolaurate, and vitamin E, suitably vitamin E TPGS (a water miscible form of vitamin E composed of a hydrophobic vitamin E part and a hydrophilic PEG chain).. A pharmaceutical composition comprising a combination of a benzodiazepine antagonist and a benzodiazepine agent may further comprise a disintegrator, a plasticiser, a sweetener, a flavouring agent, and / or a saliva stimulant, or any combination thereof.

[0064] In a suitable embodiment, a pharmaceutical composition as described in relation to the present invention comprises an effective amount of flumazenil and an effective amount of diazepam, wherein the pharmaceutical composition is in a dissolvable form suitable for sub- lingual delivery, such as an oral thin film. An effective amount of flumazenil may be a concentration of 0.0.1-0.1% by weight based on the total weight of the composition. An effective amount of diazepam may be a concentration of 0.5-1.5% by weight based on the total weight of the composition. The dissolvable composition may further comprise a permeation enhancer, for example Tween 80, at a concentration of 0.1-0.5% by weight based on the total weight of the composition. The dissolvable composition may further comprise a disintegrator, a plasticiser, a sweetener, a flavouring agent, and / or a saliva stimulant, or any combination thereof.

[0065] Diagnosis of misuse or overdose

[0066] A combination or composition of the present invention may be administered to a subject who has been diagnosed as suffering from or experiencing, or at risk of suffering from or experiencing, one or more symptoms of benzodiazepine misuse or overuse. Suitably, a subject has been diagnosed by a medical practitioner or healthcare professional. Diagnosis may include testing a subject for a benzodiazepine in the subjects urine, saliva or blood. Testing asubject for a benzodiazepine may include a measurement of the amount of the drug is present in the subjects urine, saliva or blood.

[0067] A symptom of benzodiazepine misuse or overuse may include, but is not limited to, euphoria, drowsiness, sedation, hypotension, confusion, unconsciousness, difficulty breathing, respiratory depression, pinpoint pupils, slurred speech, nystagmus, ataxia, coma, and cardiorespiratory arrest. Other descriptions of benzodiazepine misuse or overuse symptoms may be known to the skilled person. Suitably, a subject may experience or suffer from 2 or more, suitably 3 or more of the above mentioned symptoms. A diagnosis may be based on qualitative and quantitative features of the symptoms.

[0068] One or more of the symptoms may be persistent. One or more of the symptoms may be intermittent. One or more of the symptoms may be chronic.

[0069] Suitably, a combination or composition of the present invention may be administered to a subject who has been diagnosed as suffering from or experiencing unconsciousness, difficulty breathing, respiratory depression, coma, and cardiorespiratory arrest. A diagnosis may also be based on one or more psychological, , and / or psychiatric evaluations.

[0070] The frequency and / or severity of one or more symptoms may be assessed over any suitable time frame, for example a few minutes, 5, 10, 15, 20, 30, or 45 minutes, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 hours, 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks or more. It will be recognized that any of the times listed herein may constitute an upper or lower time range, and may be combined with any other time range to constitute a time range comprising an upper or lower limit. Any two or more symptoms may be assessed over the same or different time frames.

[0071] Assessment or evaluation of symptoms, for example frequency and / or severity may be continued during treatment for benzodiazepine misuse or overuse, for all or part of the duration of a course of treatment. Such an assessment allows the effect of treatment or prevention to be monitored, and a dosage regime to be adjusted accordingly. For example, reduction in the frequency, duration and / or severity of one or more symptoms may lead to a reduction in the frequency and / or amount of the first and / or second therapeutic agent administered to the subject. Depending upon the symptoms which show a reduction in frequency, duration and / or severity, it may be decided to reduce the frequency and / or amount of one of the first or second therapeutic agents independently, or both of the therapeutic agents, by the same or different amounts.

[0072] Therapeutic effect

[0073] A first and / or second therapeutic agent as described herein may fully or partially reverse, or ameliorate the severity and / or duration of one or more symptoms of benzodiazepine misuse or overuse, which may include but are not limited to, euphoria, drowsiness, sedation, hypotension, confusion, unconsciousness, difficulty breathing, respiratory depression, pinpoint pupils, slurred speech, nystagmus, ataxia, coma, and cardiorespiratory arrest.

[0074] The present compositions may comprise one or more flavouring agents to improve the palatability.

[0075] A therapeutic effect may include an immediate reversal of one or more symptoms, such as euphoria, unconsciousness, difficulty breathing, respiratory depression, cardiorespiratory arrest, following administration of a combination or composition of a first and second therapeutic agent as described herein.

