Nasal olanzapine formulations and methods of use thereof

Abstract

A composition for nasal administration of olanzapine and methods of using the same for treating various symptoms of schizophrenia, schizoaffective disorder and bipolar disorder, such as acute agitation, mania and mixed episodes. The nasal olanzapine composition contains dodecylmaltoside to improve the bioavailability of olanzapine and is administered via the nasal mucosa to avoid direct systemic administration.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 323,592, filed March 25, 2022, which is incorporated by reference in its entirety herein.

[0002] Field The present disclosure relates generally to compositions comprising olanzapine and an alkyl maltoside, suitable for nasal administration and effective for the treatment of acute agitation associated with schizophrenia, schizoaffective disorder, and bipolar disorder, as well as the maintenance treatment of schizophrenia, schizoaffective disorder, bipolar disorder, and treatment-resistant depression.

[0003] background Olanzapine is an atypical antipsychotic approved for the treatment of schizophrenia, schizoaffective disorder, and bipolar disorder. Patients suffering from these disorders are prone to agitation episodes that range from mild to severe, fluctuate rapidly, and escalate into aggressive behavior within a short period of time. Symptoms include motor restlessness, increased reactivity to external stimuli, irritability, and inappropriate speech, which can escalate into physical aggression, typically directed toward family members or medical personnel.

[0004] Intramuscular injections of olanzapine are commonly used to treat acute agitation episodes because they have a shorter time to peak concentration than oral or orally disintegrating tablets. Rapid onset is highly desirable, and historically, intramuscular injections of olanzapine have been the approved rapid-acting route of administration in the United States. However, intramuscular injections of olanzapine require reconstitution prior to administration, must be administered by a healthcare professional (HCP), may require restraints, are invasive, and can be painful. Additionally, in uncooperative patients, they pose a risk of needlestick injury to healthcare professionals, caregivers, and patients.

[0005] What is needed is a non-invasive, convenient, needle-free method of administering olanzapine that is accessible to patients in acutely agitated states without the assistance of an HCP and has a rapid onset of therapeutic benefit. Such a method would also be beneficial in providing therapeutic benefit to subjects suffering from schizophrenia, schizoaffective disorder, bipolar disorder, and / or treatment-resistant depression in a form that is more easily administered than currently available oral formulations. Summary of the Invention

[0006] In one embodiment, the present disclosure provides a composition comprising about 1% w / v to about 15% w / v olanzapine or a pharma- ceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v dodecylmaltoside, about 30% w / v to about 40% w / v N,N-dimethylacetamide, and about 40% w / v to about 70% w / v polyethylene glycol, the composition being a non-aqueous solution containing less than about 3% w / v water.

[0007] In some embodiments, the composition comprises about 2.5% w / v to about 12% w / v olanzapine or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 0.20% w / v to about 0.50% w / v dodecyl maltoside. In some embodiments, the composition comprises about 34% w / v to about 38% w / v N,N-dimethylacetamide. In some embodiments, the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da. In some embodiments, the polyethylene glycol has an average molecular weight of about 600 Da. In some embodiments, the composition comprises about 44% w / v to about 66% w / v polyethylene glycol. In some embodiments, the amount of olanzapine is about 1 mg to about 15 mg or a pharma- ceutically acceptable salt thereof. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. In some embodiments, the composition comprises about 2.5% w / v to about 12% w / v olanzapine or a pharma- ceutically acceptable salt thereof, about 0.20% w / v to about 0.50% w / v dodecylmaltoside, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol. In some embodiments, the composition comprises less than about 1% w / v water. In some embodiments, the composition comprises less than 0.1% w / v water.

[0008] Some embodiments relate to a single-use spray device comprising a composition according to the present disclosure, the single-use spray device being configured to dispense an amount of the composition equivalent to 2.5 mg to 15 mg of olanzapine upon actuation of the device.

[0009] Some embodiments relate to a metered dose, multi-dose spray device comprising a composition according to the present disclosure and configured to dispense an amount of the composition equivalent to 2.5 mg to 15 mg of olanzapine upon actuation of the device.

[0010] Some embodiments relate to a method of treating acute agitation associated with one or more of schizophrenia, schizoaffective disorder, and bipolar disorder in a subject in need thereof, comprising administering intranasally to the nasal mucosa of the subject a composition comprising about 1% w / v to about 15% w / v of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v of dodecylmaltoside, about 30% w / v to about 40% w / v of N,N-dimethylacetamide, and about 40% w / v to about 70% w / v of polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v of water.

[0011] Some embodiments relate to a method of treating depression associated with bipolar disorder, the method comprising: intranasally administering to the nasal mucosa of the subject a composition comprising about 1% w / v to about 15% w / v of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v of dodecylmaltoside, about 30% w / v to about 40% w / v of N,N-dimethylacetamide, and about 40% w / v to about 70% w / v of polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v of water.

[0012] Some embodiments relate to a method of treating mania associated with bipolar disorder, the method comprising: intranasally administering to the nasal mucosa of the subject a composition comprising about 1% w / v to about 15% w / v of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v of dodecylmaltoside, about 30% w / v to about 40% w / v of N,N-dimethylacetamide, and about 40% w / v to about 70% w / v of polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v of water.

[0013] Some embodiments relate to a method of treating a mixed episode associated with bipolar disorder, the method comprising: intranasally administering to the nasal mucosa of the subject a composition comprising about 1% w / v to about 15% w / v of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v of dodecylmaltoside, about 30% w / v to about 40% w / v of N,N-dimethylacetamide, and about 40% w / v to about 70% w / v of polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v of water.

[0014] In some embodiments, the composition for use in the methods described herein comprises about 1 mg to about 15 mg of olanzapine or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition for use in the methods described herein comprises about 2.5 mg to about 10 mg of olanzapine or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition for use in the methods described herein comprises about 0.20% w / v to about 0.50% w / v of dodecyl maltoside. In some embodiments, the composition for use in the methods described herein comprises about 34% w / v to about 38% w / v of N,N-dimethylacetamide. In some embodiments, the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da. In some embodiments, the composition for use in the methods described herein comprises about 44% w / v to about 66% w / v of polyethylene glycol. In some embodiments, a composition for use in the methods described herein comprises about 2.5 mg to about 12 mg of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.20% to about 0.50% w / v dodecyl maltoside, about 34% to about 38% w / v N,N-dimethylacetamide, and about 44% to about 66% w / v polyethylene glycol.

[0015] In some embodiments, the severity of acute agitation in the subject is reduced within about 20 minutes after administration. In some embodiments, the compositions for use in the methods disclosed herein are provided in a pre-primed single-use administration device comprising about 75 μL to about 200 μL of the composition. In some embodiments, the administering step comprises administering about 75 μL to about 200 μL of the composition to each nostril of the subject. In some embodiments, the depressive, manic, or mixed episode manifests as a recurrent episode, and one or more of the frequency, length, and severity of the recurrent episode are reduced. In some embodiments, the compositions for use in the methods disclosed herein comprise less than 1% w / v water. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows the saturation solubility of the dimethylacetamide / PEG200 binary solvent system. [Diagram 2] FIG. 2 shows the overlay of the chromatograms obtained in the solubility test. [Diagram 3] FIG. 3 shows an overlay of chromatograms of 10 mg / mL olanzapine in 100% PEG200. [Figure 4] FIG. 4 shows an overlay of chromatograms of 150 mg / mL olanzapine in 50 / 50 dimethylacetamide / PEG200. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Before describing the compositions and methods, it should be understood that various aspects of the nasal olanzapine compositions and methods of use thereof are disclosed herein. Unless otherwise indicated, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. It should also be understood that the terms used herein are for the purpose of describing particular aspects or embodiments only, and are not intended to limit the scope. The disclosed nasal olanzapine compositions, methods of making them, and methods of using them are not strictly limited to the specific compositions, steps, or methods described, as these may vary to an extent recognized by those skilled in the art without departing from the benefits and advantages imparted by the compositions and methods. For the purpose of describing various aspects and embodiments of the nasal olanzapine compositions, methods of making them, and methods of using them, preferred compositions and methods are described below, although those skilled in the art will readily recognize obvious modifications and substitutions that may be made to achieve the same results by equivalent means or functions.

[0018] It will be further understood that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0019] The compositions disclosed herein are suitable for administration to the nasal cavity, and therefore the terms "nasal solution," "nasal composition," and "nasal formulation" are used interchangeably to mean a composition suitable for administration to the nasal mucous membranes lining the nasal cavity.

[0020] The nasal olanzapine compositions disclosed herein can be used to treat various symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, and depression, particularly treatment-resistant depression.

[0021] Schizophrenia is a definite mental illness that affects how a person thinks, feels, and behaves, with a breakdown in the relationships between these aspects of a person's life, leading to inappropriate behaviors and emotions, withdrawal from reality and relationships, and a sense of mental fragmentation. Generally, schizophrenia develops in at least three stages: prodromal, first episode, and chronic. There are also individual differences in all stages of the disease, with some people at ultra-high risk, clinical high risk, or at risk for developing psychosis (Fusar-Poli et al., "The Psychosis High-Risk State: A Comprehensive State-of-the-Art Review," JAMA Psychiatry 70:107-120 (2013), incorporated herein by reference in its entirety). The methods described herein are suitable for treating subjects at any stage of schizophrenia and at any risk level for psychosis.

[0022] Schizoaffective disorder is a combination of symptoms of schizophrenia and symptoms of a mood disorder such as depression or bipolar disorder. Symptoms may occur simultaneously or at different times. There are often periods of severe symptoms followed by periods of improvement. Symptoms include delusions, hallucinations, depressive episodes, and manic periods of high energy. There are two types of schizoaffective disorder: bipolar, characterized by manic episodes and sometimes major depressive episodes, and depressive, characterized only by major depressive episodes.

[0023] Bipolar disorder, sometimes known as manic depression, is a mental illness that causes intense mood swings (mania) and depression, as well as changes in sleep, energy, thinking, and behavior. People with bipolar disorder experience periods ("episodes") of feeling excessively happy and energetic, and periods of feeling very sad, hopeless, and lethargic. Episodes of mood swings may occur infrequently or multiple times a year. Bipolar I disorder is characterized by at least one manic episode, which may be preceded or followed by hypomanic episodes (a less severe form of mania) or depressive episodes. Bipolar II disorder is characterized by at least one major depressive episode and at least one hypomanic episode, but no manic episodes.

[0024] Mania and hypomania are two different types of episodes, but the symptoms are the same. Mania is more severe than hypomania and causes significant problems with work, school, social activities, and relationships. Mania can cause escape from reality (psychosis) and may require hospitalization. A major depressive episode involves symptoms severe enough to cause significant difficulties in daily life, including work, school, social activities, and relationships. A mixed episode is when manic and depressive symptoms occur simultaneously or in rapid succession without recovery in between.

[0025] Generally, bipolar disorder is a progressive disease that develops through at least three stages: prodromal, symptomatic, and residual (Kapczinski et al., "Clinical Implications of a Staging Model for Bipolar Disorders," Expert Rev Neurother 9:957-966 (2009), and McNamara et al., "Preventative Strategies for Early-Onset Bipolar Disorder: Towards a Clinical Staging Model," CNS Drugs 24:983-996 (2010), which are incorporated herein by reference in their entireties). The methods described herein are suitable for treating subjects with any of the aforementioned bipolar disorders, and subjects at any stage of a particular bipolar disorder.

[0026] Acute agitation is defined as excessive motor activity associated with a feeling of inner tension and may be associated with schizophrenia, schizoaffective disorder, and bipolar disorder (as well as many other psychiatric disorders).

[0027] Treatment-resistant depression (TRD) generally refers to the failure to achieve an adequate response to at least one antidepressant trial of sufficient dose and duration.

[0028] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to protect against or delay (e.g., attenuate or postpone onset) an undesirable physiological condition, disorder, or disease (partially or fully), or to obtain a beneficial or desired clinical result, such as partial or total restoration or inhibition of the decline of a parameter, value, function, or outcome that was or becomes abnormal. For purposes of this disclosure, beneficial or desired clinical results include alleviation of symptoms; reduction in the extent or momentum or rate of onset of a condition, disorder or disease; stabilization of the condition (i.e., not worsening), stabilization (i.e., not worsening) of the state of the condition, disorder or disease, delay in the onset or slowing of progression of the condition, disorder or disease, improvement in the state of the condition, disorder or disease, and remission (whether partial or total), whether or not it leads to immediate relief of actual clinical symptoms, or enhancement or amelioration of the condition, disorder or disease. Treatment seeks to elicit a clinically significant response without undue side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. As used herein, "treating" refers to a condition that is not a cause of death or a cause of injury. " and other grammatical forms (e.g., treat, treatment) also include improving symptoms of a disease or condition, such as schizophrenia, schizoaffective disorder, bipolar disorder, or TRD. Improvement includes a reduction in the frequency, length, or severity of one or more symptoms. The physiological causes of many psychiatric disorders or illnesses, including schizophrenia, schizoaffective disorder, bipolar disorder, and TRD, are not fully understood, but are believed to result from abnormalities in biochemical signaling in the brain. Thus, the compositions and methods disclosed herein may temporarily treat symptoms caused by abnormal biochemical signaling or temporarily alter biochemical signaling, but may not adequately treat the underlying cause of the abnormal signaling.Thus, a subject "treated" with the compositions and methods described herein will experience an improvement in the symptoms of the disease or condition, but may require maintenance therapy, i.e., a long-term administration regimen, to maintain said improved symptoms. In many cases, a long-term administration regimen may continue for months, years, or even the remainder of the subject's life.

[0029] In any embodiment, the methods and compositions disclosed herein may comprise the steps and components described. As used herein, "comprise" is used to describe the steps or components included in the described method or composition, but is open language used to indicate that other elements may also be included, even if the elements are not explicitly described. In any embodiment, the methods and compositions disclosed herein may consist essentially of the steps and components mentioned. As used herein, "consist essentially of" is used to describe the steps or components included in the described method or composition, but is used to indicate that other elements may also be included, but that the other elements will not materially affect the properties of the composition or the results of the method. In any embodiment, the methods and compositions disclosed herein may consist of the steps and components mentioned. As used herein, "consist of" is closed language used to describe the steps or components included in the described method or composition, but is used to indicate that other elements may also be included, but that the other elements will not materially affect the properties of the composition or the results of the method. The use of the terms comprise, comprised or comprising may be interchanged with "consist essentially of" or "consist of."

