Intranasal olanzapine formulations and methods of using the same

Abstract

The present disclosure provides compositions for intranasal delivery of olanzapine and methods for their use in treating various symptoms of schizophrenia, schizoaffective disorder, and bipolar I disorder, such as acute agitation, mania, and mixed episodes. The intranasal olanzapine compositions comprise dodecylmaltoside for improving the bioavailability of olanzapine and are administered via the nasal mucosa to avoid direct systemic administration.

Description

Cross-reference of related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 621,378, filed January 16, 2024, and U.S. Provisional Application No. 63 / 562,060, filed March 6, 2024, each of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure generally relates to compositions comprising olanzapine and alkyl maltodextrin, said compositions being suitable for intranasal administration and effective for the treatment of acute agitation associated with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, chemotherapy-induced nausea and vomiting, and maintenance therapy for schizophrenia, schizoaffective disorder, type I bipolar disorder, and treatment-resistant depression. Background Technology

[0003] Olanzapine is an atypical antipsychotic approved for the treatment of schizophrenia, schizoaffective disorder, and bipolar I disorder. Individuals affected by these conditions are prone to episodes of agitation, which can range from mild to severe, fluctuate rapidly, and escalate into aggressive behavior within short periods; symptoms include motor restlessness, increased responsiveness to external stimuli, irritability, and inappropriate speech, and may develop into physical aggression, often directed at family members and healthcare providers.

[0004] Intramuscular (IM) injection of olanzapine is commonly used to treat acute agitation because it reaches peak concentration more quickly than oral or orally disintegrating tablets. Rapid onset of action is highly desirable, and traditionally, intramuscular olanzapine has been the approved rapid-acting administration route in the United States. However, intramuscular olanzapine requires reconstitution before administration, must be administered by a healthcare provider (HCP), may require restraint, is invasive, and can be painful. Additionally, in less cooperative patients, it poses a risk of needlestick injury to healthcare workers, caregivers, and patients.

[0005] What is needed is a non-invasive, convenient, needle-free method of olanzapine delivery that can be used for patients with acute agitation without the assistance of hemorrhage control (HCP) and has a rapid onset of action. Such a method could also benefit the treatment of individuals with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, chemotherapy-induced nausea and vomiting, and / or treatment-resistant depression via a more convenient administration method than currently available oral formulations. Summary of the Invention

[0006] In one embodiment, this disclosure provides a method for treating acute agitation in an individual in need of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v water. In some embodiments, the composition is administered about 0.08 hours (4.8 minutes) after administration (T0). max The concentration of C reached approximately 31.513 ng / ml. max In some embodiments, the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max In some embodiments, the composition is administered to achieve an AUC of approximately 509.81 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 323.9 ng·h / ml and about 695.72 ng·h / ml. 0-t In some embodiments, the composition is administered at an AUC of approximately 526.47 ng·h / ml. ∞ In some embodiments, the composition is administered to achieve an AUC between about 329.22 ng·h / ml and about 723.72 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-tApproximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ Approximately 85% to approximately 90%.

[0007] In some embodiments, the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is about 3:2. In some embodiments, the composition contains less than 1% w / v water. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition. In some embodiments, the dosing comprises administering about 75 μL to about 200 μL of the composition into each nostril of the individual. In some embodiments, the dosing comprises administering about 100 μL of the composition into each nostril of the individual. In some embodiments, the severity of the acute agitation of the individual decreases within about 5 minutes after dosing.

[0008] In another embodiment, this disclosure provides a method for treating acute agitation associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium in an individual in need. The method comprises administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol to the nasal mucosa of the individual, wherein the composition is a non-aqueous solution containing less than about 3% w / v water. In some embodiments, the composition is administered over about 0.17 hours (10.2 minutes) (T0). max The concentration of C reached approximately 32.270 ng / ml. max In some embodiments, the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. max In some embodiments, the composition is injected to achieve an AUC of approximately 463.45 ng·h / ml. 0-tIn some embodiments, the composition is administered to achieve an AUC between about 388.89 ng·h / ml and about 538.01 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC of approximately 474.91 ng·h / ml. ∞ In some embodiments, the composition is administered to achieve an AUC between about 399.14 ng·h / ml and about 550.68 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the polyethylene glycol has an average molecular weight of approximately 200 Da to approximately 1000 Da. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 4:1 to approximately 1:4. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 3:2. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, the dosing comprises administering approximately 75 μL to approximately 200 μL of the composition to each nostril of the individual. In some embodiments, the dosing comprises administering approximately 100 μL of the composition to each nostril of the individual. In some embodiments, the composition contains less than 1% w / v water. In some embodiments, the severity of the acute agitation of the individual decreases within approximately 20 minutes after dosing.

[0009] In another embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

[0010] In some embodiments, the composition is administered about 0.08 hours (4.8 minutes) after administration (T0). maxThe concentration of C reached approximately 31.513 ng / ml. max In some embodiments, the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 407.85 ng·h / ml and about 611.772 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 421.18 ng·h / ml and about 631.76 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the polyethylene glycol has an average molecular weight of approximately 200 Da to approximately 1000 Da. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 4:1 to approximately 1:4. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 3:2. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, the dosing comprises administering approximately 75 μL to approximately 200 μL of the composition to each nostril of the individual. In some embodiments, the dosing comprises administering approximately 100 μL of the composition to each nostril of the individual. In some embodiments, the composition contains less than 1% w / v water.

[0011] In another embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v water. In some embodiments, the composition is administered over about 0.17 hours (10.2 minutes) (T0). max The concentration of C reached approximately 32.270 ng / ml. max In some embodiments, the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 370.76 ng·h / ml and about 556.14 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 379.93 ng·h / ml and about 569.89 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, the dosing comprises administering approximately 75 μL to approximately 200 μL of the composition to each nostril of the individual. In some embodiments, the dosing comprises administering approximately 100 μL of the composition to each nostril of the individual. In some embodiments, the composition contains less than 1% w / v water.

[0012] In another embodiment, this disclosure provides a method for treating acute agitation in an individual in need of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising: intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.064 hours and 0.096 hours (T0.06). max The concentration of C10 reached between approximately 25.210 ng / ml and approximately 37.816 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 407.85 ng·h / ml and about 611.772 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 421.18 ng·h / ml and about 631.76 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition further comprises one or more non-aqueous solvents. In some embodiments, the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methyl benzoate, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, riacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, caprylic triglyceride, or any combination thereof. In some embodiments, the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, administration comprises administering about 75 μL to about 200 μL of the composition into each nostril of the individual. In some embodiments, administration comprises administering about 100 μL of the composition into each nostril of the individual. In some embodiments, the severity of the individual's acute agitation decreases within about 5 minutes after administration.

[0013] In another embodiment, this disclosure provides a method for treating acute agitation in an individual in need of treatment associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising: intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.136 hours and 0.204 hours (T0.05). max The concentration of C10 reached between approximately 25.816 ng / ml and approximately 38.724 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 370.76 ng·h / ml and about 556.14 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 379.93 ng·h / ml and about 569.89 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition further comprises one or more non-aqueous solvents. In some embodiments, the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methyl benzoate, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, caprylic triglyceride, or any combination thereof. In some embodiments, the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, administration comprises administering about 75 μL to about 200 μL of the composition into each nostril of the individual. In some embodiments, administration comprises administering about 100 μL of the composition into each nostril of the individual. In some embodiments, the severity of the individual's acute agitation decreases within about 20 minutes after administration.

[0014] In another embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising: administering intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.064 hours and 0.096 hours (T0.06). max The concentration of C10 was between approximately 25.210 ng / ml and approximately 37.816 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 407.85 ng·h / ml and about 611.772 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 421.18 ng·h / ml and about 631.76 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-tApproximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition further comprises one or more non-aqueous solvents. In some embodiments, the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methyl benzoate, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, caprylic triglyceride, or any combination thereof. In some embodiments, the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof. In some embodiments, according to the method of technical claim 60, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, administration comprises administering about 75 μL to about 200 μL of the composition to each nostril of the individual. In some embodiments, administration comprises administering about 100 μL of the composition to each nostril of the individual.

[0015] In another embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising: administering intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at an interval between about 0.136 hours and 0.204 hours (T0.05). max The concentration of C10 reached between approximately 25.816 ng / ml and approximately 38.724 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 370.76 ng·h / ml and about 556.14 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 379.93 ng·h / ml and about 569.89 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is...∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition further comprises one or more non-aqueous solvents. In some embodiments, the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methyl benzoate, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, caprylic triglyceride, or any combination thereof. In some embodiments, the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, administration comprises administering about 75 μL to about 200 μL of the composition to each nostril of the individual. In some embodiments, administration comprises administering about 100 μL of the composition to each nostril of the individual. Attached Figure Description

[0016] Figure 1 Describe the saturated solubility of the dimethylacetamide / PEG 200 binary solvent system.

[0017] Figure 2 A superposition of chromatograms derived from solubility studies.

[0018] Figure 3 A superimposed chromatogram of 100% PEG 200 containing 10 mg / mL olanzapine was plotted.

[0019] Figure 4 A superimposed chromatogram of 50 / 50 dimethylacetamide / PEG 200 containing 150 mg / mL olanzapine was plotted.

[0020] Figure 5 The changes in olanzapine concentration (ng / ml) in plasma over time (0-2 hours) are depicted under various formulations tested.