[0076] A combination or composition of the present invention may additionally comprise a beta blocker (e.g. atenolol, esmolol, metoprolol) and / or a cholinergic agent (e.g. a muscarinic receptor antagonist / anticholinergic, M3 receptor agonist or a nicotinic receptor general or selective agonist) which may enhance the desired clinical effect.

[0077] A therapeutic effect may be observed or measured by assessing, for example, the return and ease of spontaneous respiration, increase in rate of breathing, and / or return to consciousness, reduced confusion, increased ability to follow commands, increased alertness, improvement in clarity of expression and / or speech. Methods such as measuring hemodynamic parameters for example hypertension, hypotension, tachycardia or bradycardia pulse rate, blood pressure blood oxygen concentrations, and return to consciousness (for example using the Glasgow Coma Scale) will be known and available to a person skilled in the art. Suitably, a therapeutic effect will provide a systolic blood pressure of 90 mmHg to 160 mmHg, and a diastolic blood pressure of 50 mmHg to 100 mmHg, a heart rate of 50 BPM or above.

[0078] Pharmaceutically effective dose

[0079] Suitably, a "pharmaceutically effective amount" will be an amount which is effective at achieving a beneficial clinical effect. A beneficial clinical effect may be fully or partially reversal, or amelioration of the severity and / or duration of one or more symptoms of benzodiazepine misuse or overuse, which may include but is not limited to, euphoria, drowsiness, sedation, hypotension, confusion, unconsciousness, difficulty breathing,respiratory depression, pinpoint pupils, slurred speech, nystagmus, ataxia, coma, and cardiorespiratory arrest.

[0080] A pharmaceutically effective amount of a therapeutic agent according to the present invention may be an amount which antagonises, blocks, inhibits or stimulates over 50%, 60%, 70%, 80% of brain benzodiazepine receptors within ten minutes after administration. A pharmaceutically effective amount of a therapeutic agent enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy.

[0081] Suitably, a pharmaceutically effective amount of a benzodiazepine antagonist may be an amount which inhibits 50%, 60%, 70%, 80% or more of benzodiazepine receptors within ten minutes after administration, suitably 70% or 80% or more of benzodiazepine receptors within ten minutes after administration. Suitably, a pharmaceutically effective amount of a benzodiazepine antagonist may be an amount which inhibits 50%, 60%, 70%, 80% or more of brain benzodiazepine receptors within ten minutes after administration, suitably 70% or 80% or more of brain benzodiazepine receptors within ten minutes after administration.

[0082] Suitably, a pharmaceutically effective amount of a GABA agonist, for example a benzodiazepine agent may be an amount which activates (e.g via binding) 50%, 60%, 70%, 80% or more of benzodiazepine receptors within ten minutes after administration, suitably 70% or 80% or more of benzodiazepine receptors within ten minutes after administration. Suitably, a pharmaceutically effective amount of a benzodiazepine may be an amount which inhibits 50%, 60%, 70%, 80% or more of brain benzodiazepine receptors within ten minutes after administration, suitably 70% or 80% or more of brain benzodiazepine receptors within ten minutes after administration.

[0083] A pharmaceutically effective amount may be an amount that is effective to achieve a reduction of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% compared to the expected reduction in a parameter of a symptom, compared to the parameter in an individual not treated with the agent.

[0084] Pharmaceutical composition

[0085] The combination of a first therapeutic agent and a second therapeutic agent as described herein may be provided as a pharmaceutical composition. A pharmaceutical composition will generally comprise a pharmaceutically acceptable carrier and a pharmacologically effectiveamount of one or more therapeutic agents, for example the first and second therapeutic agents as described herein.

[0086] The first therapeutic agent may be a benzodiazepine antagonist and may be provided in the pharmaceutical composition in a pharmacologically effective amount. A suitable pharmacologically effective amount will be that which alleviates one or more symptoms of a benzodiazepine misuse or overuse, suitably which prevents a patient experiencing a euphoric effect. The pharmacologically effective amount will depend upon the mode of administration, and may be repeated until the adverse effect of the benzodiazepine is alleviated, for example the subject awakens from a coma. A suitable pharmacologically effective amount of the first therapeutic agent in a mucosal delivery system may be 0.01-1% by weight based on the total weight of the composition, more suitably 0.01-0.5% by weight based on the total weight of the composition, more suitably 0.01-0.1% by weight based on the total weight of the composition.