[0030] The singular forms "a," "an," and "the" include the plural unless the context clearly indicates otherwise. Thus, for example, reference to a "cell" is a reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth.

[0031] The term "about" as used herein means plus or minus 1% of a given value. For example, "about 50%" means a range of 49.5% to 50.5%. The term "about" as used herein means plus or minus 2% of a given value. For example, "about 50%" means a range of 49% to 51%. The term "about" as used herein means plus or minus 3% of a given value. For example, "about 50%" means a range of 48.5% to 51.5%. The term "about" as used herein means plus or minus 4% of a given value. For example, "about 50%" means a range of 48% to 52%. The term "about" as used herein means plus or minus 5% of a given value. For example, "about 50%" means a range of 47.5% to 52.5%. The term "about" as used herein means plus or minus 6% of a given value. For example, "about 50%" means a range of 47% to 53%. The term "about" as used herein means plus or minus 7% of a given value. For example, "about 50%" means a range of 46.5% to 53.5%. The term "about" as used herein means plus or minus 8% of a given value. For example, "about 50%" means a range of 46% to 54%. The term "about" as used herein means plus or minus 9% of a given value. For example, "about 50%" means a range of 45.5% to 54.5%. The term "about" as used herein means plus or minus 10% of a given value. For example, "about 50%" means a range of 45% to 55%. The term "about" as used herein can also mean plus or minus 5% of a given value. For example, "about 50%" means a range of 47.5% to 52.5%. The term "about" as used herein can also mean plus or minus 15% of a given value. For example, "about 50%" means in the range of 42.5% to 57.5%. As used herein, the term "about" can also mean plus or minus 20% of a given value. For example, "about 50%" means in the range of 40% to 60%.

[0032] The terms "subject" and "patient" as used herein expressly include human and non-human mammalian subjects. The term "non-human mammal" as used herein includes, but is not limited to, household pets and domesticated animals. Non-limiting examples of such animals include primates, cows, sheep, ferrets, mice, rats, pigs, camels, horses, rabbits, goats, dogs and cats.

[0033] As used herein, the term "effective amount" refers to an amount that results in a measurable inhibition of at least one symptom or parameter of a particular disorder or pathological process. For example, an effective amount of olanzapine is about 1 mg to about 15 mg.

[0034] The term "therapeutically effective amount" or "effective amount" of a compound or composition of the present disclosure as used herein refers to a predetermined amount that confers a therapeutic effect on the treated subject at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject sees or feels an effect, or the physician observes a change). An effective amount of a compound of the present disclosure is broadly about 1 mg to about 15 mg of olanzapine. The effects contemplated herein include both medical and / or prophylactic treatment, as appropriate. The specific dose of a compound administered in accordance with the present disclosure to obtain a therapeutic and / or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the co-administration of other active ingredients, the condition being treated, the activity of the particular compound employed, the particular composition employed, the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the particular compound employed, and the duration of treatment; The effective amount to be administered will be determined by the physician in light of the relevant circumstances as described above and the exercise of sound medical judgment. A therapeutically effective amount of a compound of the present disclosure is typically an amount sufficient to achieve an effective systemic concentration or a local concentration in a tissue when administered in a physiologically acceptable excipient composition. The total daily dose of a compound of the present disclosure administered to a human or other animal in a single or divided dose may be, for example, an amount of about 1 mg to about 15 mg. A single dose composition may contain such amounts or multiples thereof to make up a daily dose. In general, a treatment regimen according to the present disclosure involves administration to a patient in need of such treatment, and typically includes a compound according to formula I or a pharma- ceutically acceptable salt thereof, in a single or multiple doses per day.

[0035] A therapeutically effective amount of olanzapine may be administered as a therapeutically effective dose of the nasal olanzapine composition disclosed herein. A therapeutically effective amount of a nasal olanzapine composition may be administered in a single dose (e.g., to one nostril of a subject) or in two or more doses (e.g., a first dose administered to one nostril and a second dose administered to a second nostril to provide a therapeutically effective dose). A therapeutically effective dose may include 1 mg to about 15 mg of olanzapine or a pharma- ceutically acceptable salt thereof. In some embodiments, the nasal olanzapine composition may further include about 0.1 mg to about 1 mg of dodecyl maltoside, about 30 mg to about 40 mg of N,N-dimethylacetamide (DMA), and about 40 mg to about 70 mg of polyethylene glycol ("PEG"). Suitable volumes for administration to one or more nostrils of a subject can be about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 200 μL, or any value therebetween.

[0036] Thus, the nasal olanzapine compositions and methods of use provided herein represent a substantial improvement in the treatment of the aforementioned, particularly in the treatment of acute agitation associated with schizophrenia, schizoaffective disorder, and bipolar disorder, by providing rapid realization of therapeutic benefit following administration.

[0037] composition The present disclosure provides a nasal composition comprising olanzapine or a pharma- ceutically acceptable salt thereof. The nasal olanzapine composition is suitable for nasal administration and is intended for nasal administration as described above. Olanzapine is chemically known as 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine and has the chemical structure of formula I: [ka]

[0038] Although formula I shows olanzapine in free base form, olanzapine may be present in any nasal olanzapine composition described herein as a salt form (e.g., dicarboxylate such as tartrate), solvate (e.g., hydrate), polymorph, cocrystal, complex, or any combination thereof. All descriptions of the concentration or amount of olanzapine refer to the free base form, but pharma- ceutically acceptable salts, solvates, hydrates, cocrystals, or any combination thereof may be used. Those skilled in the art will be able to determine the therapeutically equivalent amount of a pharma- ceutically acceptable salt of olanzapine compared to the amount of the free base.

[0039] The term "pharmaceutical acceptable" as used herein refers to molecular entities and compositions that are generally considered safe and non-toxic. In particular, pharmaceutical acceptable carriers, diluents or other excipients used in the pharmaceutical compositions of the present disclosure are physiologically acceptable, compatible with other ingredients, and typically do not cause allergic or similar unpleasant reactions (e.g., upset stomach, dizziness, etc.) when administered to a patient.Preferably, the term "pharmaceutical acceptable" as used herein means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more particularly in humans.

[0040] As used herein, the phrase "pharmaceutically acceptable salt(s)" includes salts of the disclosed compounds that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds or compounds identified according to the disclosed methods. Pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. Certain compounds of the present disclosure may form pharma-ceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron, and diethanolamine salts. Pharmaceutically acceptable base addition salts are also formed with amines, such as organic amines. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0041] A composition for nasal delivery of olanzapine (herein "nasal olanzapine composition") comprises olanzapine or a pharma- ceutically acceptable salt thereof, an alkyl maltoside, N,N-dimethylacetamide (DMA), and polyethylene glycol (PEG). Preferably, the PEG is characterized by an average molecular weight of about 200 Da to less than about 1000 Da, such as about 300 Da to about 800 Da, or about 500 Da to about 700 Da, such as PEG-600. Examples of suitable alkyl maltosides include C9-C maltosides, such as dodecyl maltoside and tetradecyl maltoside. 14Maltosides, particularly n-dodecyl-β-D-maltoside. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2.

[0042] A composition for nasally administering a therapeutically effective amount of olanzapine (herein "nasal olanzapine composition") comprises olanzapine or a pharma- ceutically acceptable salt thereof, an alkyl maltoside, N,N-dimethylacetamide (DMA), and polyethylene glycol (PEG). Preferably, the PEG is characterized by an average molecular weight of about 200 Da to less than about 1000 Da, such as about 300 Da to about 800 Da, or about 500 Da to about 700 Da, such as PEG-600. Examples of suitable alkyl maltosides include C9-C alkyl maltosides such as dodecyl maltoside and tetradecyl maltoside. 14 Maltosides, particularly n-dodecyl-β-D-maltoside. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2.

[0043] The intranasal olanzapine composition may comprise one or more doses, each dose comprising a therapeutically effective amount of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.1 mg to about 1 mg of dodecyl maltoside, about 30 mg to about 40 mg of DMA, and about 40 mg to about 70 mg of polyethylene glycol. The intranasal olanzapine composition may comprise about 1% w / v to about 15% w / v of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.1% w / v to about 1% w / v of dodecyl maltoside, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol. In any embodiment, one or more doses of the nasal olanzapine compositions described above may be used to deliver a therapeutically effective amount of olanzapine to a subject in need thereof to treat an olanzapine-treatable disorder, condition, or disease, such as schizophrenia, schizoaffective disorder, bipolar disorder, and TRD.

[0044] The intranasal olanzapine composition may comprise one or more doses, each dose comprising about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.1 mg to about 1 mg of dodecyl maltoside, about 30 mg to about 40 mg of DMA, and about 40 mg to about 70 mg of polyethylene glycol. The intranasal olanzapine composition may comprise about 1% w / v to about 15% w / v of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.1% w / v to about 1% w / v of dodecyl maltoside, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol. In any embodiment, one or more doses of the nasal olanzapine compositions described above may be used to deliver a therapeutically effective amount of olanzapine to a subject in need thereof to treat an olanzapine-treatable disorder, condition, or disease, such as schizophrenia, schizoaffective disorder, bipolar disorder, and TRD.

[0045] In another example, each dose may contain a therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.20 mg to about 0.50 mg of dodecyl maltoside, about 34 mg to about 38 mg of DMA, and about 44 mg to about 66 mg of polyethylene glycol. Thus, an intranasal olanzapine composition may contain about 2.5% w / v to about 12% w / v of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol. In any embodiment, one or more doses of the nasal olanzapine compositions described above may be used to deliver a therapeutically effective amount of olanzapine to a subject in need thereof to treat an olanzapine-treatable disorder, condition, or disease, such as schizophrenia, schizoaffective disorder, bipolar disorder, and TRD.

[0046] In another example, each dose may contain about 2.5 mg to about 12 mg of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.20 mg to about 0.50 mg of dodecyl maltoside, about 34 mg to about 38 mg of DMA, and about 44 mg to about 66 mg of polyethylene glycol. Thus, an intranasal olanzapine composition may contain about 2.5% w / v to about 12% w / v of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol. In any embodiment, one or more doses of the nasal olanzapine compositions described above may be used to deliver a therapeutically effective amount of olanzapine to a subject in need thereof to treat an olanzapine-treatable disorder, condition, or disease, such as schizophrenia, schizoaffective disorder, bipolar disorder, and TRD.

[0047] In another example, each dose may contain a therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.25 mg to about 0.50 mg of dodecyl maltoside, about 34 mg to about 38 mg of DMA, and about 44 mg to about 66 mg of polyethylene glycol. Thus, an intranasal olanzapine composition may contain about 2.5% w / v to about 10% w / v of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol. In any embodiment, one or more doses of the nasal olanzapine compositions described above may be used to deliver a therapeutically effective amount of olanzapine to a subject in need thereof to treat an olanzapine-treatable disorder, condition, or disease, such as schizophrenia, schizoaffective disorder, bipolar disorder, and TRD.

[0048] In another example, each dose may contain about 2.5 mg to about 10 mg of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.25 mg to about 0.50 mg of dodecyl maltoside, about 34 mg to about 38 mg of DMA, and about 44 mg to about 66 mg of polyethylene glycol. Thus, an intranasal olanzapine composition may contain about 2.5% w / v to about 10% w / v of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol. In any embodiment, one or more doses of the nasal olanzapine compositions described above may be used to deliver a therapeutically effective amount of olanzapine to a subject in need thereof to treat an olanzapine-treatable disorder, condition, or disease, such as schizophrenia, schizoaffective disorder, bipolar disorder, and TRD.

[0049] In any embodiment, the nasal olanzapine composition may contain olanzapine or a pharma- ceutically acceptable salt thereof at least substantially dissolved in the composition (herein "nasal olanzapine solution"). As used herein, "substantially dissolved" indicates that at least 99.5% of the olanzapine is dissolved in the nasal olanzapine composition. Thus, the nasal olanzapine composition is free or substantially free (i.e., contains 0.5% w / v or less) of any solid particulates that comprise olanzapine, including microparticles, microspheres, nanoparticles, and nanospheres. In any embodiment, at least 99.9% of the olanzapine may be dissolved in the nasal olanzapine composition, and any solid particulates that comprise olanzapine may comprise 0.1% w / v or less. The nasal olanzapine composition may be sprayable in liquid form and is not a dry powder formulation.

[0050] In any embodiment, the nasal olanzapine composition may comprise a therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof at least substantially dissolved in the composition (herein, "nasal olanzapine solution"). As used herein, "substantially dissolved" refers to at least 99.5% of the olanzapine being dissolved in the nasal olanzapine composition. Thus, the nasal olanzapine composition is free or substantially free (i.e., comprises 0.5% w / v or less) of any solid particulates that comprise olanzapine, including microparticles, microspheres, nanoparticles, and nanospheres. In any embodiment, at least 99.9% of the olanzapine may be dissolved in the nasal olanzapine composition, and any solid particulates that comprise olanzapine may comprise 0.1% w / v or less. The nasal olanzapine composition may be sprayable in liquid form and is not a dry powder formulation.

[0051] In any embodiment, the nasal olanzapine solution is at least substantially free of water (herein a "non-aqueous nasal olanzapine solution"). As used herein, "substantially free of water" indicates that the solution contains less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.25%, or less than about 0.1% water.