[0021] Figure 6 The changes in olanzapine concentration (ng / ml) in plasma over time (0–240 hours) are depicted under various formulations tested.

[0022] Figure 7Describe the CONSORT participant flow chart. Abbreviations: DDM, dodecyl maltodextrin; OLZ, olanzapine.

[0023] Figure 8 Plot the mean olanzapine plasma concentration-time curve. A. 0–2 hours. B. 0–240 hours. Abbreviations: DDM, dodecyl maltodextrin, IM, intramuscular.

[0024] Figure 9 Describe the sedation assessment categorized by maximum severity. Abbreviations: DDM, dodecyl maltodextrin; IM, intramuscular. Detailed Implementation

[0025] Before describing the compositions and methods of the present invention, it should be understood that various aspects of intranasal 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 one of ordinary skill in the art. It should also be understood that the terminology used in the specification is for the purpose of describing particular aspects or embodiments only and is not intended to be limiting. The disclosed intranasal olanzapine compositions, methods of their manufacture, and methods of use are not strictly limited to the specific compositions, processes, or methods described, as these may vary to the extent that one of ordinary skill in the art would recognize without departing from the benefits and advantages imparted by the compositions and methods. Although one of ordinary skill in the art will readily recognize obvious variations and substitutions that can achieve the same results by equivalent means or functions, preferred compositions and methods are now described for the purpose of describing various aspects and embodiments of intranasal olanzapine compositions, methods of their manufacture, and methods of their use.

[0026] It should be further understood that certain features of this disclosure (described in the context of individual embodiments for clarity) may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, the various features of this disclosure described in the context of a single embodiment may also be provided individually or in any suitable sub-combination.

[0027] The compositions disclosed herein are suitable for administration into the nasal cavity. Therefore, the phrases “intranasal solution,” “intranasal composition,” and “intranasal formulation” are used interchangeably to mean compositions suitable for administration into the nasal mucosa lining the nasal cavity.

[0028] The intranasal olanzapine composition disclosed in this article can be used to treat schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, chemotherapy-induced nausea and vomiting, and depression, especially various symptoms of treatment-resistant depression.

[0029] Schizophrenia is a severe mental illness that affects an individual's thinking, feelings, and behavior, and involves a breakdown in the relationships between these aspects of an individual's life, leading to inappropriate actions and feelings, detachment from reality and interpersonal relationships, and feelings of schizophrenia. Generally, schizophrenia develops in at least three stages: the prodromal phase, the first episode, and the chronic phase. Heterogeneity also exists among individuals at all stages of the illness, with some individuals considered extremely high risk, clinically high risk, or at risk of psychotic episodes (Fusar-Poli et al., “The Psychosis High-Risk State: A Comprehensive State-of-the-Art Review”, JAMA Psychiatry 70:107-120 (2013), which is incorporated herein by reference in its entirety). The methods described herein are suitable for treating individuals at any stage of schizophrenia and at any risk level for psychosis. In some embodiments, the individual may be an adult or an adolescent.

[0030] Schizoaffective disorder is a combination of symptoms from schizophrenia and mood disorders such as depression or bipolar I disorder. Symptoms may occur simultaneously or at different times. Periods of severe symptoms are usually followed by periods of improvement. Symptoms may include delusions, hallucinations, depressive episodes, and manic episodes of heightened energy. There are two types of schizoaffective disorder: bipolar, characterized by manic episodes and sometimes major depressive episodes; and depressive, characterized by major depressive episodes only.

[0031] Bipolar disorder, sometimes called manic-depressive disorder, is a mental disorder characterized by severe elevated (manic) and depressed (depressive) moods, as well as changes in sleep, energy, thinking, and behavior. People with bipolar disorder may experience periods of excessive happiness and energy (“episodes”) and other periods of intense sadness, despair, and lethargy. These mood swings may occur infrequently or frequently throughout the year. Type I bipolar disorder is characterized by at least one manic episode, which may precede or follow a hypomanic (a milder form of mania) or depressive episode. Type II bipolar disorder is characterized by at least one major depressive episode and at least one hypomanic episode without a manic episode. In some embodiments, bipolar disorder comprises Type I bipolar disorder, Type II bipolar disorder, or a combination thereof.

[0032] Mania and hypomania are two distinct types of episodes, but they share similar symptoms. Mania is more severe than hypomania and causes more significant problems in work, school, and social activities, as well as interpersonal difficulties. Mania can also trigger detachment from reality (psychosis) and require hospitalization. Major depressive episodes include symptoms severe enough to cause significant difficulty in daily activities such as work, school, social activities, or interpersonal relationships. Mixed episodes are defined by simultaneous or rapid, consecutive episodes of manic and depressive symptoms without intermediate remission.

[0033] Generally, bipolar disorder is a progressive condition that develops in at least three phases: the prodromal phase, the symptomatic phase, and the residual phase (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), all of which are incorporated herein by reference in their entirety). The methods described herein are suitable for treating individuals with any of the aforementioned bipolar disorders and individuals at any stage of a particular bipolar disorder.

[0034] Alzheimer's disease is the most common type of dementia. It is a progressive disease that begins with mild memory loss and can lead to a loss of the ability to converse and respond to the environment. Alzheimer's disease involves parts of the brain that control thinking, memory, and language.

[0035] Autism spectrum disorder (ASD) is a developmental disorder caused by differences in brain function. People with ASD typically have problems with social communication and interaction, and their behaviors or interests may be restricted or repetitive. People with ASD may also have different ways of learning, engaging in activities, or paying attention.

[0036] Post-traumatic stress disorder (PTSD) is a mental health condition triggered by a frightening event, whether experienced or witnessed. Symptoms may include flashbacks, nightmares, irritability, and severe anxiety, as well as feelings of being unable to control the event. PTSD symptoms may begin within a month of the traumatic event, but sometimes they may not appear until years later. These symptoms can cause significant problems in social or work settings and in interpersonal relationships. They can also interfere with the ability to handle normal daily tasks. PTSD symptoms are generally classified into four types: intrusive memories, avoidance, negative changes in thoughts and mood, and changes in physical and emotional responses. Symptoms can vary over time or from person to person.

[0037] Attention-deficit / hyperactivity disorder (ADHD) is characterized by a persistent pattern of inattention and / or hyperactivity-impulsivity that can interfere with function or development. People with ADHD experience a persistent pattern of symptoms in the following ways: inattention means that a person may have difficulty maintaining focus, concentration, and orderliness in performing tasks, and these problems are not due to defiance or lack of comprehension; hyperactivity means that a person seems to be constantly active, including in inappropriate situations, or excessively fidgeting, patting, or talking. In adults, hyperactivity may mean extreme restlessness or excessive talking; impulsivity means that a person may act without thinking or have difficulty with self-control. Impulsivity may also include a desire for immediate rewards or an inability to delay gratification. Impulsive individuals may interrupt others or make significant decisions without considering long-term consequences.

[0038] Delirium is an altered state of consciousness characterized by episodes of confusion that can develop over hours or days. Many different health conditions are associated with delirium, including infections, responses to sedatives, hypoxia, and organ failure. Individuals with delirium may experience altered perceptions of their location. Hypoactive delirium is the most common type. It can cause subtle changes such as unusual drowsiness and lethargy. The individual may be unresponsive to caregivers or family members and may appear dazed or “unconscious.” Hyperactive delirium is characterized by restlessness and agitation. Individuals with this type may wander or pace, experience hallucinations and mood swings, or refuse care due to delusions (persistent, unfounded beliefs) that they feel unsafe. Mixed delirium can cause alternating episodes of hypoactive and hyperactive symptoms in the same individual. COVID delirium can be either hypoactive or hyperactive and is associated with the use of a ventilator or breathing tube during treatment for SARS-CoV-2 coronavirus infection. It may be caused by the ICU experience itself and exacerbated by hypoxia when COVID causes pneumonia or heart damage.

[0039] In the United States, more than one million cancer patients undergo chemotherapy or radiation therapy each year. Nausea and vomiting are the most common adverse reactions to chemotherapy, occurring in approximately 70 to 80% of cases without appropriate antiemetic intervention. The resulting impact on appetite can lead to malnutrition, electrolyte imbalances, and decreased treatment adherence.

[0040] Acute agitation is defined as excessive motor activity associated with feelings of inner tension and may be associated with schizophrenia, schizoaffective disorder, type I bipolar disorder (and many other mental disorders), Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium.

[0041] Treatment-resistant depression (TRD) is generally defined as an inadequate response to at least one antidepressant trial at an appropriate dose and duration.

[0042] As used herein, the terms “treat,” “treated,” or “treating” refer to both therapeutic treatment and preventative or preventative measures aimed at preventing (partially or completely) or alleviating (e.g., reducing or delaying its onset) an unwanted physical symptom, condition, or disease, or achieving a beneficial or desired clinical outcome, such as partial or complete recovery, or inhibiting a decline in a parameter, value, function, or outcome that has or will become abnormal. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to: symptom relief; reduction of the degree, intensity, or rate of development of a symptom, condition, or disease; stabilization (i.e., non-worsening) of the state of a symptom, condition, or disease; delaying the onset of a symptom, condition, or disease or slowing its progression; improvement of the state of a symptom, condition, or disease; and relief (partial or complete), whether or not it translates into an immediate reduction in actual clinical symptoms, or an enhancement or improvement of a symptom, condition, or disease. Treatment seeks to elicit a clinically significant response without excessive side effects. Treatment also includes extended survival compared to expected survival without treatment. As used herein, the word “treatment” and its other grammatical forms (e.g., treat, treatment) can also improve symptoms of a disease or condition (such as schizophrenia, schizoaffective disorder, bipolar disorder, or TRD). Improvement may include a reduction in the frequency, duration, or severity of one or more symptoms. The physiological causes of many psychotic symptoms or diseases, including schizophrenia, schizoaffective disorder, bipolar disorder, and TRD, are not fully understood, but are thought to be caused by abnormal biochemical signaling in the brain. Therefore, 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. In this way, an individual being “treated” with the compositions and methods described herein will experience symptom improvement of their disease or condition, but maintenance therapy or extended administration may be necessary to maintain said symptom improvement. In many cases, extended administration may last for months, years, or even the remainder of the individual's life.