[0087] The second therapeutic agent may be a GABA agonist, for example a benzodiazepine agent and may be provided in the pharmaceutical composition in a pharmacologically effective amount. A suitable in a pharmacologically effective amount will be that which alleviates one or more symptoms of benzodiazepine withdrawal. The pharmacologically effective amount will depend upon the mode of administration, and may be repeated until the adverse effect of the benzodiazepine withdrawal is alleviated, for example the subject does not experience or experiences reduced withdrawal symptoms. A suitable in a pharmacologically effective amount of the second therapeutic agent in a mucosal delivery system may be 0.01-10% by weight based on the total weight of the composition, more suitably 0.5-5% by weight based on the total weight of the composition, more suitably 0.5-1.5% by weight based on the total weight of the composition.

[0088] The first therapeutic agent may be provided at a concentration of 0.01-1% by weight based on the total weight of the composition and the second therapeutic agent may be provided at a concentration of 0.01-10% by weight based on the total weight of the composition. Suitably, the first therapeutic agent may be provided at a concentration of 0.01-0.5% by weight based on the total weight of the composition and the second therapeutic agent t may be provided at a concentration of 0.5-5% by weight based on the total weight of the composition. Suitably, first therapeutic agent may be provided at a concentration of 0.0.1-0.1% by weight based on the total weight of the composition and the second therapeutic agent may be provided at a concentration more suitably 0.5-1.5% by weight based on the total weight of the composition.

[0089] A pharmaceutical composition may be formulated as a powder, a granule, a solution, a suspension, an aerosol, a solid, a pill, a tablet, a capsule, a gel, a film, a topical cream, a suppository, a transdermal patch, and / or another suitable formulation.

[0090] A pharmaceutical composition of the present invention may be formulated for parenteral administration. Parenteral delivery includes intravenous (IV), intrathecal, subcutaneous (SC), intramuscular (IM), mucosal, and other parenteral routes. Parenteral delivery methods and systems may comprise delivery by injection, infusion, and / or implantation. IV injection may be direct delivery to the veins resulting in rapid systemic delivery. IV injection may comprise use of an injection directly to a vein, or delivery to a catheter, wherein the catheter may be inserted into a vein. The IV route may also utilize an IV bolus for delivery, an IV drip (IV infusion), and / or use of various metering pumps. Subcutaneous (SC) delivery may refer to administration of the combination or composition to beneath the skin. Suitably, this may be done by injection below the epidermis and dermis layers of the skin. Subcutaneous delivery may sometimes be referred to as hypodermic injection. Intramuscular (IM) delivery may refer to administration of the drug to a muscle, generally by injection, e.g., into the muscles of the upper arm or gluteal area. Mucosal drug delivery may generally refer to bringing the pharmaceutical composition into physical contact with one or more mucosal tissues, such as oral mucosa, nasal mucosa, vaginal mucosa, and / or rectal mucosa. The oral mucosa may comprise sublingual regions below the tongue and buccal regions of the inner cheeks.

[0091] Suitably, a combination or composition of the present invention may be formulated for buccal administration. Buccal delivery may refer to a topical route of administration by which drugs may partially diffuse through the oral mucosa (e.g., tissues which may line the mouth) and may then enter directly into the bloodstream. Suitably, a combination or composition of the present invention may be formulated for sublingual administration. Sublingual delivery may refer to a pharmacological route of administration (delivery) by which drugs may diffuse into the blood through tissues (e.g., sublingual mucosa) under the tongue. Sublingual delivery may be in tablet (pill) formulation, capsule formulation and / or film formulation. Sublingual and buccal formulations may be substantially equivalent. Suitably, a composition of the present invention for oral administration may be in the form of a sublingual or buccal film.

[0092] Nasal inhalation delivery may refer to a pharmacological route of administration by which drugs may diffuse into the blood through the thin mucosa within the nasal cavity (e.g.,the single epithelial cell layer lining some of the nasal cavity). A composition for nasal inhalation delivery may be powder and / or liquid formulations.

[0093] The composition, for example where in the form of a film as described herein, may be formulated for unidirectional drug release that facilitates effective drug permeation the selected body surface, for example the mucosa. A composition, for example a film, of the present invention may therefore comprise a directional release mechanism, for example a unidirectional release mechanism for a pharmaceutically active agent as described herein.

[0094] Suitably, the combination or composition of the present invention may be formulated for controlled or sustained release.