[0052] In any embodiment, additional inactive excipients such as viscosity enhancers, texture modifiers, preservatives, stabilizers, and flavor or aroma enhancers can be included in the nasal olanzapine composition without affecting the efficacy of olanzapine to provide a therapeutic benefit to the subject. In any embodiment, the nasal olanzapine solution consists essentially of olanzapine, dodecyl maltoside, DMA, and polyethylene glycol, each in any amount disclosed at any time herein. Similarly, the non-aqueous nasal olanzapine solution can consist essentially of olanzapine, dodecyl maltoside, DMA, and polyethylene glycol, in any embodiment. Similarly, the nasal olanzapine solution can consist of olanzapine, dodecyl maltoside, DMA, and polyethylene glycol, in any embodiment. In any embodiment, the non-aqueous nasal olanzapine solution can consist of olanzapine, dodecyl maltoside, DMA, and polyethylene glycol, each in any amount disclosed at any time herein.

[0053] The nasal olanzapine compositions disclosed herein, which may be non-aqueous solutions, solutions, or both, contain about 0.1% w / v to about 1% w / v (i.e., 0.1 mg to 1 mg per 105 mg of composition) of dodecyl maltoside, such as dodecyl α- or β-D-maltoside. For example, in any embodiment, the nasal olanzapine composition may contain about 0.1% w / v to about 1% w / v of dodecyl maltoside, such as about 0.20% to about 0.50% of dodecyl maltoside, such as dodecyl-β-D-maltoside. Dodecyl maltoside is commercially available, for example, under the trade name INTRAVAIL®, from Aegis Therapeutics, LLC. (San Diego, Calif., USA), a wholly owned subsidiary of Neurelis, Inc. (San Diego, Calif., USA).

[0054] The nasal olanzapine compositions disclosed herein, which may be non-aqueous solutions, solutions, or both, contain about 30% w / v to about 40% w / v of DMA, including about 30% w / v, about 31% w / v, about 32% w / v, about 33% w / v, about 34% w / v, about 35% w / v, about 36% w / v, about 37% w / v, about 38% w / v, about 39% w / v, about 40% w / v, and any value therebetween. A therapeutically effective amount of about 75 μL to about 150 μL of a nasal olanzapine composition may contain about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, or about 40 mg of DMA, or any value therebetween, such as about 37 mg to about 38 mg. DMA is commercially available from, for example, Belle Chemical Company (Metairie, Louisiana, USA), Sigma Aldrich (St. Louis, Missouri, USA), and Eastman Chemicals (Kingsport, Tennessee, USA).

[0055] The nasal olanzapine compositions disclosed herein, which may be non-aqueous solutions, solutions, or both, further comprise about 40% w / v to about 70% w / v of polyethylene glycol having an average molecular weight of about 200 Da to about 1000 Da, preferably about 200 Da to about 700 Da, such as PEG-600 having an average molecular weight of 600 Da. The nasal olanzapine compositions disclosed herein, which may be non-aqueous solutions, solutions, or both, further comprise about 44% w / v to 66% w / v of polyethylene glycol having an average molecular weight of about 200 Da to about 1000 Da, preferably about 200 Da to about 700 Da, such as PEG-600 having an average molecular weight of 600 Da. For example, a nasal olanzapine composition may contain about 44% w / v to about 60% w / v, about 50% w / v to about 60% w / v, about 55% w / v to about 66% w / v, about 52% w / v to about 62% w / v, or about 56% w / v to about 60% w / v polyethylene glycol. A therapeutically effective amount of about 75 μL to about 150 μL of a nasal olanzapine composition may contain, for example, about 44 mg to about 66 mg of polyethylene glycol, for example, about 52 mg to about 66 mg of polyethylene glycol or about 54 mg to about 66 mg of polyethylene glycol.

[0056] In any embodiment, the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da, for example, about 200 Da to about 900 Da, about 200 Da to about 800 Da, about 200 Da to about 700 Da, about 300 Da to about 900 Da, about 300 Da to about 800 Da, about 300 Da to about 700 Da, about 400 Da to about 900 Da, about 400 Da to about 800 Da, about 400 Da to about 700 Da, about 500 Da, or about 600 Da. The polyethylene glycol may be a mixture of polyethylene glycol molecules of differing sizes and / or branching indices producing a bulk average molecular weight of about to about 900 Da, about, about 500 Da to about 800 Da, about 500 Da to about 700 Da, or any value therebetween, such as about 200 Da, about 300 Da, about 400 Da, about 500 Da, about 600 Da, about 700 Da, about 800 Da, about 900 Da, about 1000 Da, etc.

[0057] PEG-600 is commercially available, for example, from Dow Chemicals (Midland, Mich., USA) under the trade name CARBOWAX™, from BASF (Ludwigshafen, Germany) under the trade name KOLLISOLV®, from Sasol (Sandton, South Africa) under the trade name NOVELUTION®, from Double Bond Chemical (Taiwan) under the trade name DOUBLEMER®, and from Sigma Aldrich.

[0058] Advantageously, it has been observed that the nasal olanzapine compositions as described herein do not support bacterial growth and therefore are substantially free or free of antibacterial or other preservatives.However, the use of antibacterial agents does not prevent the therapeutic benefits of administering a therapeutically effective amount of olanzapine via the nasal olanzapine compositions, solutions, or non-aqueous solutions described herein.Thus, the nasal olanzapine compositions as disclosed herein (including non-aqueous solutions) can be free or substantially free of preservatives, antidegradants, antibacterial agents, or antifungal agents.

[0059] The nasal olanzapine composition disclosed herein can exhibit properties that are compatible with and non-irritating to the nasal mucosa. Such properties include tonicity, osmolality and viscosity. Thus, the nasal olanzapine composition is formulated to provide a vehicle for the delivery of drugs that exhibit suitable drug solubility and stability and are essentially non-irritating to the nasal mucosa.

[0060] A therapeutically effective amount of a nasal olanzapine composition as disclosed herein may be administered to a subject in one or more volumes via the subject's nasal mucosa. Such volumes include, for example, about 10 μL to about 200 μL, about 50 μL to about 150 μL, about 75 μL to about 125 μL, about 75 μL, about 100 μL, or about 125 μL. For example, about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof) may be administered in a volume of about 25 μL, about 50 μL, about 75 μL, about 100 μL, about 125 μL, or about 150 μL. The dose may be administered to a single nostril or may be split between the nostrils. For example, 2.5 mg of olanzapine in about 100 μL, 5 mg of olanzapine in about 100 μL, 7.5 mg of olanzapine in about 100 μL, 10 mg of olanzapine in about 100 μL, or 15 mg of olanzapine in about 100 μL can be administered to a single nostril. A 5 mg dose can also be administered as a 2.5 mg dose of olanzapine in about 100 μL to each nostril. Similarly, a 10 mg dose of olanzapine can also be administered as a 5 mg dose of olanzapine in about 100 μL to each nostril. Similarly, a 15 mg dose of olanzapine can also be administered as, for example, a 7.5 mg dose of olanzapine in about 100 μL to each nostril. A therapeutically effective amount of olanzapine is about 1 mg to about 15 mg of olanzapine, for example, about 2.5 mg to about 10 mg of olanzapine, about 2.5 mg to about 7.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 10 mg, about 5 mg to about 7.5 mg, about 7.5 mg to about 10 mg, about 1 mg to about 5 mg, about 1 mg to about 15 mg, about 2.5 mg to about 15 mg, about 5 mg to about 15 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg of olanzapine, about 12 mg of olanzapine, or about 15 mg of olanzapine.

[0061] How to use By delivering olanzapine to the nasal mucosa of a subject via any of the nasal olanzapine compositions disclosed herein, a rapid and effective therapeutic effect is induced in the subject. Furthermore, nasal administration of the nasal olanzapine compositions as disclosed herein can achieve similar pharmacokinetic properties when compared to known formulations such as oral, intravenous, or intramuscular administration. For example, the olanzapine T achieved after administration of the nasal olanzapine compositions can be max , C max , and AUC, respectively, are each greater than or equal to the T achieved following intramuscular administration of olanzapine (e.g., ZYPREXA®). max , C max For example, the C of 5 mg of intramuscular (IM) olanzapine may be about 80% to about 125%, about 90% to about 125%, about 100% to about 125%, about 90% to about 110%, or about 80% to about 110% of the AUC. max was about 4-5 times that of oral administration (7 ng / mL), and the T max The T is reported to be about 15 to 45 minutes. In contrast, when 5 mg of olanzapine is administered via a nasal olanzapine composition as disclosed herein, the T is reported to be within about 11 to about 57 minutes. max ) with a C of about 22ng / mL to about 44ng / mL max can be achieved. max The T is reported to be about 4-5 times that of a 10 mg oral dose (14 ng / mL). In contrast, when 10 mg of olanzapine is administered via the nasal olanzapine composition described herein, the T is reported to be about 11 minutes to about 57 minutes. max ) with a C of about 44.8ng / mL to about 87.5ng / mL max The bioavailability of olanzapine administered via a nasal olanzapine composition as disclosed herein may be comparable to that of orally or intramuscularly administered olanzapine, e.g., AUC of about 123 ng hr / ml to about 257 ng hr / mL for a dose containing 5 mg olanzapine, or about 248 ng hr / ml to about 356 ng hr / mL for a dose containing 10 mg olanzapine. 0-∞ Shows.

[0062] A therapeutically effective amount of olanzapine can be administered to the nasal mucosa of a subject in need thereof by one or more administrations of a nasal olanzapine composition. In some embodiments, the nasal olanzapine composition, which can be a non-aqueous solution, a solution, or both, comprises about 1% w / v to about 15% w / v olanzapine, about 0.1% w / v to about 1% w / v dodecyl maltoside, about 30% w / v to about 40% w / v DMA, and about 40% w / v to about 70% w / v polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. Each dose administered can contain a therapeutically effective amount of olanzapine (or a pharma- ceutically acceptable salt thereof). In other embodiments, each dose administered may contain about 1 mg to about 10 mg, or about 2.5 mg to about 15 mg, or about 2.5 mg to about 10 mg of olanzapine (or a pharma- ceutically acceptable salt thereof). Olanzapine may be administered via an intranasal olanzapine composition as disclosed herein to treat any condition, disorder, or disease treatable with olanzapine. Some example conditions are described herein to provide examples of conditions treatable with olanzapine via the intranasal olanzapine compositions disclosed herein, but not to limit the wide variety of conditions that may be so treatable.

[0063] In some embodiments, olanzapine administered via a nasal olanzapine composition as disclosed herein may result in a lower incidence of adverse events, fewer serious adverse events, or a combination thereof, as compared to olanzapine administered via intramuscular or intravenous injection.

[0064] acute excitement For example, olanzapine can be administered via nasal olanzapine compositions as disclosed herein to treat acute agitation associated with schizophrenia, schizoaffective disorder, and bipolar disorder. Such nasal olanzapine compositions can be used as monotherapy or as co-therapy with one or more additional drugs commonly used to treat acute agitation in these conditions, such as, but not limited to, lithium and valproate. The methods described herein are suitable for treating subjects at any stage of the condition / disorder. Administration can be performed at any time before or after the onset of acute agitation.

[0065] A method of treating acute agitation associated with schizophrenia, schizoaffective disorder, or bipolar disorder in a subject in need thereof can include administering a therapeutically effective amount of olanzapine to at least one nasal mucosa of at least one nostril of the subject via a nasal olanzapine composition. A therapeutically effective amount of olanzapine for an adult subject can be about 1 to about 15 mg, e.g., 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, or 15 mg of olanzapine or a pharma- ceutically acceptable salt thereof. In some embodiments, treating acute agitation associated with schizophrenia, schizoaffective disorder, or bipolar disorder in a subject in need thereof comprises a change from baseline in the Positive and Negative Symptoms Scale (PANSS) Agitation component (i.e., poor impulse control, tension, hostility, uncooperativeness, and agitation items) where at least one individual item has a score of 4 or greater using a 1-7 scoring system (1=none, 4=moderate, 7=extreme) at about 2 hours post-administration. In some embodiments, treating acute agitation associated with schizophrenia, schizoaffective disorder, or bipolar disorder in a subject in need thereof comprises an improvement from baseline in the Positive and Negative Symptoms Scale (PANSS) Agitation component at about 2 hours post-administration.

[0066] Thus, in another aspect, the disclosure provides a method of treating acute agitation associated with schizophrenia, schizoaffective disorder, or bipolar disorder in a subject in need thereof: administering to the nasal mucosa of the subject a solution comprising about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. A therapeutically effective amount of olanzapine may be administered in one or more doses of the nasal olanzapine composition.

[0067] Administering a therapeutically effective amount of olanzapine via a nasal olanzapine composition can include spraying one or more volumes of the nasal olanzapine composition into each nostril, such as spraying a first volume of the nasal olanzapine composition into a first nostril followed by a second volume of the nasal olanzapine composition into a second nostril. Optionally, a third and / or fourth volume of the nasal olanzapine composition can be administered immediately after the first and second volumes. In any embodiment, one or more doses can be administered to administer a therapeutically effective dose of olanzapine.

[0068] If the subject's acute agitation is not satisfactorily treated within about 2 to about 4 hours of the first administration, the nasal olanzapine composition can be administered a second time, and again, if not satisfactorily treated within about 2 to about 4 hours, a third time. Thus, in another aspect, the present disclosure provides a method of treating acute agitation associated with schizophrenia, schizoaffective disorder, or bipolar disorder: administering a first dose of a nasal olanzapine composition disclosed herein to the nasal mucosa of a subject during or before the acute agitation, wherein if sufficient cessation or prevention of the agitation is not achieved within about 2 hours, about 3 hours, or about 4 hours after administration of the first dose, administering one or more subsequent doses of the nasal olanzapine composition to the subject. In some embodiments, the nasal olanzapine composition comprises a therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof). In some embodiments, the nasal olanzapine composition further comprises about 0.20 mg to about 0.50 mg dodecyl maltoside, about 30% w / v to about 40% w / v DMA, and about 40% w / v to about 70% w / v polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. For example, a first dose of an intranasal olanzapine composition containing about 2.5 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20 mg to about 0.50 mg of dodecyl maltoside, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol can be administered, and when the acute arousal has sufficiently ceased, a second dose of the intranasal olanzapine composition can be administered. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2.The second dose may be the same amount and strength as the first dose or may be different. Optionally, if sufficient cessation of the acute arousal is not achieved within about 2 hours, about 3 hours, or about 4 hours, the method may further comprise administering a third dose of the nasal olanzapine composition.