[0043] In any embodiment, the methods and compositions disclosed herein may comprise the described steps and components. As used herein, “comprise” is an open-ended language used to describe the steps or components included in the described method or composition but indicates that other elements may also be included, even if not explicitly quoted. In any embodiment, the methods and compositions disclosed herein may consist substantially of the described steps and components. As used herein, “consistently composed of” is used to describe the steps or components included in the described method or composition and indicates that other elements may also be included, but which will not significantly 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 described steps and components. As used herein, “consistently composed of” is a closed-ended language used to describe the steps or components included in the described method or composition and excludes elements other than those explicitly described. Any use of the terms “comprise,” “comprises,” or “comprising” may be replaced by “consistently composed of” or “composed of.”

[0044] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural indicators. Thus, for example, a reference to a “cell” is a reference to one or more cells and their equivalents known to a person skilled in the art, and so on.

[0045] As used herein, the term "about" means a given value plus or minus 1%. For example, "about 50%" means within the range of 49.5% to 50.5%. As used herein, the term "about" means a given value plus or minus 2%. For example, "about 50%" means within the range of 49% to 51%. As used herein, the term "about" means a given value plus or minus 3%. For example, "about 50%" means within the range of 48.5% to 51.5%. As used herein, the term "about" means a given value plus or minus 4%. For example, "about 50%" means within the range of 48% to 52%. As used herein, the term "about" means a given value plus or minus 5%. For example, "about 50%" means within the range of 47.5% to 52.5%. As used herein, the term "about" means a given value plus or minus 6%. For example, "about 50%" means within the range of 47% to 53%. As used herein, the term "about" means a given value plus or minus 7%. For example, "about 50%" means within the range of 46.5% to 53.5%. As used herein, the term "about" means a given value plus or minus 8%. For example, "about 50%" means within the range of 46% to 54%. As used herein, the term "about" means a given value plus or minus 9%. For example, "about 50%" means within the range of 45.5% to 54.5%. As used herein, the term "about" means a given value plus or minus 10%. For example, "about 50%" means within the range of 45% to 55%. As used herein, the term "about" can also mean a given value plus or minus 5%. For example, "about 50%" means within the range of 47.5% to 52.5%. As used herein, the term "about" can also mean a given value plus or minus 15%. For example, "about 50%" means within the range of 42.5% to 57.5%. As used in this article, the term "about" can also mean a given value plus or minus 20%. For example, "about 50%" means within the range of 40% to 60%.

[0046] As used herein, the terms “individual” and “patient” explicitly include individuals of both human and non-human mammals. As used herein, the term “non-human mammal” extends to, but is not limited to, domestic pets and domesticated animals. Non-limiting examples of such animals include primates, cattle, sheep, ferrets, mice, rats, pigs, camels, horses, rabbits, goats, dogs, and cats. In some embodiments, the individual or patient is an adult. In some embodiments, the individual or patient is an adolescent.

[0047] As used herein, the term "effective dose" refers to a measurable amount that causes at least one symptom or a specific condition or pathological process to be inhibited. For example, the effective dose of olanzapine can be from about 1 mg to about 15 mg.

[0048] As used herein, the term "therapeutic effective amount" or "effective amount" for compounds or compositions of this disclosure refers to a predetermined amount that imparts a therapeutic effect to the treated individual at a reasonable benefit / risk ratio suitable for any medical treatment. Therapeutic effects can be objective (i.e., measurable by some test or labeling) or subjective (i.e., indicated or felt by the individual or observed by a physician). Effective amounts of the compounds of this disclosure can be broadly in the range of about 1 mg to about 15 mg of olanzapine. As needed, the effects covered herein include both medical therapeutic and / or preventative treatment. To obtain therapeutic and / or preventative effects, the specific dose of the compound administered according to this disclosure will, of course, be determined by the specific circumstances surrounding the case, including, for example, the compound administered, the route of administration, co-administration of other active ingredients, the condition being treated, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health condition, sex, and diet; the time of administration, the route of administration, the rate of excretion of the specific compound used, and the duration of treatment. The effective amount administered will be determined by a physician taking into account the foregoing relevant circumstances and exercising reasonable medical judgment. The therapeutically effective amount of the compounds disclosed herein is generally such that, when administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or a local concentration in tissues. The total daily dose of the compounds of this disclosure administered to humans or other animals in a single dose or in multiple doses may be, for example, from about 1 mg to about 15 mg. A single-dose composition may contain such amounts or approximations thereof to constitute a daily dose. Generally, treatment regimens according to this disclosure involve daily administration in single or multiple doses to a patient requiring such treatment, typically comprising from about 1 mg to about 10 mg, from about 1 mg to about 15 mg, from about 1 mg to about 30 mg, from about 1 mg to about 60 mg, or from about 1 mg to about 120 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0049] A therapeutically effective dose of olanzapine can be administered as a therapeutically effective dose of the intranasal olanzapine composition disclosed herein. The therapeutically effective dose of the intranasal olanzapine composition can be administered in a single volume (e.g., administered into one nostril of an individual) or in two or more volumes (e.g., a first volume administered into one nostril and a second volume administered into a second nostril to produce a therapeutically effective dose). The therapeutically effective dose may comprise 1 mg to about 15 mg of olanzapine or a pharmaceutically acceptable salt thereof. In some embodiments, the intranasal olanzapine composition may further comprise about 0.1 mg to about 1 mg of dodecyl maltodextrin, 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 into one or more nostrils of an individual may be about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 200 μL, or any value between these values.

[0050] Therefore, the intranasal olanzapine composition and its method of use provided herein represent substantial improvements in the aforementioned treatments, particularly in the treatment of acute agitation associated with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, and delirium, said improvements being due to the rapid realization of post-treatment benefits.

[0051] Composition

[0052] This disclosure provides an intranasal composition comprising olanzapine or a pharmaceutically acceptable salt thereof. As described above, the intranasal olanzapine composition is suitable and intended for intranasal administration. 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:

[0053]

[0054] Formula I describes olanzapine in its free base form; however, olanzapine may be present in any intranasal olanzapine composition described herein in salt form (e.g., dicarboxylate, such as tartrate), solvate (e.g., hydrate), polymorph, cocrystal, complex, or any combination thereof. All statements regarding the concentration or amount of olanzapine refer to its free base form; however, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or any combination thereof may be used. When compared to the amount of free base, those skilled in the art will be able to determine the therapeutically equivalent amount of a pharmaceutically acceptable salt of olanzapine.

[0055] As used herein, the term "pharmaceutical acceptable" refers to molecular entities and compositions generally considered safe and non-toxic. In particular, pharmaceutically acceptable carriers, diluents, or other excipients used in the pharmaceutical compositions of this disclosure are physiologically tolerable, compatible with other components, and generally do not cause allergic reactions or similar adverse reactions (e.g., stomach upset, dizziness, etc.) when administered to a patient. Preferably, as used herein, the term "pharmaceutical acceptable" means approved by a federal regulatory agency or state government, or listed in the United States Pharmacopeia (US Pharmacopoeia) or other recognized pharmacopoeia for use in animals and more specifically in humans.

[0056] As used herein, the phrase "pharmaceutically acceptable salt" includes salts of the compounds of this disclosure that are safe and effective for use in mammals and have the desired biological activity. Pharmaceutically acceptable salts include salts containing acidic or basic groups present in the compounds of this disclosure or in compounds identified according to the methods of this disclosure. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, hydrobroms, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)). Certain compounds of this disclosure can form pharmaceutically 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. They can also form pharmaceutically acceptable base addition salts with amines (such as organic amines). Examples of suitable amines are N,N'-diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucosamine, and procaine.

[0057] Compositions for intranasal delivery of olanzapine (hereinafter referred to as "intranasal olanzapine compositions") comprise olanzapine or a pharmaceutically acceptable salt thereof, an alkyl maltodextrin, 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 maltodextrins include C9-C... 14Maltodextrin, such as dodecyl maltodextrin and tetradecyl maltodextrin, particularly n-dodecyl-β-D-maltodextrin. 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.

[0058] Compositions for intranasal delivery of therapeutically effective amounts of olanzapine (hereinafter referred to as "intranasal olanzapine compositions") comprise olanzapine or a pharmaceutically acceptable salt thereof, an alkyl maltodextrin, 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 maltodextrins include C9-C... 14 Maltodextrin, such as dodecyl maltodextrin and tetradecyl maltodextrin, particularly n-dodecyl-β-D-maltodextrin. 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.