[0095] A pharmaceutical composition may comprise one or both of the therapeutic agents, and may also comprise other agents such as, for example, binders, fillers, disintegrants, permeation enhancer, sustained-release agents, coloring agents, diluents, anti-adherents, glidants, flow aids, plasticizers, lubricants, excipients, preservatives, stabilizers, and solvents. For oral delivery, the components of the formulation may be soluble. For oral delivery, a composition may be formulated to be palatable. A composition for oral delivery may comprise one or more flavouring agents, or flavour masking agents, for example a sweetener such as saccharin and / or sucrose and suitable flavoring.

[0096] Suitably, a pharmaceutical composition of the present invention may be a mucosal drug delivery system, or may be a mucosal drug delivery film, formulated for sub-lingual, buccal, nasal, rectal or vaginal delivery, comprising diazepam and flumazenil. Suitably, a pharmaceutical composition of the present invention is an oral formulation, comprising diazepam and flumazenil. Suitably, a pharmaceutical composition of the present invention is an oral thin film, comprising diazepam and flumazenil. Suitably, the pharmaceutical composition comprises a permeation enhancer as described herein.

[0097] A combination or composition of the invention may be presented in dosage forms such as capsules, tablets, powders, granules, film, or as a suspension or solution. Capsule formulations may be gelatin, soft-gel or solid. Suitably, the composition is a dissolvable film, for example an oral thin film. An oral thin film is a thin, flexible, polymer based matrix, loaded with one or more pharmaceutically active agents for delivery to a patient. Such a film typicaly disintergrated and dissolves immediately when applied to the mucosa, for example sub-lingually or buccally. An oral thin film may comprise one or more layers. Suitably, an oral thin film may consist of one layer.

[0098] A suitable dissolvable film for use in the present invention may disintegrate at dissolve at body temperature, for example between 36-40°C. Suitably, a film according to the present invention may be smooth, to provide a good mouth feel. Suitably, a film according to the present invention will adhere well to the mucosa.

[0099] A pharmaceutically active agent may be embedded in the matrix of a film.

[0100] The oral thin films are taken orally and dissolve immediately in the mouth or are applied to the mucosa. They are placed on or under the tongue or buccally, where they dissolve or disintegrate. High drug loadings of the oral thin film are desirable e.g.0.5 mg per mg of gel film.

[0101] Suitably, one or both of the therapeutic agents may be in unit dose form such as a film, tablet, capsule, suppository or vial. Suitable unit doses, i.e., pharmaceutically effective amounts, may be determined during clinical trials designed appropriately for each of the conditions for which administration of a chosen compound is indicated and will, of course, vary depending on the desired clinical endpoint.

[0102] A pharmaceutical composition as described herein may further comprise a carrier, a plasticiser, a permeation enhancer, and / or one or more excipients.

[0103] A carrier may be provided. Examples for suitable carriers may include water-soluble cellulose derivatives, such as hydroxy propyl methyl cellulose. A suitable carrier for use in combination with diazepam and flumazenil may be HPMC. Any suitable viscosity may be used, for example Metalose 60SH-50. If present, a carrier may be provided at a concentration in the range of 1-20 % by weight based on the total weight of the composition, suitably 1-15% by weight based on the total weight of the composition, suitably 5-10% by weight based on the total weight of the composition.

[0104] A plasticiser may be provided to lower the melting point and reduce the glass transition temperature, and / or improve the muco-adhesive properties of the composition, for example where it is in the form of a film. Examples for suitable plasticizers may include polyols, such as glycerol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol or glycerol monoesters with fatty acids, and glycerol triesters such as triacetin, esters of citric acid such as triethyl citrate, acetyltributylcitrate, water, ethanol, α- tocopherol benzyl benzoate, butyl stearate, chlorobutanol, dibutyl phthalate, dimethylphthalate, diethyl phthalate, dibutyl sebacate, stearic acid, tricaprylin. A suitable plasticiser for use in combination with diazepam and flumazenil may be glycerol. If present, a plasticiser may be provided at a concentration in the range of 0.01-10 % by weight based on the total weight of the composition.

[0105] A permeation enhancer may be provided to enhance penetration of a therapeutic agent into the circulatory system of a subject. A permeation enhancer may also be referred to as a penetration enhancer. Examples for suitable permeation enhancers may include: : a polymeric stabiliser, for example Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer), a detergent for example sucrose monolaurate, vitamin E, suitably vitamin E TPGS (a water miscible form of vitamin E composed of a hydrophobic vitamin E part and a hydrophilic PEG chain), sulfoxides, such as decylmethylsulfoxide, diethylsulfoxide and dimethylsulfoxide, azones such as 1-dodecylazacycloheptan-2-one and laucapram, fatty acids, such as oleic acid, capric acid, monoglycerides and diglycerides, surfactants, such as Tween, sodium lauryl sulfate, and polyoxyethylene ethers, water, and polyols such as polyethylene glycol, propylene glycol and ethanol. A suitable permeation enhancer for use in combination with diazepam and flumazenil may be selected from Tween 80, polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft co-polymer, sucrose monolaurate and vitamin E TPGS.. If present, a permeation enhancer may be provided at a concentration in the range of 0.01-1% by weight based on the total weight of the composition.