[0069] Depressive episodes associated with bipolar I disorder Olanzapine may be administered via an intranasal olanzapine composition as disclosed herein to treat depressive episodes associated with bipolar I disorder in adults, children, or adolescents (e.g., ages 10-17). In any embodiment, the intranasal olanzapine composition may be used either as a monotherapy or as a combination therapy with one or more additional agents commonly used to treat depression associated with bipolar I disorder, such as fluoxetine. Administering a therapeutically effective amount of olanzapine to a subject in need thereof via an intranasal olanzapine composition as disclosed herein can reduce the severity or incidence of depressive episodes associated with bipolar I disorder. In one example, acute bipolar depression may be treated by administering a therapeutically effective amount of olanzapine via an intranasal olanzapine composition as disclosed herein at any time prior to or after the onset of acute bipolar depression. For example, in any embodiment, a subject diagnosed with bipolar I disorder may be treated with a therapeutically effective amount at least once daily as part of a maintenance regimen. In some embodiments, treating a depressive episode associated with bipolar I disorder in an adult, child, or adolescent (e.g., ages 10-17) comprises a change from baseline in the adult, child, or adolescent's Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with a total score of 0-60. In some embodiments, treating a depressive episode associated with bipolar I disorder in an adult, child, or adolescent (e.g., ages 10-17) comprises an improvement in the adult's, child's, or adolescent's MADRS score after about 8 weeks of administration.

[0070] A method for treating acute bipolar depression in a subject in need thereof may include administering a therapeutically effective amount of olanzapine to at least one nasal mucosa of at least one nostril via a nasal olanzapine composition disclosed herein. A therapeutically effective amount of olanzapine for an adult subject may be, for example, about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof) once a day, which may be administered according to the disclosure above to treat depressive episodes associated with bipolar I disorder, optionally in combination with fluoxetine, such as about 20 mg of fluoxetine, administered substantially simultaneously by any route of administration. A therapeutically effective amount of olanzapine for an adult subject may be, for example, about 5 mg of olanzapine (or a pharma- ceutically acceptable salt thereof) once a day, which may be administered according to the disclosure above to treat depressive episodes associated with bipolar I disorder, optionally in combination with fluoxetine, such as about 20 mg of fluoxetine, administered substantially simultaneously by any route of administration. For example, fluoxetine can be administered in oral dosage form.The therapeutically effective amount of olanzapine in children or adolescent subjects can be administered substantially simultaneously by any administration route, for example, about 2.5 mg of olanzapine (or its pharma- ceutically acceptable salt) can be administered once a day according to the above disclosure to treat depressive episodes associated with bipolar I disorder, optionally in combination with fluoxetine, such as about 20 mg of fluoxetine.For example, fluoxetine can be administered in oral dosage form.

[0071] Thus, in another aspect, the disclosure provides a method of treating a depressive episode associated with bipolar I disorder in a subject in need thereof, the method comprising administering intranasally to the nasal mucosa of the subject a first volume of a nasal olanzapine composition, which may be a non-aqueous solution, a solution, or both, comprising about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. A therapeutically effective amount of olanzapine may be administered in one or more doses of the nasal olanzapine composition.

[0072] The step of administering a therapeutically effective amount of olanzapine via a nasal olanzapine composition may include spraying one or more volumes of a nasal olanzapine composition disclosed herein into each nostril, such as spraying a first volume of a nasal olanzapine composition disclosed herein into a first nostril, then spraying a second volume of a nasal olanzapine composition into a second nostril. Optionally, a third volume and / or a fourth volume of a nasal olanzapine composition disclosed herein may be administered after the first volume and the second volume. In any embodiment, one or more doses may be administered to achieve administration of a therapeutically effective amount of olanzapine.

[0073] Bipolar I Disorder (manic or mixed episodes) Olanzapine may be administered via the intranasal olanzapine compositions disclosed herein to treat manic and / or mixed episodes associated with bipolar I disorder in adults and adolescents (e.g., ages 13-17). In any embodiment, administration of olanzapine via the intranasal olanzapine compositions disclosed herein may be utilized either as a monotherapy or as a combination therapy with one or more additional agents commonly used to treat manic and mixed episodes associated with bipolar disorder, such as lithium or sodium valproate.

[0074] Administering a therapeutically effective amount of olanzapine to a subject in need thereof via such nasal olanzapine compositions disclosed herein may reduce the severity, frequency, or duration of one acute bipolar manic episode / s and / or mixed episode / s in a subject experiencing such symptoms. In one example, a manic episode and / or mixed episode associated with bipolar I disorder may be treated by administering a therapeutically effective amount of olanzapine via a nasal olanzapine composition disclosed herein at any time before or after the onset of a manic episode and / or mixed episode. For example, a subject diagnosed with bipolar I disorder may be treated once a day as a maintenance treatment. In some embodiments, administering a therapeutically effective amount of olanzapine to a subject in need thereof via such nasal olanzapine compositions disclosed herein may result in a change from baseline in the subject's Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the extent of manic symptoms (irritability, disruptive / aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language / thought disorder, thought content, appearance, and insight) on a scale ranging from 0 (no manic features) to 60 (highest score). In some embodiments, administering a therapeutically effective amount of olanzapine to a subject in need thereof via such nasal olanzapine compositions disclosed herein may result in an improvement in the subject's Y-MRS score.

[0075] A method for treating manic and / or mixed episodes associated with bipolar I disorder in a subject in need thereof may include administering a therapeutically effective amount of olanzapine to the nasal mucosa of the subject via one or more doses of the nasal olanzapine composition disclosed herein. A therapeutically effective amount of olanzapine for treating manic and / or mixed episodes associated with bipolar I disorder in a child or adolescent subject may be, for example, about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof). A therapeutically effective amount of olanzapine for treating manic and / or mixed episodes associated with bipolar I disorder in a child or adolescent subject may be, for example, about 2.5 mg to about 5 mg of olanzapine (or a pharma- ceutically acceptable salt thereof) once daily, which may be increased to a target maintenance dose of 10 mg / day. To treat manic and / or mixed episodes associated with bipolar I disorder, a therapeutically effective amount of olanzapine may be administered via a nasal olanzapine composition disclosed herein, optionally in combination with fluoxetine, such as about 20 mg of fluoxetine, which may be administered substantially simultaneously by any route of administration. For example, fluoxetine may be administered via an oral dosage form.

[0076] A therapeutically effective amount of olanzapine for treating manic and / or mixed episodes associated with bipolar I disorder in an adult subject can be, for example, about 10 mg of olanzapine (or a pharma- ceutically acceptable salt thereof) administered once daily, optionally in combination with a therapeutic amount of lithium (e.g., 50 μg / mL to 125 μg / mL), which can be administered in accordance with the disclosure above to treat manic and / or mixed episodes associated with bipolar I disorder, by any route of administration and substantially simultaneously.

[0077] Thus, in another aspect, the disclosure provides a method of treating manic and / or mixed episodes associated with bipolar I disorder in a subject in need thereof, comprising: intranasally administering a first volume of a nasal olanzapine composition described herein to the nasal mucosa of the subject. In some embodiments, the nasal olanzapine composition can be a non-aqueous solution, a solution, or both. In some embodiments, the therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof is from about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof). In some embodiments, the nasal olanzapine composition further comprises from about 0.20% w / v to about 0.50% w / v dodecyl maltoside, from about 30% w / v to about 40% w / v DMA, and from about 40% w / v to about 70% w / v polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is from about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2.

[0078] The step of administering a therapeutically effective amount of olanzapine via the nasal olanzapine composition disclosed herein may include spraying one or more volumes of the nasal olanzapine composition into each nostril, such as spraying a first volume of the nasal olanzapine composition into a first nostril, then spraying a second volume of the nasal olanzapine composition into a second nostril. Optionally, a third volume and / or a fourth volume of the nasal olanzapine composition may be administered after the first volume and the second volume. In any embodiment, one or more doses may be administered to achieve administration of a therapeutically effective amount of olanzapine.

[0079] Schizophrenia and related disorders Olanzapine administered intranasally via an olanzapine composition as disclosed herein may also be used as a maintenance therapy for treating schizophrenia and related psychotic disorders, such as schizoaffective disorder, in adult and adolescent (e.g., 13-17 years of age) subjects. Such intranasal olanzapine compositions described herein may be used as monotherapy or as combination therapy with one or more additional agents commonly used to treat schizophrenia or schizoaffective disorder, such as amisulpride.

[0080] A method for treating or managing schizophrenia or related psychotic disorder in a subject in need thereof may include applying a therapeutically effective amount of olanzapine to the nasal mucosa of the subject via one or more doses of the nasal olanzapine composition described herein.For example, administering a therapeutically effective amount of olanzapine via the nasal olanzapine composition described herein may include spraying one or more doses of the nasal olanzapine composition into each nostril, for example, spraying a first dose of the nasal olanzapine composition into a first nostril, and then spraying a second dose of the nasal olanzapine composition into a second nostril.Optionally, a third and / or fourth dose of the nasal olanzapine composition may be administered after the first and second doses.In any embodiment, one or more doses may be administered to achieve administration of a therapeutically effective amount of olanzapine.

[0081] As a maintenance therapy, olanzapine administered intranasally to a subject via a nasal olanzapine composition disclosed herein can be used to prevent (i.e., inhibit the onset) or manage (e.g., reduce the incidence, severity, or duration) of one or more positive symptoms of schizophrenia or schizoaffective disorder, such as, but not limited to, delusions, hallucinations, disturbances in thinking or speech, difficulty concentrating, and movement disorders. Olanzapine administered intranasally to a subject via a nasal olanzapine composition as disclosed herein can be used to prevent (i.e., inhibit the onset) or manage (e.g., reduce the incidence, severity, or duration) of one or more negative symptoms of schizophrenia or schizoaffective disorder, such as, but not limited to, lack of anhedonia, speech disorder, flattening, withdrawal, struggles with basic daily activities, and lack of compliance.

[0082] In some embodiments, as disclosed herein, olanzapine administered intranasally via the olanzapine compositions described herein can also be used as a maintenance therapy to treat schizophrenia and related disorders, such as schizoaffective disorder, in adult and adolescent (e.g., 13-17 years old) subjects, resulting in an improvement in the subject's Brief Psychiatric Rating Scale (BPRS), an improvement in the subject's Clinical Global Impression (CGI) score, an improvement in the subject's Scale for Positive and Negative Symptoms (PANSS) score, and an improvement in the subject's Scale for Rating Negative Symptoms (SANS) score. The BPRS, a multi-item inventory of general psychopathology, has traditionally been used to assess the efficacy of drug treatments in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, abnormal thought content) is considered a particularly useful subset for the assessment of schizophrenia patients suffering from active psychosis. The second traditional assessment, the CGI, reflects the impression of a trained observer familiar with the symptoms of schizophrenia on the patient's overall clinical condition.

[0083] Thus, the present disclosure provides a method of treating a subject diagnosed with one or more of schizophrenia or schizoaffective disorders, comprising administering a therapeutically effective amount of olanzapine to the subject's nasal mucosa via one or more doses of a nasal olanzapine composition described herein. In some embodiments, the nasal olanzapine composition can be a non-aqueous solution, a solution, or both. In some embodiments, the therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof). In some embodiments, the nasal olanzapine composition further comprises about 0.20% w / v to about 0.50% w / v dodecyl maltoside, about 30% w / v to about 40% w / v DMA, and about 40% w / v to about 70% w / v polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. Schizophrenia and / or schizoaffective disorder can be treated by administering a therapeutically effective amount of olanzapine via nasal olanzapine composition at least once a day, such as once a day, twice a day, or three times a day. In any embodiment, an adult subject can be administered a first dose, such as about 5 mg of olanzapine, on the first day, and a higher dose, such as 7.5 mg of olanzapine or 10 mg of olanzapine, on one or more subsequent days, with a target maintenance dose of 10 mg / day.

[0084] Administering a therapeutically effective amount of olanzapine via a nasal olanzapine composition disclosed herein may include spraying one or more volumes of the nasal olanzapine composition into each nostril, such as spraying a first volume of the nasal olanzapine composition into a first nostril, then spraying a second volume of the nasal olanzapine composition into a second nostril. Optionally, a third volume and / or a fourth volume of the nasal olanzapine composition can be administered after the first volume and the second volume. In any embodiment, one or more doses can be administered to achieve administration of a therapeutically effective amount of olanzapine.

[0085] Treatment-Resistant Depression (TRD) Olanzapine administered intranasally via the nasal olanzapine compositions described herein may also be used to treat TRD in adult subjects. Such nasal olanzapine compositions may be used as monotherapy or as combination therapy with one or more additional agents commonly used to treat depression, such as fluoxetine.

[0086] A method of treating or managing TRD in a subject in need thereof may include applying a therapeutically effective amount of olanzapine to the nasal mucosa of the subject via one or more doses of a nasal olanzapine composition described herein. In some embodiments, the therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof). In some embodiments, the nasal olanzapine composition further comprises about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. The therapeutically effective amount of olanzapine may be about 5 mg of olanzapine, about 7.5 mg of olanzapine, or about 10 mg of olanzapine (or an equivalent amount of a salt thereof).

[0087] Thus, in another aspect, the disclosure provides a method of treating TRD in a subject in need thereof comprising administering a therapeutically effective amount of olanzapine via one or more doses of a nasal olanzapine composition described herein, which can be a non-aqueous solution, a solution, or both, as disclosed herein, comprising from about 1% w / v to about 15% w / v olanzapine (or a pharma- ceutically acceptable salt thereof), from about 0.1% w / v to about 1% w / v dodecyl maltoside, from about 30% w / v to about 40% w / v DMA, and from about 40% w / v to about 70% w / v polyethylene glycol. For example, a therapeutically effective amount of about 75 μL to about 150 μL of a nasal olanzapine composition may contain about 2.5 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2.