[0059] Intranasal olanzapine compositions may comprise one or more doses, each dose comprising a therapeutically effective amount of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.1 mg to about 1 mg of dodecyl maltodextrin, about 30 mg to about 40 mg of DMA, and about 40 mg to about 70 mg of polyethylene glycol. Intranasal olanzapine compositions may comprise 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 maltodextrin, 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 intranasal olanzapine composition described above may be used to deliver a therapeutically effective amount of olanzapine to an individual in need to treat conditions, symptoms, or diseases treatable with olanzapine, such as schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, and TRD.

[0060] Intranasal olanzapine compositions may comprise one or more doses, each dose comprising about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.1 mg to about 1 mg of dodecyl maltodextrin, about 30 mg to about 40 mg of DMA, and about 40 mg to about 70 mg of polyethylene glycol. Intranasal olanzapine compositions may comprise 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 maltodextrin, 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 intranasal olanzapine composition described above may be used to deliver a therapeutically effective amount of olanzapine to an individual in need to treat conditions, symptoms, or diseases treatable with olanzapine, such as schizophrenia, schizoaffective disorder, bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, and TRD.

[0061] In another example, each dose may contain a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof, about 0.20 mg to about 0.50 mg of dodecyl maltodextrin, about 34 mg to about 38 mg of DMA, and about 44 mg to about 66 mg of polyethylene glycol. Therefore, an intranasal olanzapine composition may contain 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 maltodextrin, 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 intranasal olanzapine composition described above may be used to deliver a therapeutically effective amount of olanzapine to an individual in need to treat conditions, symptoms, or diseases treatable with olanzapine, such as schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, and TRD.

[0062] In another example, each dose may contain about 2.5 mg to about 12 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.20 mg to about 0.50 mg of dodecyl maltodextrin, about 34 mg to about 38 mg of DMA, and about 44 mg to about 66 mg of polyethylene glycol. Therefore, an intranasal olanzapine composition may contain 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 maltodextrin, 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 intranasal olanzapine composition described above may be used to deliver a therapeutically effective amount of olanzapine to an individual in need to treat conditions, symptoms, or diseases treatable with olanzapine, such as schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, and TRD.

[0063] In another example, each dose may contain a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25 mg to about 0.50 mg of dodecyl maltodextrin, about 34 mg to about 38 mg of DMA, and about 44 mg to about 66 mg of polyethylene glycol. Therefore, an intranasal olanzapine composition may contain about 2.5% w / v to about 10% w / v of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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 intranasal olanzapine composition described above may be used to deliver a therapeutically effective amount of olanzapine to an individual in need to treat conditions, symptoms, or diseases treatable with olanzapine, such as schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, and TRD.

[0064] In another example, each dose may contain about 2.5 mg to about 10 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25 mg to about 0.50 mg of dodecyl maltodextrin, about 34 mg to about 38 mg of DMA, and about 44 mg to about 66 mg of polyethylene glycol. Therefore, an intranasal olanzapine composition may contain about 2.5% w / v to about 10% w / v of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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 intranasal olanzapine composition described above may be used to deliver a therapeutically effective amount of olanzapine to an individual in need to treat conditions, symptoms, or diseases treatable with olanzapine, such as schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, and TRD.

[0065] In any embodiment, the intranasal olanzapine composition may contain olanzapine or a pharmaceutically acceptable salt thereof that is substantially dissolved in the composition (“intranasal olanzapine solution” herein). As used herein, “substantially dissolved” indicates that at least 99.5% of the olanzapine is dissolved in the intranasal olanzapine composition. Therefore, the intranasal olanzapine composition does not contain or substantially does not contain (i.e., contains 0.5% w / v or less) any olanzapine-containing solid particulate matter, including micron particles, microspheres, nanoparticles, and nanospheres. In any embodiment, at least 99.9% of the olanzapine is soluble in the intranasal olanzapine composition and contains 0.1% w / v or less of any olanzapine-containing solid particulate matter. The intranasal olanzapine composition may be a sprayable liquid and is not a dry powder formulation.

[0066] In any embodiment, the intranasal olanzapine composition may comprise a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof (“intranasal olanzapine solution” herein) substantially dissolved in the composition. As used herein, “substantially dissolved” indicates that at least 99.5% of the olanzapine is dissolved in the intranasal olanzapine composition. Therefore, the intranasal olanzapine composition is free from or substantially free from (i.e., contains 0.5% w / v or less) any olanzapine-containing solid particulate matter, including micron particles, microspheres, nanoparticles, and nanospheres. In any embodiment, at least 99.9% of the olanzapine is soluble in the intranasal olanzapine composition and contains 0.1% w / v or less of any olanzapine-containing solid particulate matter. The intranasal olanzapine composition may be a sprayable liquid and is not a dry powder formulation.

[0067] In any embodiment, the intranasal olanzapine solution may be at least substantially free of water (“non-aqueous intranasal olanzapine solution” herein). 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.

[0068] In any embodiment, the intranasal olanzapine composition may include additional inactive excipients, such as viscosity enhancers, texture modifiers, preservatives, stabilizers, and flavor or odor enhancers, without affecting the efficacy of olanzapine in providing therapeutic benefit to an individual. In any embodiment, the intranasal olanzapine solution may consist essentially of olanzapine, dodecyl maltodextrin, DMA, and polyethylene glycol, each in any amount disclosed at any point herein. Similarly, in any embodiment, the non-aqueous intranasal olanzapine solution may consist essentially of olanzapine, dodecyl maltodextrin, DMA, and polyethylene glycol. Likewise, in any embodiment, the intranasal olanzapine solution may consist of olanzapine, dodecyl maltodextrin, DMA, and polyethylene glycol. In any embodiment, the non-aqueous intranasal olanzapine solution may consist of olanzapine, dodecyl maltodextrin, DMA, and polyethylene glycol, each in any amount disclosed at any point herein.

[0069] As disclosed herein, intranasal olanzapine compositions may be non-aqueous, solution-based, or both, comprising about 0.1% w / v to about 1% w / v (i.e., 0.1 mg to 1 mg per 105 mg composition) of dodecyl maltoside, such as dodecyl α- or β-D-maltoside. For example, in any embodiment, the intranasal olanzapine composition may comprise 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 (e.g., dodecyl-β-D-maltoside). Dodecyl maltoside is commercially available, such as dodecyl maltoside sold under the trademark INTRAVAIL® by Aegis Therapeutics, LLC. (San Diego, CA, USA), a wholly owned subsidiary of Neurellis, Inc. (San Diego, CA, USA).

[0070] The intranasal olanzapine compositions disclosed herein, which may be non-aqueous, solution, 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 between therewith. A therapeutically effective dose of about 75 μL to about 150 μL of the intranasal 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 between therewith, such as about 37 mg to about 38 mg. DMA can be purchased, for example, from Belle Chemical Company (Metairie, LA, USA), Sigma Aldrich (St. Louis, MO, USA), and Eastman Chemicals (Kingsport, TN, USA).

[0071] The intranasal olanzapine compositions disclosed herein, which may be non-aqueous, solution-based, or both, further comprise about 40% w / v to about 70% w / v of polyethylene glycol with an average molecular weight of about 200 Da to about 1000 Da, preferably about 200 Da to about 700 Da, such as PEG-600 with an average molecular weight of 600 Da. The intranasal olanzapine compositions disclosed herein, which may be non-aqueous, solution-based, or both, further comprise about 44% w / v to 66% w / v of polyethylene glycol with an average molecular weight of about 200 Da to about 1000 Da, preferably about 200 Da to about 700 Da, such as PEG-600 with an average molecular weight of 600 Da. For example, intranasal olanzapine compositions may contain polyethylene glycol at approximately 44% w / v to approximately 60% w / v, approximately 50% w / v to approximately 60% w / v, approximately 55% w / v to approximately 66% w / v, approximately 52% w / v to approximately 62% w / v, or approximately 56% w / v to approximately 60% w / v. A therapeutically effective dose of approximately 75 μL to approximately 150 μL of an intranasal olanzapine composition may contain, for example, approximately 44 mg to approximately 66 mg of polyethylene glycol, such as approximately 52 mg to approximately 66 mg or approximately 54 mg to approximately 66 mg of polyethylene glycol.

[0072] In any embodiment, the polyethylene glycol can be a mixture of polyethylene glycol molecules of different sizes and / or branching indices, said polyethylene glycol molecules producing an average volume average molecular weight of about 200 Da to about 1000 Da, such as 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 to about 900 Da, about 500 Da to about 800 Da, about 500 Da to about 700 Da, or any value between these values, 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. Da or about 1000 Da.

[0073] PEG-600 may be purchased, for example, from Dow Chemicals (Midland, MI, USA) under the trademark CARBOWAX™, from BASF (Ludwigshafen, Germany) under the trademark KOLLISOLV®, from Sasol (Sandton, South Africa) under the trademark NOVELUTION®, from Double Bond Chemical (Taiwan, China) under the trademark DOUBLEMER®, and from Sigma-Aldrich.

[0074] Advantageously, it has been observed that intranasal olanzapine compositions as described herein do not support bacterial growth and are therefore likely to be substantially free of or contain no antibacterial agents or other preservatives. However, the use of antibacterial agents does not preclude the therapeutic benefit of administering a therapeutically effective amount of olanzapine via intranasal olanzapine compositions, solutions, or non-aqueous solutions as described herein. Therefore, any intranasal olanzapine composition (including non-aqueous solutions) disclosed herein may be free of or substantially free of any preservatives, antidegradants, antibacterial agents, or antifungal agents.