[0106] An auxiliary enhancer may be provided to enhance penetration of a therapeutic agent into the circulatory system of a subject. An auxiliary enhancer may also be provided as a solubiliser. Examples for suitable auxiliary enhancers may include: sulfoxides, such as decylmethylsulfoxide, diethylsulfoxide and dimethylsulfoxide, azones such as 1- dodecylazacycloheptan-2-one and laucapram, fatty acids, such as oleic acid, capric acid, monoglycerides and diglycerides, surfactants, such as Tween, sodium lauryl sulfate, and polyoxyethylene ethers, water, and polyols such as polyethylene glycol, propylene glycol and ethanol. A suitable auxiliary enhancer for use in combination with diazepam and flumazenil may be PEG1500. If present, an auxiliary enhancer may be provided at a concentration in the range of 0.01-10% by weight based on the total weight of the composition.

[0107] One or more excipients may also be included, for example taste-masking agents, sweetening agents, flavoring agents, lubricants, pigments, coloring agents, stabilizers, disintegrators, fillers, saliva stimulating agents, emulsifiers, surfactants, enhancers, pHregulating agents, buffers, buffering agents, release modifiers, softeners, moisturizers, mold release agents, adhesives, anti-adherents and antioxidants.

[0108] One or more excipients may include a disintegrator. A suitable disintegrator may be polyvinylpyrrolidone, such as PVP K30. If present, a disintegrator may be provided at a concentration in the range of 0.01-10% by weight based on the total weight of the composition.

[0109] One or more excipients may include a sweetener, a flavouring agent and / or a saliva stimulant. A suitable sweetener may be isomalt. A suitable flavouring agent may be lemon flavour. A suitable saliva stimulant may be citric acid. If present, a sweetener, a flavouring agent and a saliva stimulant may each be provided at a concentration in the range of 0.01-1% by weight based on the total weight of the composition. Dosage

[0110] The first and second therapeutic agents may be administered according to a defined dosage regimen. The dosage regime for each of the first and second therapeutic agents may be the same or may be different. A dosage regime for each of the first and second therapeutic agents may be same for all or part of the treatment or prevention regimen, or may be different for all or part of the treatment or prevention regimen. The first and second therapeutic agents may be administered once, or may be divided into a number of smaller doses to be administered at intervals of time, or may be administered by continuous infusion. The first and second therapeutic agents may be administered independently, separately or as a combined formulation, hourly, 12 times daily, 8 times daily, 6 times daily, 4 times daily, twice daily, once daily, every two days, every four days, once per week, once every 10 days, or once every 2 weeks, for example. In one embodiment, the first and second therapeutic agents may each be administered one or more times daily, suitably two or three times daily. In an embodiment, the first and second therapeutic agents are administered according to the same dosing regimen. However, it is envisaged that they may each be administered according to a different dosage regimen.

[0111] Suitably the first and second therapeutic agents may be administered once or twice or three times per day.

[0112] Suitably the first and second therapeutic agents may be administered during a defined therapeutic window.

[0113] The therapeutic window may be after onset of one or more symptoms of benzodiazepine misuse or overuse, and suitably during the presence of one or more such symptoms. Suitably, a combination or composition of the present invention may be administered under a suitable dosage regimen until amelioration or relief from one or more of said symptoms.

[0114] A pharmaceutically effective amount will vary depending on the therapeutic agent(s), the extent or severity of the condition, symptom, or affliction, kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion, and the physical features of the subject such as age, weight, etc. The precise dose to be employed in the compositions will also depend on the route of administration, and should be decided according to the judgment of the practitioner and each patient's circumstances. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and / or dosing regimens. The dosage regime may be adjusted accordingly where the subject is a child. For a child, the dosage may be adjusted accordingly based upon age, weight, or sex.

[0115] An effective amount also includes an amount of a therapeutic agent that avoids or substantially attenuates undesirable side effects.