[0088] In some embodiments, administering a therapeutically effective amount of olanzapine via one or more doses of a nasal olanzapine composition described herein results in a decrease in the subject's total MADRS compared to baseline. In some embodiments, treating or managing TRD in a subject in need thereof can include applying a therapeutically effective amount of olanzapine to the subject's nasal mucosa via a single daily dose of a nasal olanzapine composition described herein.

[0089] TRD can be treated by administering a therapeutically effective amount of olanzapine via a nasal olanzapine composition at least once a day, such as once a day, twice a day, or three times a day. In any embodiment, an adult subject can be administered an initial dose, for example, about 5 mg of olanzapine on the first day, and a higher olanzapine dose, for example, 7.5 mg of olanzapine or 10 mg of olanzapine on one or more subsequent days, with a target maintenance dose of 10 mg / day. Administering a therapeutically effective amount of olanzapine via a nasal olanzapine composition can include spraying one or more volumes of the nasal olanzapine composition into each nostril, such that a first volume of the nasal olanzapine composition is sprayed into a first nostril, and then a second volume of the nasal olanzapine composition is sprayed into a second nostril. Optionally, a third and / or fourth volume of the nasal olanzapine composition can be administered after the first and second volumes. In any embodiment, one or more doses can be administered to achieve administration of a therapeutically effective amount of olanzapine.

[0090] Other uses The intranasal olanzapine compositions disclosed herein may also be used to treat one or more of depression, agitation associated with neurodevelopmental disorders such as autism spectrum disorder, obsessive-compulsive disorder (OCD), Tourette's syndrome, and / or rage attacks associated with autism spectrum disorder, and the like. Thus, the present disclosure provides a method of inhibiting or reducing the incidence, severity, or duration of one or more of these conditions or symptoms in a subject in need thereof (e.g., diagnosed with obsessive-compulsive disorder, Tourette's syndrome, autism spectrum disorder), comprising administering a therapeutically effective amount of olanzapine to the nasal mucosa of the subject via one or more doses of an intranasal olanzapine composition described herein. In some embodiments, the intranasal olanzapine composition may be a non-aqueous solution, a solution, or both. In some embodiments, the therapeutically effective amount of olanzapine or a pharma- ceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof). In some embodiments, the nasal olanzapine composition further comprises about 0.20% w / v to about 0.50% w / v dodecyl maltoside, about 30% w / v to about 40% w / v DMA, and about 40% w / v to about 70% w / v polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. For example, a therapeutically effective dose of about 75 μL to about 150 μL of a nasal olanzapine composition disclosed herein may contain about 2.5 mg to about 10 mg of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20 mg to about 0.50 mg of dodecyl maltoside, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol. In another example, a dose of a nasal olanzapine composition may contain about 2.5 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol.In another example, about 75 μL to about 150 μL of a therapeutically effective amount of a nasal olanzapine composition can include about 2.5 mg to about 10 mg of olanzapine (or a pharma- ceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2.

[0091] Treatment effect Nasally administering a therapeutically effective amount of olanzapine to a subject in need thereof via a nasal olanzapine composition described herein may be effective in reducing one or more quantitatively measurable symptoms of schizophrenia, schizoaffective disorder, bipolar I disorder, and / or TRD. In any embodiment, a therapeutically effective amount of a nasal olanzapine composition may include about 1 mg to about 15 mg of olanzapine, about 0.1 mg to about 1 mg of dodecyl maltoside, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol, optionally in a non-aqueous solution, solution, or both. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. Nasal administration of such compositions containing a therapeutically effective amount of olanzapine may provide a subject with one or more therapeutic benefits, some of which may be measured quantitatively or semi-quantitatively according to various assessments described herein below.

[0092] For example, in any embodiment, administering a therapeutically effective amount of olanzapine intranasally to a subject via a nasal olanzapine composition as disclosed herein can reduce the subject's positive score, negative score, or total (composite) PANSS (Positive and Negative Symptom Scale) score. The PANSS is a medical scale used to measure the severity of symptoms in patients with schizophrenia and is outlined in Table 1 below. The minimum score for each item is 1, with a minimum total score of 30. [Table 1]

[0093] In another example, in any embodiment, administering a therapeutically effective amount of olanzapine intranasally to a subject with schizophrenia via a nasal olanzapine composition can reduce the subject's score on the Clinical Global Impression-Schizophrenia (CGI-S) scale. The CGI-S scale is a scale that assesses the severity of symptoms, treatment response, and efficacy of treatment studies in patients with mental disorders, and includes a three-item observer rating scale that assesses severity, overall improvement, and efficacy index. The severity scale is a seven-point scale in which patients are ranked from 1 (normal, not at all ill) to 7 (most severely ill patients). The improvement scale is a seven-point scale in which patients are ranked from 1 (very improved) to 7 (very worse). The efficacy index is a four-by-four rating scale that assesses the therapeutic effect and associated side effects, ranging from marked / great improvement to unchanged / worsening, and from no side effects to more than therapeutic effects.

[0094] In yet another example and in any embodiment, administering a therapeutically effective amount of olanzapine intranasally to a subject experiencing agitation via a nasal olanzapine composition as disclosed herein can improve the subject's score on the Agitation-Sedation Scale (ACES) and / or Agitation Behavior Scale (ABS). The ACES is comprised of a single item assessing overall agitation and sedation at the time of assessment, ranging from 1 (significant agitation) to 9 (absent), with 7 representing significant sedation. The ABS measures the behavioral aspects of agitation, calculated as a 56-point scale based on the sum of the responses to 14 questions describing the behavioral patterns of agitation. Each question ranges from 1 (none) to 4 (excessive).

[0095] In yet another example and in any embodiment, administering a therapeutically effective amount of olanzapine intranasally to a subject via a nasal olanzapine composition as disclosed herein can reduce the total score on the Brief Psychiatric Rating Scale (BPRS), which scores various symptoms such as somatic concerns, anxiety, emotional withdrawal, conceptual disorganization, guilt, tension, mannerisms / postures, grandiosity, depressed mood, hostility, suspiciousness, hallucinatory behavior, motor retardation, uncooperativeness, abnormal thinking, blunted affect, agitation, and disorientation on a scale of 1 (not present) to 7 (extremely severe).

[0096] In another example and in any embodiment, administering a therapeutically effective amount of olanzapine intranasally to a subject experiencing an episode of bipolar depression via a nasal olanzapine composition as disclosed herein reduces the subject's score on the Hamilton Rating Scale for Depression. The Hamilton Depression Scale (HAM-D) is a multi-item questionnaire that assesses a variety of symptoms, including depressed mood, guilt, suicidal thoughts, insomnia, work / interest, retardation, agitation, anxiety, GI symptoms, physical symptoms, genital symptoms, hypochondria, weight loss, and insight. Each item is scored on a 3- or 5-point scale, with 0 being normal or absent and higher values ​​representing greater severity of symptoms.

[0097] In another example and in any embodiment, as disclosed herein, administering a therapeutically effective amount of olanzapine intranasally via a nasal olanzapine composition to a subject experiencing an episode of bipolar depression can improve the subject's score on one or more of the demotivational behavior HAM-D factor, the HAM-D suicide item, the Hamilton Anxiety Scale, and the Beck Depression Inventory. Each of these tests is familiar to those skilled in the art.

[0098] In another example and in any embodiment, intranasal administration of a therapeutically effective amount of olanzapine via a nasal olanzapine composition as disclosed herein to a subject experiencing an episode of bipolar depression may improve the subject's Young Mania Rating Scale (YMRS) score. The YMRS has 11 items and is based on the subject's subjective report of their clinical condition over the past 48 hours.

[0099] Manufacturing method In any embodiment, the nasal olanzapine composition can be substantially free of olanzapine microparticles, nanoparticles, or combinations thereof. The order of addition of any of the components of the nasal olanzapine composition is not particularly important, as long as olanzapine is completely or at least substantially dissolved in the composition. For example, in any embodiment, the nasal olanzapine composition, which may be a non-aqueous solution, a solution, or both, as disclosed herein, can be prepared by dissolving an alkyl glycoside (e.g., dodecyl maltoside) in DMA, and then adding and dissolving olanzapine. Polyethylene glycol can then be added, and the resulting mixture can be stirred.

[0100] The formulation process can be adjusted to account for the variability of nasal olanzapine compositions. For example, nasal olanzapine compositions can be prepared by first combining DMA and olanzapine, mixing the ingredients until uniform, adding dodecyl maltoside, and mixing until the dodecyl maltoside is dissolved and the solution is uniform. The mixture can be made to volume by adding a sufficient amount of polyethylene glycol to achieve the final target weight of the nasal olanzapine composition. The nasal olanzapine composition produced according to this process can be prepared in different doses of olanzapine, such as, but not limited to, 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12 mg, or 15 mg. Suitable for administration to the nasal mucosa, nasal olanzapine compositions as disclosed herein may be formulated as nebulizable olanzapine compositions containing 1 mg to about 15 mg of olanzapine (or a pharma- ceutically acceptable salt thereof) in a nasally administrable volume, such as about 25 μL, about 50 μL to about 500 μL, about 100 μL to about 250 μL, about 75 μL to about 125 μL, about 75 μL, about 100 μL, or about 125 μL.

[0101] Thus, in another aspect, the present disclosure provides a device adapted for intranasal delivery of any of the nasal olanzapine compositions disclosed herein. Such devices may be provided or supplied as pre-primed devices or may be primed by the subject prior to use. The device may be a metered dose device and / or a single dose device, a double dose device, or a multi-dose device. Such devices typically include a piston, a vortex chamber, and an actuator to deliver a spray that is formed when the composition in the reservoir is forced through the vortex chamber. The device may be actuated by the subject by placing the thumb on the actuator and holding the device between the second and third fingers. The device may further include a pressure point mechanism to ensure repeatability of actuation force and emitted plume / spray characteristics.

[0102] Dosing device Another aspect of the present disclosure relates to a device adapted for intranasal delivery of such compositions to a subject, the device including a reservoir configured to contain any of the nasal olanzapine compositions as described above. In particular, such compositions may include about 1% w / v to about 15% w / v olanzapine, about 0.1% w / v to about 1% w / v dodecyl maltoside, about 30% w / v to about 40% w / v DMA, and about 40% w / v to about 70% w / v polyethylene glycol. For example, the composition may include about 2.5% w / v to about 12% w / v olanzapine, about 0.20% w / v to about 0.50% w / v, about 30% w / v to about 40% w / v DMA, and about 44% w / v to about 66% w / v polyethylene glycol. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2. Such devices may optionally be supplied as pre-primed devices. Such devices may optionally be multi-dose devices having single or multiple reservoirs; in the latter case, each reservoir contains a single dose of the nasal olanzapine composition. Each single-dose reservoir may contain, for example, 25 μL to about 200 μL of the nasal olanzapine composition. Each multi-dose reservoir may contain up to 20 mL or more of the nasal olanzapine composition, depending on its therapeutic use.

[0103] The term "pre-primed" as used herein refers to a device, such as a nasal spray, that can deliver a pharmaceutical composition to a patient in need thereof upon the first actuation of the spray pump, i.e., without the need to prime the pump prior to administration, such as by actuating the pump one or more times until a spray appears. The term "actuation" as used herein refers to the operation of the device such that a pharmaceutical composition is delivered therefrom.

[0104] Pre-primed single-dose and multi-dose devices consisting of a reservoir, piston, and vortex chamber are suitable devices for delivering nasal olanzapine compositions as described herein. A spray is formed as the liquid is forced through the vortex chamber. These devices are held between the second and third fingers with the thumb resting on the actuator. A pressure point mechanism built into some devices ensures reproducibility of actuation force and ejected spray characteristics. Currently, commercially available nasal migraine medications such as IMITREX® (GlaxoSmithKline, Brentford, UK) and ZOMIG® (Pfeiffer / Aptar single-dose device), the commercially available influenza vaccine Flu-Mist (Becton Dickinson single-dose spray device), and the nasal formulation of naloxone for opioid overdose rescue, NARCAN NASAL® (narcan.com; Adapt Pharma), are administered with this type of device.

[0105] For drugs intended for single or sporadic use, where strict control of dosage and composition is important, single or double dose spray devices, such as those available from Aptar (Crystal Lake, IL, USA), are preferred. Other suitable devices that may be employed to deliver the compositions described herein include, but are not limited to, simple variations of the single dose spray device (MAD™) offered by LMA (LMA, Salt Lake City, UT, USA). A standard syringe is fitted with a nosepiece with a spray tip. The liquid drug to be administered is first injected into the syringe, and then the spray tip is fitted to the syringe. Another suitable device is a pre-filled device based on the same principle, capable of single or double administration (ACCUSPRAY™, Becton Dickinson Technologies, Research Triangle Park, NC, USA). The devices of the present disclosure may alternatively be comprised of a conventional simple metered dose spray pump, requiring priming and some degree of overfilling to maintain compliance of the dose with the labeled number of administrations. These devices are suitable for drugs administered daily over extended periods of time.

[0106] Disclosed embodiments In a first embodiment, the present disclosure provides a composition comprising about 1% w / v to about 15% w / v olanzapine or a pharma- ceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v dodecylmaltoside, about 30% w / v to about 40% w / v N,N-dimethylacetamide, and about 40% w / v to about 70% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v water or less than about 1% w / v water.

[0107] The first embodiment optionally includes one or more of the following elements.

[0108] Element 1: The composition of the first embodiment, comprising about 2.5% w / v to about 12% w / v of olanzapine or a pharma- ceutically acceptable salt thereof.

[0109] Element 2: The composition of the first embodiment, comprising about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, and optionally element 1.

[0110] Element 3: The composition of the first embodiment, comprising about 34% w / v to about 38% w / v N,N-dimethylacetamide, and optionally element 1 or element 2.

[0111] Element 4: The composition of the first embodiment, wherein the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da, and the composition optionally comprises one or more of elements 1 to 3.

[0112] Element 5: The composition of the first embodiment, wherein the polyethylene glycol has an average molecular weight of about 600 Da, and the composition optionally comprises one or more of elements 1-4.

[0113] Element 6: The composition of the first embodiment, comprising about 44% w / v to about 66% w / v polyethylene glycol, and optionally one or more of elements 1-5.