[0075] The intranasal olanzapine compositions disclosed herein exhibit properties that are compatible with and non-irritating to the nasal mucosa. These properties include tension, osmotic pressure, and viscosity. Therefore, the intranasal olanzapine compositions have been formulated to exhibit appropriate drug solubility and stability, and provide a medium for delivering a drug that is substantially non-irritating to the nasal mucosa.

[0076] The therapeutically effective dose of the intranasal olanzapine composition disclosed herein can be administered to an individual via the nasal mucosa in one or more volumes. Such volumes include, for example, from about 10 μL to about 200 μL, from about 50 μL to about 150 μL, from about 75 μL to about 125 μL, from about 75 μL, from about 100 μL, or from about 125 μL. For example, a dose of about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof) can be administered in volumes of about 25 μL, about 50 μL, about 75 μL, about 100 μL, about 125 μL, or about 150 μL. The dose can be administered into a single nostril or divided into two nostrils. For example, a dose of 2 mg olanzapine in about 100 μL, a dose of 2.5 mg olanzapine in about 100 μL, a dose of 4 mg olanzapine in about 100 μL, a dose of 5 mg olanzapine in about 100 μL, a dose of 7.5 mg olanzapine in about 100 μL, a dose of 10 mg olanzapine in about 100 μL, or a dose of 15 mg olanzapine in about 100 μL can be administered into a single nostril. The 5 mg dose can alternatively be administered as a dose of 2.5 mg olanzapine in about 100 μL into each nostril. Similarly, a dose of 10 mg olanzapine can alternatively be administered as a dose of 5 mg olanzapine in about 100 μL into each nostril. Likewise, a dose of 15 mg olanzapine can, for example, be administered as a dose of 7.5 mg olanzapine in about 100 μL into each nostril. The therapeutically effective dose of olanzapine can range from about 1 mg to about 15 mg, for example, about 2.5 mg to about 10 mg, 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 olanzapine, about 12 mg olanzapine, or about 15 mg olanzapine. The therapeutically effective dose of olanzapine can also be about 2 mg olanzapine, 4 mg olanzapine, or 7.5 mg olanzapine.

[0077] How to use

[0078] Delivery of olanzapine to the nasal mucosa via any of the intranasal olanzapine compositions disclosed herein induces a rapid and effective therapeutic benefit for the individual. Furthermore, intranasal administration of the intranasal olanzapine compositions disclosed herein achieves similar pharmacokinetic properties compared to known formulations, such as those administered orally, intravenously, or intramuscularly. For example, the olanzapine T-value achieved after administration of the intranasal olanzapine composition is [not specified in the original text]. max C maxOne or more of AUC can be T values ​​achieved after intramuscular administration of olanzapine (e.g., Zyprexa®). max C max Or approximately 80% to 125%, 90% to 125%, 100% to 125%, 90% to 110%, or 80% to 110% of the AUC. For example, it has been reported that the C of 5 mg intramuscular (IM) olanzapine... max It is approximately 4-5 times the oral dose (7 ng / mL), and it has been reported that oral and IM olanzapine T max The time is approximately 15 to approximately 45 minutes. In contrast, 5 mg of olanzapine administered via an intranasal olanzapine composition as disclosed herein can be administered within approximately 11 to approximately 57 minutes (T0). max The concentration of C within the range reached approximately 22 ng / mL to approximately 44 ng / mL. max According to reports, the C of 10 mg olanzapine is... max This is approximately 4 to 5 times the oral dose of 10 mg (14 ng / mL). In contrast, 10 mg olanzapine administered via the intranasal olanzapine composition as described herein can be delivered in approximately 11 to 57 minutes (T0). max The concentration of C within the container reached approximately 44.8 ng / mL to approximately 87.5 ng / mL. max The bioavailability of olanzapine administered via the intranasal olanzapine composition disclosed herein is comparable to that of olanzapine administered orally or intramuscularly, exhibiting, for example, an AUC of approximately 123 ng·hr / mL to approximately 257 ng·hr / mL for a dose containing 5 mg olanzapine. 0-∞ Or, for doses containing 10 mg olanzapine, it exhibits an AUC of approximately 248 ng·hr / mL to approximately 356 ng·hr / mL. 0-∞ .

[0079] In some embodiments, the bioavailability of olanzapine administered via an intranasal olanzapine composition as disclosed herein can be approximately 90% of that of intramuscularly administered olanzapine. In some embodiments, the bioavailability of olanzapine administered via an intranasal olanzapine composition as disclosed herein (e.g., Test Product I - Treatment A, Test Product II - Treatment B) can be approximately 90% of that of intramuscularly administered olanzapine.

[0080] In some embodiments, 7.5 mg of olanzapine administered via an intranasal olanzapine composition having about 0.25% w / v dodecyl maltodextrin as disclosed herein can achieve an effect in about 0.08 hours (4.8 minutes) (T). max The concentration of C reached approximately 31.513 ng / ml. maxIn some embodiments, 7.5 mg of olanzapine administered via an intranasal olanzapine composition having about 0.25% w / v dodecyl maltodextrin as disclosed herein can be administered within about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max In some embodiments, the composition is administered to achieve an AUC of approximately 509.81 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 323.9 ng·h / ml and about 695.72 ng·h / ml. 0-t In some embodiments, the composition is administered at an AUC of approximately 526.47 ng·h / ml. ∞ In some embodiments, the composition is administered to achieve an AUC between about 329.22 ng·h / ml and about 723.72 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ Approximately 85% to approximately 90%.

[0081] Figure 5 The changes in olanzapine concentration (ng / ml) in plasma over time (0-2 hours) are depicted under various formulations tested. Figure 6 The changes in olanzapine concentration (ng / ml) in plasma over time (0-250 hours) are depicted under various formulations tested.

[0082] In some embodiments, 7.5 mg of olanzapine administered via an intranasal olanzapine composition having about 0.5% w / v dodecyl maltodextrin as disclosed herein can achieve an effect in about 0.17 hours (10.2 minutes) (T max The concentration of C reached approximately 32.270 ng / ml. max In some embodiments, 7.5 mg of olanzapine administered via an intranasal olanzapine composition having about 0.5% w / v dodecyl maltodextrin as disclosed herein can be administered within about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T max The concentration of C within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. maxIn some embodiments, the composition is injected to achieve an AUC of approximately 463.45 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 388.89 ng·h / ml and about 538.01 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC of approximately 474.91 ng·h / ml. ∞ In some embodiments, the composition is administered to achieve an AUC between about 399.14 ng·h / ml and about 550.68 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ Approximately 85% to approximately 90%.

[0083] In contrast, 7.5 mg olanzapine administered via the intranasal olanzapine composition described herein can be delivered within approximately 30 to approximately 60 minutes (T0). max The concentration of C reached approximately 13.787 ng / mL to approximately 27.187 ng / mL. max .

[0084] In some embodiments, the intranasal olanzapine compositions disclosed herein achieve T1 in less than about 15 to about 45 minutes. max .

[0085] A therapeutically effective amount of olanzapine can be administered to the nasal mucosa of an individual in need via one or more doses of an intranasal olanzapine composition. In some embodiments, the intranasal olanzapine composition, which may be non-aqueous, 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 maltodextrin, 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 may contain a therapeutically effective amount of olanzapine (or a pharmaceutically acceptable salt thereof). In other embodiments, each administered dose 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 pharmaceutically acceptable salt thereof). Olanzapine can be administered via intranasal olanzapine compositions as disclosed herein to treat any condition, symptom, or disease that can be treated with olanzapine. Several example conditions will now be described, merely to provide examples of conditions that can be treated with olanzapine via the intranasal olanzapine compositions disclosed herein, but not to limit the variety of conditions that can be treated in this manner.

[0086] In some embodiments, olanzapine administered via intranasal olanzapine compositions as disclosed herein may cause a lower incidence of adverse events, a lower severity of adverse events, or a combination thereof, compared to olanzapine administered via intramuscular or intravenous injection.

[0087] Some embodiments relate to methods for treating acute agitation in individuals in need of treatment associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the methods comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

[0088] In some embodiments, the composition is administered about 0.08 hours (4.8 minutes) after administration (T0). max The concentration of C reached approximately 31.513 ng / ml. maxIn some embodiments, the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max In some embodiments, the composition is administered to achieve an AUC of approximately 509.81 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 323.9 ng·h / ml and about 695.72 ng·h / ml. 0-t In some embodiments, the composition is administered at an AUC of approximately 526.47 ng·h / ml. ∞ In some embodiments, the composition is administered to achieve an AUC between about 329.22 ng·h / ml and about 723.72 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the polyethylene glycol has an average molecular weight of approximately 200 Da to approximately 1000 Da. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 4:1 to approximately 1:4. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 3:2. In some embodiments, the composition contains less than 1% w / v water. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, the dosing comprises administering approximately 75 μL to approximately 200 μL of the composition to each nostril of the individual. In some embodiments, the dosing comprises administering approximately 100 μL of the composition to each nostril of the individual. In some embodiments, the severity of the acute agitation of the individual decreases within approximately 5 minutes after dosing.