[0116] A specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0117] Pharmaceutically effective concentrations and amounts may be determined for each application herein empirically by testing the compounds in known in vitro and in vivo systems, such as those described herein, dosages for humans or other animals may then be extrapolated therefrom.

[0118] Thus, for example, in some aspects, an effective amount is an amount that is effective to achieve a reduction of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% compared to the expected reduction in the parameter in an individual not treated with the agent.

[0119] Kits

[0120] The present invention also provides a kit comprising a combination or a first and second therapeutic agents as described in herein, or a pharmaceutical composition as described herein.

[0121] A kit may include one or more containers filled with one or more of the therapeutic agents or pharmaceutical compositions of the invention. Additionally, the kit may include one or more additional reagents, for example buffers and solutions. A kit may also optionally include a notice or printed instructions. A kit may also include “packaging material” refers to one or more physical structures used to house the contents of the kit. The packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment. As used herein, the term “package” refers to a solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding a content of the kit.

[0122] Delivery device

[0123] The present invention also provides a delivery device comprising a combination or composition of the present invention. A delivery device may be a syrette, a syringe, an auto- injector, a film, an inhaler, and / or a spray.

[0124] Subject / patient

[0125] A subject as defined herein may be a mammal. Mammalian subjects include humans; domestic animals; farm animals; such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on. In an embodiment, a subject is a human. A subject may be an adult or may be a child, suitably a human adult or human child.

[0126] A subject may be a recreational or non-recreational drug user. A subject may be a poly-drug user. A subject may suffer from an addiction to a benzodiazepine. A subject may have previously suffered from or has been diagnosed as having an addiction to, overuse disorder of, or misuse disorder of, a benzodiazepine. A subject may have been previously evaluated as having or likely to suffer from an addiction to, overuse disorder of, or misuse disorder of, a benzodiazepine.

[0127] A subject may exhibits one or more symptoms of an addiction to, overuse of, or misuse disorder of, a benzodiazepine. A subject may be diagnosed or identified to be suffering from or experiencing, or at risk of suffering or experiencing euphoria, drowsiness, sedation, hypotension, confusion, unconsciousness, difficulty breathing, respiratory depression, pinpoint pupils, slurred speech, nystagmus, ataxia, coma, and cardiorespiratory arrest.Method of treatment

[0128] A method of treatment as described herein may additionally comprise determining that the subject exhibits or is at risk of suffering from one or more symptoms of an addiction to, overuse of, or misuse disorder of, a benzodiazepine as defined herein.

[0129] The combination of the first and second therapeutic agents may be administered simultaneously, or sequentially in any order, to a subject.

[0130] Sequential administration comprises administering a first therapeutic agent and subsequently administering a second therapeutic agent, suitably after an interval of time. In an embodiment, a first therapeutic agent may be administered first, followed by a second therapeutic agent after a suitable time interval. Alternatively, a second therapeutic agent may be administered first, followed by a first therapeutic agent after a suitable time interval.

[0131] Suitably the interval of time is selected such that both agents are able to exert their therapeutic effect at overlapping time periods.

[0132] In an embodiment, a first and second therapeutic agent may be administered simultaneously. If formulated as separate compositions, they may be administered at substantially the same time (i.e. within a few minutes of each other or so that their therapeutic effects substantially overlap). Alternatively, they may be administered as a single composition. The first and second therapeutic agents may be formulated as a single composition.

[0133] The compounds may be administered to a subject via a suitable route of administration. Routes of administration include oral administration, intraperitoneal, parenteral (e.g., intravenous), intradermal, subcutaneous, intranasal, transdermal, topical, transmucosal, rectal, sublingual or buccal administration. Where the first and second therapeutic agents are administered as separate formulations, they may have the same or different routes of administration.

[0134] In an embodiment, both the first and second therapeutic agents are administered orally. In an embodiment, the first and second therapeutic agents are provided as a single composition and administered orally.

[0135] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless thecontext otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0136] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. Examples

[0137] Quantification of flumazenil and diazepam was performed using a HPLC (Infinity 1260, Agilent Technologies) coupled with a UV diode array. The analytical methodology was based on inhouse development method. The method specifications were mention in table below. A 8-point calibration curve was produced using flumazenil and diazepam ranging from 1 - 100 µg mL-1in either mobile phase or dissolution media. The peak area for each sample was quantified against its respective calibration curve (µg mL-1) and the amount (µg) calculated by multiplying by the volume. Data presented in results, tables and figures are those after subtraction of the appropriate blank samples unless otherwise stated. Table 1. Parameters of HPLCHPLC System Infinity 1260, Agilent Technologies Column C18,150 × 4.6 mm, 5 µm Column Room Temperature Temperature W Moas bh ileso Plu ht ai so en M 20o mbi Mle A ph ma mse onium Formate and Methanol (50:50)Run Time 10 minutes Injection 10 µL Volume Flow rate 1 mL / min UV Absorbance 230, 210 and 240 nm Batch manufacturing process (lab development) Batch production (optimised formulation)