[0114] Element 7: The composition of the first embodiment, wherein the ratio of polyethylene glycol to N,N-dimethylacetamide is from about 4:1 to about 1:4, and the composition optionally comprises one or more of elements 1-6.

[0115] Element 8: The composition of the first embodiment, wherein the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2, and the composition optionally comprises one or more of elements 1-7.

[0116] Element 9: The composition of the first embodiment, wherein the amount of olanzapine is from about 2.5 mg to about 10 mg or a pharma- ceutically acceptable salt thereof, and the composition optionally comprises one or more of elements 1-8.

[0117] Element 10: The composition of the first embodiment, wherein the composition comprises less than 0.1% w / v water and optionally one or more of elements 1-9.

[0118] Element 11: The composition of the first embodiment comprising from about 2.5% w / v to about 12% w / v of olanzapine or a therapeutically equivalent amount of an olanzapine salt, from about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, from about 34% w / v to about 38% w / v of N,N-dimethylacetamide, and from about 44% w / v to about 66% w / v of polyethylene glycol, and optionally one or more of elements 1-10.

[0119] In a second embodiment, the present disclosure provides a single-use spray device comprising a composition according to embodiment 1, optionally in combination with one or more of elements 1-11, and configured to dispense an amount of the composition equivalent to 2.5 mg to 15 mg of olanzapine upon actuation of the device.

[0120] In a third embodiment, the present disclosure provides a metered dose, multi-use spray device comprising a composition according to embodiment 1, optionally in combination with one or more of elements 1-11, and configured to dispense an amount of the composition equivalent to 2.5 mg to 15 mg of olanzapine upon actuation of the device.

[0121] In a fourth embodiment, the present disclosure provides a method of treating acute agitation associated with one or more of schizophrenia, schizoaffective disorder, and bipolar disorder in a subject in need thereof, the method comprising: intranasally administering to the nasal mucosa of the subject a composition comprising about 1 mg to about 15 mg of olanzapine or a therapeutically equivalent amount of an olanzapine salt, about 0.1 mg to about 1 mg of dodecyl maltoside, about 30 mg to about 40 mg of N,N-dimethylacetamide, and about 40 mg to about 70 mg of polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v water.

[0122] Optionally, the method of the fourth embodiment further comprises element 10: reducing the severity of the acute agitation in the subject within about 20 minutes after administration.

[0123] In a fifth embodiment, the present disclosure provides a method of treating depression associated with bipolar disorder, the method comprising: intranasally administering to a subject's nasal mucosa a composition comprising about 1 mg to about 15 mg of olanzapine or a therapeutically equivalent amount of an olanzapine salt, about 0.1 mg to about 1 mg of dodecyl maltoside, about 30 mg to about 40 mg of N,N-dimethylacetamide, and about 40 mg to about 70 mg of polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v water.

[0124] In a sixth embodiment, the present disclosure provides a method of treating mania associated with bipolar disorder, the method comprising: intranasally administering to the nasal mucosa of the subject a composition comprising about 1% w / v to about 15% w / v olanzapine or a pharma- ceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v dodecylmaltoside, about 30% w / v to about 40% w / v N,N-dimethylacetamide, and about 40% w / v to about 70% w / v polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v water.

[0125] In a seventh embodiment, the present disclosure provides a method of treating a mixed episode associated with bipolar disorder, the method comprising: intranasally administering to the nasal mucosa of the subject a composition comprising about 1% w / v to about 15% w / v of olanzapine or a pharma- ceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v of dodecylmaltoside, about 30% w / v to about 40% w / v of N,N-dimethylacetamide, and about 40% w / v to about 70% w / v of polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v of water.

[0126] Any one of the fourth, fifth, sixth, or seventh embodiments can optionally include one or more of the following elements.

[0127] Element 12: The method of any one of the fourth to seventh embodiments, wherein the composition comprises about 2.5% w / v to about 12% w / v olanzapine or an equivalent amount of a salt thereof, and optionally further comprises element 11.

[0128] Element 13: The method according to any one of the fourth to seventh embodiments, wherein the composition comprises about 2.5% w / v to about 10% w / v olanzapine or an equivalent amount of a salt thereof, and optionally further comprises element 11 and / or element 12.

[0129] Element 14: The method according to any one of the fourth to seventh embodiments, wherein the composition further comprises about 0.20% w / v to about 0.50% w / v dodecyl maltoside, and optionally one or more of elements 11 to 13.

[0130] Element 15: The method according to any one of the fourth to seventh embodiments, wherein the composition further comprises about 34% w / v to about 38% w / v N,N-dimethylacetamide, and optionally one or more of elements 11 to 14.

[0131] Element 16: The method according to any one of the fourth to seventh embodiments, wherein the polyethylene glycol has an average molecular weight of from about 200 Da to about 1000 Da, and optionally further comprises one or more of elements 11 to 15.

[0132] Element 17: The method according to any one of the fourth to seventh embodiments, wherein the composition further comprises about 44% w / v to about 66% w / v polyethylene glycol, and optionally one or more of elements 11 to 16.

[0133] Element 18: The method of any one of the fourth through seventh embodiments, wherein the composition comprises from about 2.5 mg to about 12 mg of olanzapine or a therapeutically equivalent amount of an olanzapine salt, from about 0.20 mg to about 0.50 mg of dodecyl maltoside, from about 34 mg to about 38 mg of N,N-dimethylacetamide, and from about 44 mg to about 66 mg of polyethylene glycol, and optionally further comprises one or more of elements 11 to 17.

[0134] Element 19: The method of any one of the fourth to seventh embodiments, wherein the composition is provided in a pre-primed single-use administration device containing about 75 μL to about 200 μL of the composition.

[0135] Element 20: The method of any one of the fourth to seventh embodiments, wherein the administering step comprises administering about 75 μL to about 200 μL of the composition to each nostril of the subject, and optionally further comprising one or more of elements 11 to 19.

[0136] Element 21: The method of any one of the fourth to seventh embodiments, wherein the depressive, manic, or mixed episodes manifest as recurrent episodes, and one or more of the frequency, length, and severity of the recurrent episodes are reduced, optionally further comprising one or more of elements 11 to 20.

[0137] Element 22: The method of any one of the fourth to seventh embodiments, wherein after said administration, the subject is less likely to discontinue use of the composition compared to the likelihood of discontinuing use of an intramuscularly or orally administered olanzapine composition, optionally further comprising one or more of elements 11 to 21.

[0138] Element 23: The method according to any one of the fourth to seventh embodiments, wherein the composition further comprises less than about 1% w / v water, and optionally one or more of elements 11 to 22.

[0139] Element 24: The method according to any one of the fourth to seventh embodiments, wherein the ratio of polyethylene glycol to N,N-dimethylacetamide is from about 4:1 to about 1:4, and optionally further comprising one or more of elements 11 to 23.

[0140] Element 25: The method according to any one of the fourth to seventh embodiments, wherein the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2, and optionally further comprising one or more of elements 11 to 24.

[0141] Working Example Example 1: Formulation

[0142] Various non-limiting examples of nasal olanzapine compositions described herein are shown in Table 2 below. The formulations represent 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 11 mg, 12 mg, and 15 mg of olanzapine. In each case, the % w / w can be calculated by dividing the amount of the component in mg by the total number of mg in the composition (e.g., 105 mg). For example, a composition containing 2.5 mg of olanzapine contains about 2.38% w / w of olanzapine. Similarly, 12 mg of olanzapine corresponds to 11.43% w / w of olanzapine. In any embodiment, olanzapine may exist as a salt (e.g., a dicarboxylate such as a tartrate), a solvate (e.g., a hydrate), a solvate, a polymorph, a cocrystal, a complex, or any combination thereof. In any embodiment, the formulation may contain any amount of olanzapine, including amounts between the amounts listed in Table 2. The compositions may contain about 0.25 mg to about 0.5 mg of dodecyl maltoside, a certain amount of DMA (37.80 mg), and QS to 105 mg of PEG-600. In any embodiment, the formulation may contain any amount of dodecyl maltoside, DMA, or PEG-600, including amounts between those listed in Table 2. Of note, all compositions are solutions formulated without water and are non-aqueous. Each of these formulations produces about 100 μL of solution, so each number also represents weight by volume. [Table 2]

[0143] Example 2: Formulation Development

[0144] The formulation development strategy was based on the need to develop a formulation that has suitable quality attributes for a convenient, single-dose intranasal therapeutic dose, is patient-acceptable, and is easy to use for either self- or caregiver administration. Based on this premise, an initial quality target product profile (QTPP) was developed (Table 2). [Table 3]

[0145] In addition to the factors detailed in Table 3, factors of the potential delivery system (aerosol) are also important in the QTPP. The quality attributes of the combination product are listed in Table 4. [Table 4]

[0146] Table 4 summarizes the drug product quality attributes and details which attributes were classified as critical quality attributes (CQAs) for the drug product. For the product, appearance, olanzapine assay and related substances, Intravail A3 assay, particulate matter, moisture and microbial quality were identified as a subset of CQAs that may be affected by raw materials and processing and were therefore evaluated in the initial formulation development studies. The initial studies focused primarily on appearance, olanzapine assay, and related substances. Microbiological quality was assumed to be of low risk at this stage due to the non-aqueous composition of the drug product and low residual moisture levels.

[0147] CQAs for the combination product, such as pump performance parameters (pump output, spray content uniformity, droplet size distribution, and plume shape / spray pattern) and container closure integrity, were not formally evaluated in the early stages. The use of proven, commercially available equipment provided a high level of assurance that these factors would not be an issue for the development program. Closure compatibility was informally evaluated and shown to not be a concern. [Table 5]

[0148] As summarized above, the primary objective of the initial formulation development program was to achieve adequate solubility and stability of the drug substance in an acceptable solvent system that would allow the full dose to be administered in a single 100 μL dose. Olanzapine has poor aqueous stability and solubility. The basic physicochemical parameters of olanzapine include BCS class 2, solubility in water at pH 6.8 of 0.02 mg / mL, solubility in water at 37 °C of 0.034 mg / mL, and pKa of 4.01 and 7.24. A concentration of 100 mg / mL would be required to achieve the required maximum dose, meaning that an aqueous-based system would not meet some of the key characteristics of the QTPP.

[0149] Therefore, non-aqueous systems were considered. Solvent selection was limited to pharma- ceutically acceptable excipients listed in the FDA Inactive Ingredients Database (IID), with the understanding that the solvent levels in the olanzapine formulations described herein may be higher than those listed as safe. Therefore, evidence of safety of the solvent at the concentrations proposed for the olanzapine nasal spray was established, taking into account the context of use (e.g., patient population, dose, duration of exposure). To aid in formulation evaluation, methods demonstrating stability were reviewed from the literature, and methods were selected that provided an assessment of the major degradants.

[0150] As a starting point, non-aqueous solvents from licensed intranasal formulations were tested. Specifically, vitamin E, benzyl alcohol, and ethanol were evaluated. After 2 weeks at 40°C, an increase in degradation products and color changes revealed significant incompatibility between olanzapine and each solvent. The importance of the presence of oxygen to degradation was investigated using nitrogen headspacing and was found to have little effect on the stability of the formulation series.

[0151] Other solvents, such as cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, trolamine, sesame oil, benzyl benzoate, cyclodextrin, and sterile water for injection, were also tested and showed poor solubility, poor stability, or a combination thereof. Some of these solvents were also tested with micronized olanzapine, which also showed poor solubility, poor stability, or a combination thereof.

[0152] A broad screen was then performed with and without nitrogen headspacing using a variety of solvents including oils, glycols, nonionic surfactants, and terpenoids. After 1 week at 40°C, related substances ranged from 1% to 12%, but results varied widely between solvents, with glycols showing the most promise. In general, nitrogen headspacing did not result in significant improvement, even though the main degradants were oxidative degradation products. In addition to polyethylene glycol, dimethylacetamide showed good stability in the initial screen. It should also be noted that some of the solvents evaluated (including PEG) did not have sufficient solubilizing capacity to achieve the solubility criteria of QTPP.

[0153] Next, dimethylacetamide and PEG400 were evaluated individually at approximately 5 mg / mL for 2 months at 40 °C. Due to the low solubilizing ability of PEG, concentrations were relatively low versus the higher target of 100 mg / mL. Stability results were promising for both solvents in that the main hydrolytic / oxidative degradation products, USP Related Compounds B and C, were not significantly increased compared to previously studied solvent systems. Dimethylacetamide exhibited better stability characteristics than PEG400. Based on these data, a further set of experiments was initiated, including evaluation of viscosity, olanzapine solubility and stability of the dimethylacetamide / PEG200 binary solvent system.

[0154] The solubility profile of olanzapine in PEG200 / dimethylacetamide was investigated as a first step to determine the appropriate binary composition range for further formulation development. Excess olanzapine was added to the solution, stirred overnight, filtered, and assayed. The data from these experiments are presented in Table 5 and graphically depicted in Figure 1. The impurity profiles were also compared and the chromatograms are depicted in Figure 2. [Table 6]

[0155] Based on solubility and stability data and the need for a maximum concentration of at least 100 mg / mL, it was determined that a robust formulation would be achievable with a composition containing approximately 40% or more dimethylacetamide. It was noted that USP Olanzapine related compound C (EP impurity D) was detected in solutions containing higher amounts of PEG200, again supporting the use of higher dimethylacetamide concentrations.

[0156] Complementary freeze-thaw experiments were performed with 180 mg / g solutions in 60 / 40 dimethylacetamide / PEG200, 80 / 20 dimethylacetamide / PEG200, and 100% dimethylacetamide. To confirm the robustness of the formulation, the solutions were subjected to five freeze-thaw cycles. There was no change in appearance, confirming the absence of potential crystallization due to freezing / crystal seeding, etc.

[0157] The viscosity of the three formulations was also measured and ranged from 1.9 cP (100% dimethylacetamide) to 8.3 cP (60 / 40 dimethylacetamide / PEG200).