[0089] Some embodiments relate to methods for treating acute agitation in individuals in need of treatment associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the methods comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

[0090] In some embodiments, the composition is administered over approximately 0.17 hours (10.2 minutes) (T0). max The concentration of C reached approximately 32.270 ng / ml. max In some embodiments, the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. max In some embodiments, the composition is injected to achieve an AUC of approximately 463.45 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 388.89 ng·h / ml and about 538.01 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC of approximately 474.91 ng·h / ml. ∞ In some embodiments, the composition is administered to achieve an AUC between about 399.14 ng·h / ml and about 550.68 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞The composition comprises approximately 85% to approximately 90%. In some embodiments, the polyethylene glycol has an average molecular weight of approximately 200 Da to approximately 1000 Da. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 4:1 to approximately 1:4. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 3:2. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, the dosing comprises administering approximately 75 μL to approximately 200 μL of the composition to each nostril of the individual. In some embodiments, the dosing comprises administering approximately 100 μL of the composition to each nostril of the individual. In some embodiments, the composition contains less than 1% w / v water. In some embodiments, the severity of the acute agitation of the individual decreases within approximately 20 minutes after dosing.

[0091] Some embodiments relate to methods for treating chemotherapy-induced nausea and vomiting in individuals in need, the methods comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

[0092] In some embodiments, the composition is administered about 0.08 hours (4.8 minutes) after administration (T0). max The concentration of C reached approximately 31.513 ng / ml. max In some embodiments, the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max In some embodiments, the composition is administered to achieve an AUC of approximately 509.81 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 323.9 ng·h / ml and about 695.72 ng·h / ml. 0-t In some embodiments, the composition is administered at an AUC of approximately 526.47 ng·h / ml. ∞In some embodiments, the composition is administered to achieve an AUC between about 329.22 ng·h / ml and about 723.72 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the polyethylene glycol has an average molecular weight of approximately 200 Da to approximately 1000 Da. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 4:1 to approximately 1:4. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is approximately 3:2. In some embodiments, the composition is provided in a pre-activated disposable drug delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable drug delivery device containing approximately 100 μL of the composition. In some embodiments, the dosing comprises administering approximately 75 μL to approximately 200 μL of the composition to each nostril of the individual. In some embodiments, the dosing comprises administering approximately 100 μL of the composition to each nostril of the individual. In some embodiments, the composition contains less than 1% w / v water.

[0093] Some embodiments relate to methods for treating chemotherapy-induced nausea and vomiting in individuals in need, the methods comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

[0094] In some embodiments, the composition is administered over approximately 0.17 hours (10.2 minutes) (T0). max The concentration of C reached approximately 32.270 ng / ml. max In some embodiments, the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. maxIn some embodiments, the composition is injected to achieve an AUC of approximately 463.45 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 388.89 ng·h / ml and about 538.01 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC of approximately 474.91 ng·h / ml. ∞ In some embodiments, the composition is administered to achieve an AUC between about 399.14 ng·h / ml and about 550.68 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 75 μL to approximately 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing approximately 100 μL of the composition. In some embodiments, the dosing comprises administering approximately 75 μL to approximately 200 μL of the composition to each nostril of the individual. In some embodiments, the dosing comprises administering approximately 100 μL of the composition to each nostril of the individual. In some embodiments, the composition contains less than 1% w / v water.

[0095] Acute agitation

[0096] For example, olanzapine can be administered via intranasal olanzapine compositions as disclosed herein to treat acute agitation associated with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium. These intranasal olanzapine compositions can be used as monotherapy or in combination with one or more additional agents 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 individuals at any stage of the condition / symptom. Administration can be performed at any time before or after an acute agitation episode.

[0097] Methods of treating acute agitation associated with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium in individuals in need may comprise administering a therapeutically effective amount of olanzapine to at least one nasal mucosa in at least one nostril of the individual via an intranasal olanzapine composition. The therapeutically effective amount of olanzapine for adult individuals may be between about 1 and about 15 mg, such as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, or 15 mg of olanzapine or a pharmaceutically acceptable salt thereof. In some embodiments, acute agitation associated with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium in individuals requiring treatment is included approximately 2 hours after administration as a change from baseline in the excitatory component (i.e., items of poor impulse control, tension, hostility, noncooperation, and excitatoryness, using a 1-7 rating system (1 = absent, 4 = moderate, 7 = extreme), with at least one individual item score ≥4). In some embodiments, acute agitation associated with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium in individuals in need of treatment is defined as an improvement in the excitatory component of the Positive and Negative Syndrome Scale (PANSS) relative to baseline approximately 2 hours after administration.

[0098] In another embodiment, this disclosure provides a method for treating acute agitation in an individual in need of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising: intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.064 hours and 0.096 hours (T0.06). max The concentration of C10 reached between approximately 25.210 ng / ml and approximately 37.816 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 407.85 ng·h / ml and about 611.772 ng·h / ml. 0-tIn some embodiments, the composition is administered to achieve an AUC between about 421.18 ng·h / ml and about 631.76 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition further comprises one or more non-aqueous solvents. In some embodiments, the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methylparaben, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, caprylic triglyceride, or any combination thereof. In some embodiments, the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof. In some embodiments, alcohols may include, but are not limited to, benzyl alcohol, ethanol, isopropanol, butanol, straight-chain higher alcohols, branched-chain higher alcohols, or any combination thereof. In some embodiments, glycols or glycol derivatives may include, but are not limited to, propylene glycol, glycerol (anhydrous glycerol), or any combination thereof. In some embodiments, esters may include, but are not limited to, ethyl acetate, methylparaben, or combinations thereof. In some embodiments, the oil may include cottonseed oil, sesame oil, olive oil, soybean oil, castor oil, hydrogenated derivatives (e.g., Cremphor), eucalyptol, medium-chain triglycerides (MCT oil), or any combination thereof. In some embodiments, the ether may include, but is not limited to, diethylene glycol monoethyl ether (e.g., Transcutol). In some embodiments, the dimethyl or alkyl derivative may include, but is not limited to, dimethyl sulfoxide (DMSO), dimethyl isosorbide, or any combination thereof. In some embodiments, the alkane may include, but is not limited to, isopropyl myristate and isopropyl palmitate.

[0099] In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition. In some embodiments, administration comprises administering about 75 μL to about 200 μL of the composition into each nostril of the individual. In some embodiments, administration comprises administering about 100 μL of the composition into each nostril of the individual. In some embodiments, the severity of the individual's acute agitation decreases within about 5 minutes after administration.

[0100] In another embodiment, this disclosure provides a method for treating acute agitation in an individual in need of treatment associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising: intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.136 hours and 0.204 hours (T0.05). max The concentration of C10 reached between approximately 25.816 ng / ml and approximately 38.724 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 370.76 ng·h / ml and about 556.14 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 379.93 ng·h / ml and about 569.89 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition further comprises one or more non-aqueous solvents. In some embodiments, the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methylparaben, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, caprylic triglyceride, or any combination thereof. In some embodiments, the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof. In some embodiments, glycols or glycol derivatives may include, but are not limited to, propylene glycol, glycerol (anhydrous glycerol), or any combination thereof. In some embodiments, esters may include, but are not limited to, ethyl acetate, methylparaben, or combinations thereof. In some embodiments, the oil may include cottonseed oil, sesame oil, olive oil, soybean oil, castor oil, hydrogenated derivatives (e.g., Cremphor), eucalyptol, medium-chain triglycerides (MCT oil), or any combination thereof. In some embodiments, the ether may include, but is not limited to, diethylene glycol monoethyl ether (e.g., Transcutol). In some embodiments, the dimethyl or alkyl derivative may include, but is not limited to, dimethyl sulfoxide (DMSO), dimethyl isosorbide, or any combination thereof. In some embodiments, the alkane may include, but is not limited to, isopropyl myristate and isopropyl palmitate. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition. In some embodiments, administration comprises administering about 75 μL to about 200 μL of the composition into each nostril of the individual. In some embodiments, administration comprises administering about 100 μL of the composition into each nostril of the individual. In some embodiments, the severity of the acute agitation of the individual decreases within about 20 minutes after administration.

[0101] Therefore, in another aspect, this disclosure provides a method for treating acute agitation associated with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium in an individual in need, the method comprising: administering a first volume of an intranasal olanzapine composition to the nasal mucosa of the individual, the composition being non-aqueous, a solution, or both, comprising about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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 can be administered via one or more doses of an intranasal olanzapine composition.

[0102] Administering a therapeutically effective dose of olanzapine via intranasal olanzapine composition may involve spraying one or more volumes of the intranasal olanzapine composition into each nostril, such as spraying a first volume of the intranasal olanzapine composition into a first nostril, followed by spraying a second volume of the intranasal olanzapine composition into a second nostril. Optionally, a third and / or fourth volume of the intranasal olanzapine composition may be administered shortly after the first and second volumes. In any embodiment, one or more volumes may be administered to achieve administration of a therapeutically effective dose of olanzapine.