[0138] Polymer thin films were produced containing flumazenil and diazepam. The compositions of the formulations are described in Table 2. All ingredients were weighed on an analytical balance (A&D Instruments Ltd., Abingdon, Oxford, UK; Serial No. 14214367) and combined using an Ultra-Turrax homogeniser (Janke & Kunkel, Staufen, Germany; Serial No.751808) at 5000 rpm. Films were cast from the casting gel on to a silicon coated backing polymersheet (Loparex) using a Micrometer Adjustable Film Applicator (Sheen; 1117 / 250mm) at 850 µm and dried in a cabinet drier (Mitchell Dryers Ltd., Carlisle, UK) at 60°C for 50 minutes. Thin films were cut to a target size / weight using a rotary blade. Table 2. Composition of flumazenil and diazepam (FTx301) casting film gel Excipient Category Qty (gm) %(w / w) Flumazenil Active 0.008 0.08 Diazepam Active 0.08 0.8 HPMC Metalose Carrier 60SH-50 0.7 7 Tween 80 Surfactant / permeation enhancer 0.02 0.2 Isomalt Sweetener 0.06 0.6PVP K30 Disintegrator 0.142 1.42 Glycerol Plasticiser 0.2 2 Lemon flavour Flavouring agent 0.07 0.7 Citric acid Saliva stimulant / buffer 0.04 0.4 PEG 1500 Solubiliser / auxiliary enhancer 0.15 1.5 DW Vehicle 8.53 85.3 Total weight of the gel 10 100 Characterisation of product Uniformity of weight

[0139] Uniformity of weight was calculated by individually weighing films (n=6) taken at random and determine the average mass. Not more than 2 of the individual masses deviate from the average mass by more than the percentage deviation. Uniformity of drug content

[0140] The drug content analysis was conducted three times. A single film size of 2 cm2was dissolved in 10 mL of mobile phase and then sonicated for 10 minutes. The resulting solution was centrifuged, and the supernatant was injected into the HPLC for the quantification of the drug content. Folding endurance

[0141] The film’s mechanical handling property was determined using the folding endurance methodology. The film was repeatedly folded in the same place until the film broke. The folding endurance value is the number of times the film is folded without breaking. The mean value of the triplicate readings is shown in the results. In vitro mucoadhesion

[0142] An in-house in-vitro mucoadhesion test was performed to evaluate the initial mucoadhesion property of the films. A substrate that mimics the oral mucosal layer, a hydrogel was prepared by using a 10% gelatin aqueous solution that was subjected tofreeze (-80°C) – thaw (20°C) temperature conditions for 18 hours. Drugs loaded film was then carefully placed on the surface of the gelatin hydrogel-containing Petri dish and the dish was tilted at an 80° angle. The film was observed for 30 minutes (maximum testing time) to see if it slid or detached from the initial place of attachment on the surface of the gelatin hydrogel, and, if so, the length of time (minutes) it took to detach. The duration of attachment was recorded in triplicate and the mean (minutes) is presented in the results. Disintegration

[0143] This was performed using a standard disintegration tester (Copley Scientific, UK) operated using 900ml distilled water heated to 37°C and an oscillation speed of 30±1mm / min. In vitro drug release and dissolution

[0144] Individual films (n=3) were placed into a Franz cell containing 20ml of phosphate buffer pH 7.4 heated at 37°C. The systems were continuously agitated using the inbuilt microflea. Samples were collected at 0, 5, 10, 15, 30, 45, 60 and 120 mins. Samples were analysed for flumazenil and diazepam content using the HPLC method. Results Analytical method development

[0145] A standard calibration curve of flumazenil and diazepam was prepared 1-100 µg range, and the regression coefficient (R2) value was 0.999. A higher R-squared value nearing to1 indicated the prepared calibration curve was a good fit. The average retention times during the run were 2.4 minutes for flumazenil and 7.40 minutes for diazepam. Batch manufacturing process

[0146] The film gel of optimised formulation was cast at optimised thickness of 800 µm to get the target drug load of diazepam (1-2 mg) and flumazenil (0.2 mg) in the film. Characterisation of product