[0158] At this point, it was concluded that a formulation consisting of a binary mixture of PEG and dimethylacetamide would be a promising candidate for further development. Although sufficient solubility was demonstrated and viscosity was acceptable (although increased viscosity would have been desirable to increase nasal residence time after administration), further studies on stability and the effect of PEG content were required.

[0159] A new stability study was initiated with two formulations: 150 mg / mL olanzapine in 50 / 50 dimethylacetamide / PEG200 and 10 mg / mL olanzapine in PEG200. For both formulations, samples were stored at 5°C, 25°C / 60% relative humidity (RH) and 40°C / 75% RH and monitored for appearance, assay and related substances over a period of three months. The 50 / 50 dimethylacetamide / PEG200 formulation was evaluated for six months. The data are summarized in Table 6 and overlays of the three-month chromatograms are shown in Figures 3 and 4. [Table 7] TIFF2025510082000010.tif227158TIFF2025510082000011.tif228159TIFF2025510082000012.tif114160

[0160] Several conclusions can be drawn from this data: results showed degradation in both samples, but most pronounced in the 10 mg / mL olanzapine in PEG200 sample; temperature was an important factor in the overall formulation stability; a series of peaks characteristic of the polymer were seen in both samples, suggesting possible reactions of olanzapine with different polymer chains or degradation of the polymer itself; these peaks were most pronounced in the 10 mg / mL formulation in 100% PEG200.

[0161] These data indicate that stable formulations are possible, however, PEG content (and grade) needs to be further optimized to maximize product stability.

[0162] As a first step, solubility was evaluated for mixtures of dimethylacetamide and different molecular weight grades of PEG. First, higher molecular weight PEG may impart higher viscosity to the final formulation, potentially enhancing nasal residence time. Second, higher molecular weight polymers have fewer residual hydroxyl groups, minimizing the suspected drug-excipient interactions observed with PEG200. PEG600 and PEG1000 were selected for this screening because they have significantly higher molecular weights, 3-5 times fewer hydroxyl groups, and higher viscosities than the previously used PEG200. Higher molecular weight PEGs (>1000) were excluded because of their poor miscibility with dimethylacetamide (e.g., PEG3350 is insoluble in 60-90% dimethylacetamide) and the need for the application of heat to aid dissolution (PEG600 melts in the range of 15-25 °C, PEG1000 in the range of 37-40 °C, and PEG3350 in the range of 50-54 °C). A summary of the solubility data is shown in Table 7. [Table 8]

[0163] The data show that olanzapine solubility was sufficient at PEG600 content as low as 40%, and exceeded the highest target concentration of 100 mg / mL at 70% PEG600 and 30% dimethylacetamide. PE1000 was soluble in dimethylacetamide at 40%, but not at higher concentrations. Based on this information, PEG600 was selected for further evaluation. As a first step, various formulations containing olanzapine and Intravail A3 were prepared. The dissolution and freeze-thaw properties of the formulations were evaluated. The formulation compositions are detailed in Table 8, and the results of the dissolution and freeze-thaw tests are detailed in Table 9. [Table 9]

[0164] From these data, the formulation range was narrowed down to a maximum PEG600 content of 60%. Three-month stability studies were then performed at -20°C, 25°C / 60% RH, and 40°C / 75% RH. Formulations B through E were placed on stability to allow for direct comparison between PEG grades, along with a formulation equivalent to formulation B but prepared with PEG200 instead of PEG600. Evaluation of formulations B and E was extended to 6 and 12 month time points at 40°C / 75% RH and 25°C / 60% RH. The data are presented in Tables 10 through 14.

[0165] At the start of the stability study, analytical method qualification was not completed. At the first time point (T-0), related substances values ​​were high as a result of sample degradation after sample preparation and before analysis. The analytical method was subsequently modified to address this issue, which explains why the initial related substances data at T-0 (especially the peaks at RRT1.61 and RRT1.76) were higher compared to later time points. [Table 10] [Table 11] TIFF2025510082000017.tif39165 [Table 12] [Table 13] [Table 14] TIFF2025510082000021.tif72165

[0166] Overall, these initial data indicate that the product maintains its quality attributes over the study period. PEG600 showed improved compatibility compared to PEG200, and stability to related substances improved slightly as the level of PEG600 decreased. However, 12-month and 6-month data for olanzapine 120 mg / mL in 60:40 PEG600:dimethylacetamide at 25°C / 60% RH and 40°C / 75% RH, respectively, indicate that the product has satisfactory quality attributes. At the 6-month and 12-month time points, there appears to be a decrease in some related substances. This may be due to secondary degradation of these related substances, but formal studies have not been initiated at this stage. The darkening of the solution is due to a slight increase in degradation products. The degradant with RRT 1.82 exhibits significant absorption in the visible spectrum, which is likely the primary cause of the color change. Other properties remained unchanged. Based on the stability data, the 60:40 PEG600:dimethylacetamide formulation was selected for further development.

[0167] Since the pharmaceutical product is a true solution, the solubility of olanzapine in the solvent system is an important physicochemical parameter to ensure it remains in solution and can be delivered reproducibly in dose and aerosol profile.

[0168] Olanzapine used to date is a defined polymorph, and formulation studies have confirmed solvent compositions with excess solubilizing power beyond the targeted maximum concentration of 100 mg / mL. Furthermore, freeze-thaw studies of the formulation have demonstrated the robustness of the formulation to temperature fluctuations.

[0169] Example 3: A pilot, phase 1, single-dose, open-label, randomized, parallel-group study to evaluate the pharmacokinetics, safety, and tolerability of intramuscular and intranasal formulations of olanzapine in healthy male subjects The primary objective of this study is to characterize the pharmacokinetic (PK) profile of olanzapine following single doses of olanzapine 7.5 mg intramuscular injection (Zyprexa), olanzapine 7.5 mg solution with 0.25% Intravail A3 absorption enhancer via nasal spray (NRL-4A), and olanzapine 7.5 mg solution with 0.50% Intravail A3 absorption enhancer via nasal spray (NRL-4B) in healthy men.Secondary endpoints are to evaluate the safety and tolerability of a single dose of olanzapine 7.5 mg administered with 0.25% Intravail absorption enhancer nasal spray solution (NRL-4A) and a single dose of 7.5 mg administered with 0.50% Intravail absorption enhancer nasal spray solution (NRL-4B) compared to a single dose of olanzapine 7.5 mg administered as an IM injection (Zyprexa) in healthy men.

[0170] Common pharmacological treatments for acute agitation episodes include benzodiazepines and antipsychotics, administered intramuscularly or intravenously to facilitate rapid drug action. However, their administration can result in injury to staff and / or subjects, especially if the subject is in an agitated state, and is often perceived as humiliating. Furthermore, administration requires trained medical personnel, limiting their use to clinics, emergency rooms, hospitals, or psychiatric wards.

[0171] Intranasal (IN) drug delivery is a desirable option because it is a practical, non-invasive method of administration and is convenient for self-administration or administration by healthcare professionals or family members. It allows for a rapid onset of administration (potentially comparable to IM administration), is not subject to first-pass metabolism, and has good bioavailability, which may reduce administration-related side effects and provide a better safety profile. Agitated subjects who usually suffer from psychosis and live alone may not be able to wait several hours for the therapeutic effect of an oral formulation or travel to an emergency department or health center for an IM injection, but a ready-to-use IN formulation is convenient to carry and administer, making it an attractive option in any social setting, not just the emergency department or health center.

[0172] This study was a pilot phase 1, open-label, randomized, parallel-group clinical trial designed to compare the PK, safety, and tolerability of IM (Zyprexa) and IN (NRL-4A and NRL-4B) formulations of olanzapine in healthy men.

[0173] The study will consist of a screening, baseline, and open-label treatment period. Subjects will be admitted to the Clinical Research Unit (CRU) on Day 1 (the day before dosing) and will be assessed to reconfirm eligibility to participate in the study. Subjects will remain in the CRU until post-dose assessments and sample collection on Day 4. The time for subjects to be discharged from the CRU can be agreed with unit staff, but subjects must return at the scheduled times for all assigned PK samples and for observations.

[0174] Approximately 24 healthy male subjects aged 18-55 years (inclusive) will be randomized in a 1:1:1 ratio into three treatment groups and will receive a single dose of olanzapine intramuscular (IM) injection (olanzapine 7.5 mg IM injection (Zyprexa)) or one of two intranasal formulations while lying down and reclined for up to 2 hours. Subjects will be instructed to consume at least 8 ounces of fluid before administration. The intranasal formulations are formulations 5 and 6 in Table 2 (olanzapine 7.5 mg + dodecylmaltoside 0.25 mg or olanzapine 7.5 mg + dodecylmaltoside 0.50 mg). Safety assessments will be performed after each administration and will include physical examination, vital sign measurements (e.g., blood pressure, heart rate), electrocardiogram, and laboratory tests. The occurrence of self-reported lightheadedness or dizziness will be recorded. Objective assessment of nasal irritation will be assessed after each intranasal administration using a 6-point (0-5) score. Scoring is based on assessment of the nasal mucosa by trained observers pre-dose (baseline), 30 minutes (± 5 minutes), and 1 (± 10 minutes), 2 (± 15 minutes), 4 (± 30 minutes), 6 (± 30 minutes), 8 (± 30 minutes), and 24 (± 30 minutes) hours post-dose. Irritation is assessed by assessing the degree of mucosal inflammation and bleeding. Subjects are asked to report any bleeding or irritation that occurs between the actual assessment time points.

[0175] Blood pressure (BP) and pulse rate are measured after each administration of study drug. BP and pulse rate are measured at baseline, pre-dose, 15 (± 2 min), 30 (± 2 min), 45 (± 5 min) min after administration, and at 1 hour (± 5 min), 1.25 hours (± 5 min), 1.5 hours (± 5 min), 1.75 hours (± 5 min), 2 hours (± 5 min), 2.5 hours (± 10 min), 3 hours (± 10 min), 3.5 hours (± 10 min), 4 hours (± 10 min), 8 hours (± 10 min), 12 hours (± 10 min), and 24 hours (± 10 min). BP and pulse rate are measured while the subject is seated and after standing for 3 minutes. Subjects are also asked by a trained observer if they feel lightheaded or dizzy.

[0176] Injection site reactions are scored on a 6-point scale (0-5) after each IM administration. Scoring is based on assessment of the IM injection site by trained observers at pre-dose (baseline), 30 minutes (± 5 minutes), 1 hour (± 10 minutes), 2 hours (± 15 minutes), 4 hours (± 30 minutes), 6 hours (± 30 minutes), 8 hours (± 30 minutes), and 24 hours (± 30 minutes) after administration. Subjects are asked to report any injection site reactions that occur between the actual assessment times.

[0177] Objective pain assessment is assessed using an 11-point numeric rating scale (NRS; 0–10), with 0 meaning "no pain" and 10 meaning "worst pain imaginable." Pain scores are reported by subjects immediately before administration (baseline), 15 minutes (± 2 minutes), 30 minutes (± 5 minutes), and 1 hour (± 10 minutes), 2 hours (± 15 minutes), 4 hours (± 30 minutes), 6 hours (± 30 minutes), and 8 hours (± 30 minutes) after administration.

[0178] Objective assessment of sedation is performed using a 6-point (0-5) sedation scoring system to assess the subject's degree of drowsiness after each administration of study drug. Sedation scores are reported by the subject (if awake) as well as by a trained observer using the same rating scale immediately before administration (baseline), 15 minutes (± 2 minutes), 30 minutes (± 5 minutes) after administration, and 1 hour (± 10 minutes), 2 hours (± 15 minutes), 4 hours (± 30 minutes), 6 hours (± 30 minutes), and 8 hours (± 30 minutes) after administration. Subjects are also quizzed by the trained observer about their degree of drowsiness.

[0179] Blood samples for olanzapine plasma concentration measurements are taken pre-dose (0, pre-dose), 5, 10, 15, 30, and 45 minutes after dosing, and 1, 1.25, 1.5, 1.75, 2, 4, 8, 12, 24, 36, 48, 72, 96, 144, 192, and 240 hours after dosing. Actual blood collection times may vary: 1) ±1 minute for 5-10 minute samples, 2) ±2 minutes for 15-60 minute samples, 3) ±5 minutes for 1.25-8 hour samples, 4) ±15 minutes for 12 and 24 hour samples, 5) ±2 hours for 36 and 48 hour samples, 6) ±6 hours for 72 and 96 hour samples, and 7) ±24 hours for 144, 192, and 240 hour samples.

[0180] The Columbia-Suicide Severity Rating Scale (C-SSRS), a measure of suicidal ideation and behavior, will be used to document suicidality in order to classify suicidal events using the Columbia Suicide Assessment Classification Algorithm. Suicidality assessments will be performed at screening, baseline, and prior to discharge from the clinical research unit.