[0103] If the individual's acute agitation is not satisfactorily treated within approximately 2 to 4 hours after the first administration, a second administration of the intranasal olanzapine composition may be given, and if satisfactory treatment is still not achieved within approximately 2 to 4 hours, a third administration may be given. Therefore, in another aspect, this disclosure provides a method for treating acute agitation associated with schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising: administering a first volume of the intranasal olanzapine composition disclosed herein to the nasal mucosa of the individual during or before the acute agitation, wherein if adequate cessation or prevention of agitation is not achieved within approximately 2, 3, or 4 hours after the administration of the first volume, one or more subsequent volumes of the intranasal olanzapine composition are administered to the individual. In some embodiments, the intranasal olanzapine composition comprises a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof). In some embodiments, the intranasal olanzapine composition further comprises about 0.20 mg to about 0.50 mg of dodecyl maltodextrin, 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. For example, an intranasal olanzapine composition, which may be non-aqueous, a solution, or both, comprising about 2.5 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20 mg to about 0.50 mg of dodecyl maltodextrin, about 34% w / v to about 38% w / v of DMA, and about 44% w / v to about 66% w / v of polyethylene glycol, may be administered in a first volume, and a second volume of the intranasal olanzapine composition may be administered if acute agitation is not adequately stopped. 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 volume and strength of the second volume may be the same as or different from the first dose. Optionally, if adequate cessation of acute agitation is not achieved within about 2 hours, about 3 hours, or about 4 hours, the method may further comprise administration of a third volume of the intranasal olanzapine composition.

[0104] Depressive episodes associated with type I bipolar disorder

[0105] Olanzapine can be administered via intranasal olanzapine compositions as disclosed herein to treat depressive episodes associated with type I bipolar disorder in adults, children, or adolescents (e.g., 10-17 years of age). In any embodiment, the intranasal olanzapine composition can be used as monotherapy or in combination therapy with one or more additional agents commonly used to treat depression associated with type I bipolar disorder (such as fluoxetine). Administering a therapeutically effective amount of olanzapine to an individual in need via the intranasal olanzapine compositions disclosed herein can reduce the severity or incidence of depressive episodes associated with type I bipolar disorder. In one instance, acute bipolar depression can be treated by administering a therapeutically effective amount of olanzapine via the intranasal olanzapine compositions disclosed herein at any time before or after an acute bipolar depressive episode. For example, in any embodiment, an individual diagnosed with type I bipolar disorder may be treated at least once daily with a therapeutically effective dose as part of a maintenance regimen. In some embodiments, treatment for depressive episodes associated with type I bipolar disorder in adults, children, or adolescents (e.g., 10–17 years of age) includes changes in the adult's, child's, or adolescent's Montgomery-Asberg Depression Rating Scale (MADRS) relative to baseline. MADRS is a 10-item clinician rating scale with a total score ranging from 0 to 60. In some embodiments, treatment for depressive episodes associated with type I bipolar disorder in adults, children, or adolescents (e.g., 10–17 years of age) includes improvement in the adult's, child's, or adolescent's MADRS score approximately 8 weeks after administration.

[0106] Methods for treating acute bipolar depression in individuals in need may comprise administering a therapeutically effective amount of olanzapine to at least one nasal mucosa in at least one nostril via the intranasal olanzapine composition disclosed herein. A therapeutically effective amount of olanzapine for adult individuals may be, for example, olanzapine (or a pharmaceutically acceptable salt thereof) once daily between about 1 mg and about 15 mg, administered according to the above disclosure to treat depressive episodes associated with type I bipolar disorder, optionally in combination with fluoxetine, for example, about 20 mg of fluoxetine, which may be administered substantially concurrently via any route of administration. A therapeutically effective amount of olanzapine for adult individuals may be, for example, about 5 mg of olanzapine (or a pharmaceutically acceptable salt thereof) once daily, administered according to the above disclosure to treat depressive episodes associated with type I bipolar disorder, optionally in combination with fluoxetine, for example, about 20 mg of fluoxetine, which may be administered substantially concurrently via any route of administration. For example, fluoxetine may be administered via an oral dosage form. A therapeutically effective dose of olanzapine for children or adolescents may be, for example, about 2.5 mg of olanzapine (or a pharmaceutically acceptable salt thereof) once daily, administered as disclosed above to treat depressive episodes associated with type I bipolar disorder, optionally in combination with fluoxetine, for example, about 20 mg of fluoxetine, which may be administered substantially concurrently via any route of administration. For example, fluoxetine may be administered via an oral dosage form.

[0107] Therefore, in another aspect, this disclosure provides a method for treating depressive episodes associated with type I bipolar disorder in an individual of need, the method comprising: administering a first volume of an intranasal olanzapine composition to the nasal mucosa of the individual, the composition being non-aqueous, a solution, or both, comprising about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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 can be administered via one or more doses of the intranasal olanzapine composition.

[0108] Administering a therapeutically effective amount of olanzapine via an intranasal olanzapine composition may comprise spraying one or more volumes of the intranasal olanzapine composition disclosed herein into each nostril, such as spraying a first volume of the intranasal olanzapine composition disclosed herein into a first nostril, followed by spraying a second volume of the intranasal olanzapine composition into a second nostril. Optionally, a third and / or fourth volume of the intranasal olanzapine composition disclosed herein may be administered after the first and second volumes. In any embodiment, one or more doses may be administered to achieve the administration of a therapeutically effective amount of olanzapine.

[0109] Type I bipolar disorder (manic episodes or mixed episodes)

[0110] Olanzapine can be administered via intranasal olanzapine compositions as disclosed herein to treat manic episodes and / or mixed episodes associated with type I bipolar disorder in adults and adolescents (e.g., 13–17 years of age). In any embodiment, olanzapine administration via intranasal olanzapine compositions disclosed herein can be used as monotherapy or in combination therapy with one or more additional agents commonly used to treat manic and mixed episodes associated with type I bipolar disorder (such as lithium or sodium valproate).

[0111] Administering a therapeutically effective dose of olanzapine to an individual in need via the intranasal olanzapine compositions disclosed herein can reduce the severity, frequency, or duration of an acute bipolar manic episode and / or mixed episode in an individual experiencing these symptoms. In one instance, manic episodes and / or mixed episodes associated with type I bipolar disorder can be treated by administering a therapeutically effective dose of olanzapine via the intranasal olanzapine compositions disclosed herein at any time before or after a manic episode and / or mixed episode. For example, an individual diagnosed with type I bipolar disorder may be treated once daily as maintenance therapy. In some embodiments, administration of a therapeutically effective dose of olanzapine to an individual in need via such intranasal olanzapine compositions disclosed herein can cause a change in the individual's Young Mania Rating Scale (Y-MRS) relative to baseline. The Y-MRS is an 11-item clinician rating scale conventionally used to assess the severity of manic symptoms (irritability, disruptive / aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language / thought disturbances, thought content, appearance, and insight) on a scale of 0 (no manic traits) to 60 (maximum score). In some embodiments, administration of a therapeutically effective dose of olanzapine to an individual in need via such intranasal olanzapine compositions disclosed herein can cause an improvement in the individual's Y-MRS score.

[0112] Methods of treating manic episodes and / or mixed episodes associated with type I bipolar disorder in individuals in need may comprise administering a therapeutically effective amount of olanzapine to the nasal mucosa of an individual via one or more doses of the intranasal olanzapine composition disclosed herein. A therapeutically effective amount of olanzapine for treating manic episodes and / or mixed episodes associated with type I bipolar disorder in children or adolescents may be, for example, about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof). A therapeutically effective amount of olanzapine for treating manic episodes and / or mixed episodes associated with type I bipolar disorder in children or adolescents may be, for example, about 2.0 mg to about 5 mg of olanzapine (or a pharmaceutically acceptable salt thereof) once daily, increasing to a target maintenance dose of 10 mg / day. A therapeutically effective dose of olanzapine can be administered via the intranasal olanzapine composition disclosed herein to treat manic episodes and / or mixed episodes associated with type I bipolar disorder, optionally in combination with fluoxetine, such as about 20 mg of fluoxetine, which can be administered substantially concurrently via any route of administration. For example, fluoxetine can be administered via an oral dosage form.

[0113] An effective therapeutic dose of olanzapine for treating manic episodes and / or mixed episodes associated with type I bipolar disorder in adults may be, for example, about 10 mg of olanzapine (or a pharmaceutically acceptable salt thereof) once daily, administered according to the foregoing disclosure to treat manic episodes and / or mixed episodes associated with type I bipolar disorder, optionally in combination with a therapeutic dose of lithium (e.g., 50 μg / mL to 125 μg / mL), which may be administered substantially concurrently via any route of administration.

[0114] Therefore, in another aspect, this disclosure provides a method for treating manic episodes and / or mixed episodes associated with type I bipolar disorder in an individual of need, the method comprising: administering a first volume of the intranasal olanzapine composition described herein into the nasal mucosa of the individual. In some embodiments, the intranasal olanzapine composition may be non-aqueous, a solution, or both. In some embodiments, a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof). In some embodiments, the intranasal olanzapine composition further comprises about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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.

[0115] Administering a therapeutically effective amount of olanzapine via the intranasal olanzapine composition disclosed herein may comprise spraying one or more volumes of the intranasal olanzapine composition into each nostril, such as spraying a first volume of the intranasal olanzapine composition into a first nostril, followed by spraying a second volume of the intranasal olanzapine composition into a second nostril. Optionally, a third and / or fourth volume of the intranasal olanzapine composition may be administered after the first and second volumes. In any embodiment, one or more doses may be administered to achieve a therapeutically effective amount of olanzapine.

[0116] Schizophrenia and related disorders

[0117] As disclosed herein, olanzapine administered intranasally via the intranasal olanzapine compositions described herein can also be used as maintenance therapy for the treatment of schizophrenia and related mental disorders, such as schizoaffective disorder, in adults and adolescents (e.g., 13–17 years of age). Such intranasal olanzapine compositions as described herein can be used as monotherapy or in combination with one or more additional agents commonly used to treat schizophrenia or schizoaffective disorder, such as amisulpride.