[0147] The batch manufactured films were characterised for uniformity of weight, drug content, disintegration and dissolution. The results were summarised in Table 3.Table 3. Uniformity of weight, drug content and disintegration of thin films Characterisations FTx301 average ± sdFilm thickness (µm) 50 ± 0.5 n=6 Uniformity of weight (mg) 51.2 ± 0.8 n=6 Uniformity of drug content 0.219 ± 0.007 Flumazenil (mg) n=3 Uniformity of drug content 2.006 ± 0.08 Diazepam (mg) n=3 Disintegration (min) 1 ± 0.2 n=6

[0148] Disintegration test was performed using a standard USP disintegration tester (Copley Scientific, UK) operated using 900ml distilled water heated to 37°C and an oscillation speed of 30±1mm / min. The disintegration results represent a pass as described within the BP. We consider completion of disintegration when all of the film was no longer remaining on the upper side of the wire. Since the thin films adhered to this surface this accounted for the longer time periods recorded. However it is simply an artifact of the test process which is designed primarily for tablets.

[0149] The folding endurance test was conducted to evaluate the mechanical handling and structural integrity of the film during transportation, patient administration, and storage. The results showed that films (FTx301), were able to withstand 50±2 folds without breaking. This indicated that the films possessed sufficient physical strength for routine handling. However, further evaluation of the mechanical properties of the films, such as tensile strength, elongation at break, and Young's modulus, is required to gain a better understanding of their actual mechanical properties.

[0150] In the mucoadhesion test, films attached well to the substrate surface. It was observed that films did not slide or detach from the surface of the substrate during tested time (maximum 30 minutes). This indicates films have good mucoadhesion properties under the conditions tested.

[0151] The in vitro drug release profiles of FTx301 thin films at pH 7.4 (figure 1). The thin film formulation (FTx301), achieved>70% release of flumazenil and diazepam within 5 min.

Claims

CLAIMS 1. A combination of a first and second pharmaceutically active agent, wherein the first pharmaceutically active agent is GABA agonist and the second pharmaceutically active agent is a GABA antagonist.

2. A combination according to claim 1 wherein the GABA agonist is a benzodiazepine agent.

3. A combination according to claim 1 or claim 2 wherein the benzodiazepine antagonist is flumazenil.

4. A pharmaceutical composition comprising a combination according to any one of claims 1 to 3.

5. A pharmaceutical composition according to claim 4, which is dissolvable and optionally formulated for mucosal delivery.

6. A pharmaceutical composition according to claim 4 or 5, which is an oral thin film.

7. A pharmaceutical composition according to any one of claims 4 to 6 which is formulated for sub-lingual or buccal delivery.

8. A pharmaceutical composition according to any one of claims 4 to 7, further comprising a disintegrator, a plasticiser, a sweetener, a flavouring agent, and / or a saliva stimulant, or any combination thereof.

9. A combination or composition according to any one of claims 1 to 8 for use in treating a benzodiazepine use disorder, or for use in preventing or reversing an effect of a benzodiazepine overuse or misuse disorder.

10. A combination or composition according to claim 9, for alleviation of one or more symptoms of withdrawal, euphoria, drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest in a subject who has consumed benzodiazepine.

11. A combination or composition according to any one of claims 1 to 10, wherein the GABA antagonist is present at 0.01-1%, preferably 0.01-0.5%, preferably 0.01-0.1% by weight based on the total weight of the composition.

12. A combination or composition according to any one of claims 1 to 11, wherein the GABA agonist is present at 0.01-10%, preferably 0.5-5%, preferably 0.5-1.5% by weight based on the total weight of the composition.

13. A combination or composition according to claim 11 or claim 12 wherein the GABA antagonist is provided at a concentration of 0.01-1% and the GABA agonist is provided at a concentration of 0.01-10% by weight based on the total weight of the composition.

14. A combination or composition according to any one of the previous claims, comprising a permeation enhancer, preferably wherein the permeation enhancer is selected form the group consisting of Tween 80, polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft co-polymer, sucrose monolaurate and vitamin E TPGS.

15. An oral thin film comprising a combination of pharmaceutically active agent and a permeation enhancer, preferably wherein the pharmaceutically active agent is a benzodiazepine agonist.

16. An oral thin film according to claim 15 wherein the permeation enhancer is selected form the group consisting of Tween 80, polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft co-polymer, sucrose monolaurate and vitamin E TPGS.

17. An oral thin film according to claim 15 or 16, further comprising a benzodiazepine antagonist.

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