[0181] Inclusion criteria were (1) body weight 51 kg to 111 kg, body mass index 18 to 35 kg / m; 2(2) male subjects aged 18-55 years; (3) absence of clinically significant abnormalities in medical history, physical examination, electrocardiogram (corrected QT interval (QTcF) < 450 ms or, for subjects with bundle branch block, corrected QT interval < 480 ms based on QTc values ​​obtained during a short recording period), or laboratory test results during screening; (4) absence of clinically significant abnormalities (in the opinion of the investigator) as assessed by review of medical and surgical history, physical examination, vital sign measurements, electrocardiogram, and laboratory evaluations performed at screening and on admission to the CRU; (5) normal blood pressure (systolic blood pressure 90-140 mmHg, inclusive, diastolic blood pressure < 90 mmHg) and pulse rate (50-100 beats / min, inclusive). Exclusion criteria included (1) unstable disease state, as assessed by the investigator as clinically relevant (1) Clinical laboratory values ​​evaluated (including electrocardiogram, hematology, biochemistry, urinalysis, etc.), current or past history of cardiac, cardiovascular, cerebrovascular, respiratory, gastrointestinal, endocrine, hematological, psychiatric (especially schizophrenia, schizoaffective disorder, bipolar I disorder, major depressive disorder), renal, hepatic, pulmonary, or neurological disease that the investigator considers clinically significant, use of medications that alter or pose a risk to the absorption, metabolism, or excretion of IP, or use of other medications or diseases that may interfere with the interpretation of the study data, (2) Seasonal or a history of nonseasonal allergies, nasal polyps, or nasal abnormalities that may interfere with administration of the nasal spray, or any other condition that, in the opinion of the investigator, may jeopardize the subject's safety or affect the validity of the study results; (3) a known or suspected personal or family history of adverse reactions or hypersensitivity to the IP or drugs with a similar chemical structure (personal history of hypersensitivity to any of the IP or its components, or history of drugs or other allergies that the investigator or medical monitor considers to contraindicate participation); (4) any clinically significant illness within 4 weeks prior to enrollment; (5) subjects with a lifetime history of alcohol or drug abuse, or subjects who have tested positive for opiates, cocaine, benzodiazepines, barbiturates, or amphetamines, or subjects with a history of illicit drug use (intermittent cannabis use, defined as once per week or more, is permitted, but not within the week prior to screening,(6) Subjects who have had a major traumatic injury, major surgery, or open biopsy within 30 days prior to screening; (7) Subjects with a history of major depression or suicide attempt; (8) Subjects determined by the investigator to be at significant risk for suicide, violence, or homicide (suicide risk is defined as those who answered "yes" to items 4 or 5 of the Columbia-Suicide Severity Scale (C-SSRS) suicidal ideation at screening or those who have attempted suicide within 18 months prior to screening); (9) Subjects with a history of postural orthostatic tachycardia syndrome or orthostatic hypotension upon standing on physical examination at screening; (10) History of allergy or adverse reaction to olanzapine or IP components; (11) Participation in a clinical trial within 30 days prior to the first dose of study drug (participation in an observational study (non-interventional study) is not excluded unless the study schedule overlaps with that of this study); (12) Occasional use of paracetamol (up to 2 g per day) (13) inadequate or difficult venous access that may jeopardize the quality or timing of PK samples; (14) positive blood test for HIV, Hepatitis B surface antigen (HbSAg), or Hepatitis C at screening or baseline; (15) positive urine test for alcohol, drugs of abuse (except cannabis), or cotinine at screening or baseline; (16) mentally or legally incompetent; (17) unwilling or unable to follow the procedures outlined in the clinical trial protocol; or (18) otherwise unsuitable for the clinical trial, as determined by the investigator.

[0182] Primary endpoints of the study included olanzapine plasma concentrations from serial PK sampling after IM and IN administration, maximum observed plasma concentration (Cmax), time to maximum plasma concentration (tmax), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration in plasma (AUC0-t), AUC in plasma extrapolated from time zero to infinity (AUC0-∞), terminal elimination half-life of olanzapine in plasma (t1 / 2), terminal elimination rate constant (λz), apparent clearance of olanzapine in plasma (CL / F) uncorrected for bioavailability (F), and apparent volume of distribution of olanzapine in plasma during the terminal phase (Vz / F).

[0183] Safety endpoints included incidence of AEs and serious AEs, clinical laboratory values, vital signs, ECG values, concomitant medications, mental status assessment using the C-SSRS, and biometric measures: nasal irritation, sedation, and pain scores.

[0184] Analysis populations included the PK complete population, the PK evaluable population, and the safety population.

[0185] PK complete population: All subjects who received a known IP dose and had at least one quantifiable plasma olanzapine concentration.

[0186] PK-evaluable population: Evaluable population: All subjects receiving a known dose of IP and with at least one estimable PK parameter.

[0187] Safety Population: All subjects receiving any dose of IP. Safety Assessment:

[0188] Adverse events will be collected and reviewed to assess the safety and tolerability of olanzapine nasal solution compared with IM injection. Other safety measures will include physical examination, vital signs, ECG, and laboratory tests.

[0189] Blood pressure, pulse, temperature, and respiratory rate are measured before dosing (baseline), 15 minutes (± 2 minutes), 30 minutes (± 2 minutes), 45 minutes (± 5 minutes), 1 hour (± 5 minutes), 1.25 hours (± 5 minutes), 1.5 hours (± 5 minutes), 1.75 hours (± 5 minutes), 2 hours (± 5 minutes), 2.5 hours (± 10 minutes), 3 hours (± 10 minutes), 3.5 hours (± 10 minutes), 4 hours (± 10 minutes), 8 hours (± 10 minutes), 12 hours (± 10 minutes), and 24 hours (± 10 minutes). Measurements are performed in the supine position after the subject has stood for 3 minutes. Subjects are also asked by a trained observer if they feel lightheaded or dizzy.

[0190] Objective assessment of nasal irritation will be assessed after IP (arm 2 and arm 3) and IN administration using a 6-point (0-4) scoring system. Scoring will be performed by trained observers based on evaluation of the nasal mucosa before administration (baseline), 5 (± 1) min, 10 (± 2) min, 30 (± 5) min, 1 h (± 10 min), 2 h (± 15 min), 4 h (± 30 min), 6 h (± 30 min), 8 h (± 30 min), 24 h (± 30 min), and on day 14 (end of study). Subjects will also be asked to report any bleeding or irritation that occurs between the actual evaluation time points.

[0191] Objective assessment of sedation is performed using a 6-point (0-5) sedation scoring system to assess the subject's degree of drowsiness after IP administration. Sedation scores are reported by the subject (if awake) and a trained observer using the same rating scale immediately before administration (baseline), and at 15 (± 2 min), 30 (± 5 min), 1 h (± 10 min), 2 h (± 15 min), 4 h (± 30 min), 6 h (± 30 min), and 8 h (± 30 min) after administration. Subjects are also quizzed by the trained observer regarding the degree of drowsiness.

[0192] Objective pain assessment is assessed using an 11-point NRS (0-10), where 0 means "no pain" and 10 means "worst pain imaginable." Pain scores are reported by subjects immediately before dosing (baseline), and at 15 minutes (± 2 minutes), 30 minutes (± 5 minutes), 1 hour (± 10 minutes), 2 hours (± 15 minutes), 4 hours (± 30 minutes), 6 hours (± 30 minutes), and 8 hours (± 30 minutes) after dosing.

[0193] The C-SSRS, a measure of suicidal ideation and behavior, will be used to document suicidality in order to classify suicidal events using the Columbia Suicide Assessment Classification Algorithm. Suicidality will be assessed at screening, baseline, and prior to discharge from the CRU.

[0194] All safety assessments, demographic variables, and pharmacokinetic data will be provided in the subject data listing. Study results will be tabulated and summarized using descriptive statistics. Demographic and demographic characteristics will be presented. Continuous variables will be summarized with descriptive statistics (sample size, mean, standard deviation, median, minimum, maximum). Discrete variables will be summarized with frequencies and percentages. Tabular summaries will be presented by treatment and time point where applicable.

[0195] For purposes of statistical presentation, treatment is defined as three treatment arms: a single dose of olanzapine 7.5 mg IM injection (Zyprexa), a single dose of olanzapine 7.5 mg solution with 0.25% Intravail A3 absorption enhancer via nasal spray, and a single dose of olanzapine 7.5 mg solution with 0.50% Intravail A3 absorption enhancer via nasal spray.

[0196] Electrocardiograms, vital signs, and clinical laboratory data (observations and changes from baseline) will be summarized by time point using appropriate descriptive statistics.

[0197] Chemistry and hematology parameters will be tabulated with shifts from baseline. ECG abnormalities should be reviewed by a trained cardiologist.

[0198] Adverse events will be summarized by presenting the number and percentage of subjects who experienced an adverse event. The number and percentage of subjects reporting treatment-emergent AEs will be tabulated by system organ class and preferred terminology (coded using the Medical Dictionary for Regulatory Activities). Treatment-emergent AEs will be further classified by severity and relationship to treatment.

[0199] Sedation safety measures will be summarized using frequency tables. Frequency tables will be used to summarize the results of the C-SSRS, whenever data permit.

[0200] Individual subject plasma concentrations, actual sampling times, and PK parameters are listed by treatment. Descriptive statistics are calculated for plasma concentrations and PK parameters by treatment. Individual subject plasma concentrations and mean plasma concentrations are graphed on linear and semi-log axes.

[0201] The PK parameters of olanzapine, Cmax, AUC0-t, and AUC0-∞, will be compared between treatments using an analysis of variance (ANOVA) model with treatment as a fixed effect using the natural logarithm of the PK parameters. For each PK parameter, a two-tailed t-test will be used to construct confidence intervals (CI; 90%) for the geometric mean ratio of nasal olanzapine (test drug) to IM olanzapine (reference). Point estimates and confidence limits will be exponentially scaled to the original scale. Comparability of nasal olanzapine (test drug) and IM formulations (reference) will be assessed from the geometric mean ratios and 90% CIs of each PK parameter response.

[0202] Approximately 24 healthy male subjects (8 per treatment group). Six subjects per treatment group will complete the run-in period and an interim analysis will be performed after PK results are available to determine whether additional subjects are required. Variance estimates from ANOVA models for primary endpoints (AUC, Cmax) based on the initial N=18 subjects will be used to confirm the power of statistical tests. If high variability (coefficient of variation ≥ 30%) is observed in PK parameters, it is recommended to enroll at least N=24 subjects as per protocol.

[0203] Each subject will participate in the study for up to 35 days, including a 21-day screening period and a 14-day treatment period, which includes a 4-day confinement period in the CRU and a 10-day follow-up period.

[0204] All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that no right to antedate such disclosure by virtue of prior disclosure.

[0205] All features disclosed herein, including the abstract and drawings, and all steps in the disclosed method or process, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. Each feature disclosed herein, including the abstract and drawings, may be replaced with an alternative feature serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is only one example of a generic series of equivalent or similar features. In addition to those described herein, various modifications of the present disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be included within the scope of the appended claims.

Claims

1. A composition, Olanzapine or a pharmaceutically acceptable salt in an amount of approximately 1% w / v to approximately 15% w / v, Approximately 0.1% w / v to approximately 1% w / v of dodecyl maltoside, Approximately 30% w / v to approximately 40% w / v of N,N-dimethylacetamide, and, A composition comprising polyethylene glycol in an amount of approximately 40% w / v to approximately 70% w / v, wherein the composition is a non-aqueous solution containing less than 3% w / v water.

2. A composition according to claim 1, comprising about 2.5% w / v to about 12% w / v of olanzapine or a pharmaceutically acceptable salt thereof.

3. A composition according to claim 1, comprising about 0.20% w / v to about 0.50% w / v of the dodecyl maltoside.

4. A composition according to claim 1, comprising the N,N-dimethylacetamide in an amount of about 34% w / v to about 38% w / v.

5. The composition according to claim 1, wherein the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da.

6. The composition according to claim 1, wherein the polyethylene glycol has an average molecular weight of about 600 Da.

7. A composition according to claim 1, comprising polyethylene glycol in an amount of about 44% w / v to about 66% w / v.

8. The composition according to claim 1, wherein the amount of olanzapine is about 1 mg to about 15 mg, or a pharmaceutically acceptable salt thereof.

9. The composition according to claim 1, wherein the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:

4.

10. The composition according to claim 1, wherein the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:

2.

11. A composition according to claim 1, comprising about 2.5% w / v to about 12% w / v of olanzapine or a pharmaceutically acceptable salt thereof, about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 34% w / v to about 38% w / v of N,N-dimethylacetamide, and about 44% w / v to about 66% w / v of polyethylene glycol.

12. The composition according to claim 1, wherein the composition contains less than 1% w / v of water.

13. The composition according to claim 1, wherein the composition contains less than 0.1% w / v of water.

14. A single-use spray device comprising the composition according to any one of claims 1 to 13, wherein the device is configured to discharge an amount of the composition equivalent to 15 mg of olanzapine from 2.5 mg of olanzapine when the device is in operation.

15. Use in the manufacture of a drug for the treatment of acute agitation associated with one or more of schizophrenia, schizoaffective disorder and bipolar disorder in a subject requiring the use thereof, comprising a composition comprising about 1% w / v to about 15% w / v of olanzapine or a pharmaceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v of dodecyl maltoside, about 30% w / v to about 40% w / v of N,N-dimethylacetamide, and about 40% w / v to about 70% w / v of polyethylene glycol, wherein the drug is administered intranasally to the nasal mucosa of the subject, and the composition is a non-aqueous solution containing less than about 3% w / v of water.

16. In the use according to claim 15, the composition comprises about 1 mg to about 15 mg of the olanzapine or a pharmaceutically acceptable salt thereof.

17. In the use according to claim 15, the composition comprises about 2.5 mg to about 10 mg of the olanzapine or a pharmaceutically acceptable salt thereof.

18. In the use described in claim 15, the composition comprises about 0.20 mg to about 0.50 mg of the dodecylmaltoside.

19. In the use described in claim 15, the composition comprises about 34% w / v to about 38% w / v of N,N-dimethylacetamide.

20. In the use according to claim 15, the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da.

21. In the use according to claim 15, the composition comprises about 44% w / v to about 66% w / v of polyethylene glycol.

22. In the use according to claim 15, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 4:1 to about 1:

4.

23. In the use according to claim 15, the ratio of polyethylene glycol to N,N-dimethylacetamide is approximately 3:

2.

24. In the use according to claim 15, the composition comprises about 2.5 mg to about 15 mg of the olanzapine or a pharmaceutically acceptable salt thereof, about 0.20% w / v to about 0.50% w / v of dodecyl maltoside, about 34% w / v to about 38% w / v of N,N-dimethylacetamide, and about 44% w / v to about 66% w / v of polyethylene glycol.

25. The use described in claim 15, wherein the severity of the acute excitement is reduced within approximately 20 minutes after administration.

26. In the use according to claim 15, the composition is provided in a pre-prepared, stimulated, single-use dosing device containing about 75 μL to about 200 μL of the composition.

27. In the use according to claim 15, the composition is provided in a pre-prepared, stimulated, single-use dosing device containing about 100 μL of the composition.

28. The use according to claim 15, wherein the depressive, manic, or mixed episodes manifest as recurrent episodes, and one or more of the frequency, duration, and severity of the recurrent episodes are reduced.

29. In the use described in claim 15, the composition contains less than 1% w / v of water.

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