[0118] Methods for treating or managing schizophrenia or related mental disorders in individuals in need may comprise administering a therapeutically effective amount of olanzapine to the nasal mucosa of an individual via one or more doses of an intranasal olanzapine composition as described herein. For example, administering a therapeutically effective amount of olanzapine intranasally via the intranasal olanzapine composition described herein may comprise spraying one or more doses of the intranasal olanzapine composition into each nostril, such as spraying a first dose of the intranasal olanzapine composition into a first nostril, followed by spraying a second dose of the intranasal olanzapine composition into a second nostril. Optionally, a third and / or fourth dose of the intranasal 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.

[0119] As maintenance therapy, olanzapine administered intranasally to an individual via the olanzapine composition disclosed herein may be used to prevent (i.e., suppress its onset) or manage (e.g., reduce its incidence, severity, or duration) one or more positive symptoms of schizophrenia or schizoaffective disorder, such as, but not limited to, delusions, hallucinations, thought or speech disturbances, inattention, and motor disorders. Olanzapine administered intranasally to an individual via the olanzapine composition disclosed herein may be used to prevent (i.e., suppress its onset) or manage (e.g., reduce its incidence, severity, or duration) one or more negative symptoms of schizophrenia or schizoaffective disorder, such as, but not limited to, anhedonia, speech difficulties, depression, withdrawal, difficulties with basic daily living activities, and lack of follow-through.

[0120] In some embodiments, as disclosed herein, olanzapine administered intranasally via the olanzapine composition described herein can also be used as maintenance therapy to treat schizophrenia and related mental disorders, such as schizoaffective disorder, in adults and adolescents (e.g., 13–17 years of age), resulting in improvements in the individual's Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI) score, Positive and Negative Syndrome Scale (PANSS) score, and Scale for Assessing Negative Symptoms (SANS) score. The BPRS (a multi-item scale for general psychopathology) has traditionally been used to evaluate the role of pharmacological treatment in schizophrenia. The BPRS psychotic clusters (conceptual confusion, hallucinatory behavior, paranoia, and unusual thought content) are considered a particularly useful subset for assessing patients with active psychotic schizophrenia. The second traditional assessment, the CGI, reflects the impression of a skilled observer fully familiar with the clinical presentation of schizophrenia regarding the patient's overall clinical condition.

[0121] Therefore, this disclosure provides a method for treating an individual diagnosed with one or more of schizophrenia or schizoaffective disorder, the method comprising administering a therapeutically effective amount of olanzapine to the nasal mucosa of the individual via one or more doses of the intranasal olanzapine composition described herein. In some embodiments, the intranasal olanzapine composition may be non-aqueous, a solution, or both. In some embodiments, a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof). In some embodiments, the intranasal olanzapine composition further comprises about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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. Schizophrenia and / or schizoaffective disorder can be treated with a therapeutically effective dose of olanzapine administered at least once daily (e.g., once, twice, or three times daily) via intranasal olanzapine composition. In any embodiment, a first dose, such as about 5 mg of olanzapine, may be administered to an adult individual on the first day, followed by higher doses of olanzapine, such as 7.5 mg or 10 mg of olanzapine, on one or more subsequent days, with a target maintenance dose of 10 mg / day.

[0122] Administering a therapeutically effective amount of olanzapine via the intranasal olanzapine composition disclosed herein may comprise spraying one or more volumes of the intranasal olanzapine composition into each nostril, such as spraying a first volume of the intranasal olanzapine composition into a first nostril, followed by spraying a second volume of the intranasal olanzapine composition into a second nostril. Optionally, a third and / or fourth volume of the intranasal olanzapine composition may be administered after the first and second volumes. In any embodiment, one or more doses may be administered to achieve a therapeutically effective amount of olanzapine.

[0123] Treatment-resistant depression (TRD)

[0124] Olanzapine administered intranasally via the intranasal olanzapine compositions described herein can also be used to treat TRD in adults. These intranasal olanzapine compositions can be used as monotherapy or in combination with one or more additional medications commonly used to treat depression, such as fluoxetine.

[0125] A method of treating or managing TRD in an individual may comprise administering a therapeutically effective amount of olanzapine to the nasal mucosa of an individual via one or more doses of the intranasal olanzapine composition described herein. In some embodiments, a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof). In some embodiments, the intranasal olanzapine composition further comprises about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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 the polyethylene glycol to the N,N-dimethylacetamide is about 4:1 to about 1:4. In some embodiments, the ratio of the polyethylene glycol to the N,N-dimethylacetamide is about 3:2. A therapeutically effective amount of olanzapine may be about 5 mg of olanzapine, 7.5 mg of olanzapine, or 10 mg of olanzapine (or an equivalent amount of a salt thereof).

[0126] Therefore, in another aspect, this disclosure provides a method for treating TRD in an individual in need, the method comprising administering a therapeutically effective amount of olanzapine via one or more doses of the intranasal olanzapine composition described herein, the intranasal olanzapine composition being a non-aqueous, solution, or both disclosed herein, the intranasal olanzapine 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 maltodextrin, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol. For example, a therapeutically effective dose of intranasal olanzapine composition of about 75 μL to about 150 μL may comprise about 2.5 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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.

[0127] In some embodiments, administration of a therapeutically effective amount of olanzapine via one or more doses of the intranasal olanzapine composition described herein results in a reduction in an individual's overall MADRS compared to baseline. In some embodiments, treating or managing a TRD in an individual in need may comprise administering a therapeutically effective amount of olanzapine to the individual's nasal mucosa via a single daily dose of the intranasal olanzapine composition described herein.

[0128] TRD can be treated by administering a therapeutically effective amount of olanzapine via intranasal olanzapine composition at least once daily (e.g., once, twice, or three times daily). In any embodiment, a first dose, such as about 5 mg of olanzapine, may be administered to an adult individual on the first day, followed by higher doses of olanzapine, such as 7.5 mg 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 intranasal olanzapine composition may comprise spraying one or more volumes of intranasal olanzapine composition into each nostril, for example, spraying a first volume of intranasal olanzapine composition into a first nostril, and then spraying a second volume of intranasal olanzapine composition into a second nostril. Optionally, a third and / or fourth volume of intranasal olanzapine composition may be administered after the first and second volumes. In any embodiment, one or more doses may be administered to achieve a therapeutically effective amount of olanzapine.

[0129] Nausea and vomiting caused by chemotherapy

[0130] Olanzapine administered intranasally via the intranasal olanzapine compositions described herein can also be used to treat chemotherapy-induced nausea and vomiting. These intranasal olanzapine compositions can be used as monotherapy or in combination with one or more additional agents commonly used to treat chemotherapy-induced nausea and vomiting, such as corticosteroids (e.g., dexamethasone), 5-HT3 antagonists (e.g., ondansetron or palonosetron), NK1 antagonists (e.g., aprepitant or fosaprepitant), or cannabinoids (e.g., dronabinol or nabilone).

[0131] A method for treating or managing chemotherapy-induced nausea and vomiting in an individual in need may comprise administering a therapeutically effective amount of olanzapine to the nasal mucosa of the individual via one or more doses of the intranasal olanzapine composition described herein. In some embodiments, a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof). In some embodiments, the intranasal olanzapine composition further comprises about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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 dose of olanzapine can be approximately 5 mg olanzapine, 7.5 mg olanzapine, or 10 mg olanzapine (or an equivalent dose of its salts).

[0132] Therefore, in another aspect, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising administering a therapeutically effective amount of olanzapine via one or more doses of the intranasal olanzapine composition described herein, the intranasal olanzapine composition being a non-aqueous, solution, or both disclosed herein, the intranasal olanzapine 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 maltodextrin, about 30% w / v to about 40% w / v of DMA, and about 40% w / v to about 70% w / v of polyethylene glycol. For example, a therapeutically effective dose of intranasal olanzapine composition of about 75 μL to about 150 μL may comprise about 2.5 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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.

[0133] In another embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising: administering intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.064 hours and 0.096 hours (T0.06). max The concentration of C10 was between approximately 25.210 ng / ml and approximately 37.816 ng / ml. max In some embodiments, the composition is administered to achieve an AUC between about 407.85 ng·h / ml and about 611.772 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 421.18 ng·h / ml and about 631.76 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition further comprises one or more non-aqueous solvents. In some embodiments, the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methylparaben, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, caprylic triglyceride, or any combination thereof. In some embodiments, the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof. In some embodiments, glycols or glycol derivatives may include, but are not limited to, propylene glycol, glycerol (anhydrous glycerol), or any combination thereof. In some embodiments, esters may include, but are not limited to, ethyl acetate, methylparaben, or combinations thereof. In some embodiments, the oil may include cottonseed oil, sesame oil, olive oil, soybean oil, castor oil, hydrogenated derivatives (e.g., Cremphor), eucalyptol, medium-chain triglycerides (MCT oil), or any combination thereof. In some embodiments, the ether may include, but is not limited to, diethylene glycol monoethyl ether (e.g., Transcutol). In some embodiments, the dimethyl or alkyl derivative may include, but is not limited to, dimethyl sulfoxide (DMSO), dimethyl isosorbide, or any combination thereof. In some embodiments, the alkane may include, but is not limited to, isopropyl myristate and isopropyl palmitate. In some embodiments, according to the method of claim 60, the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition. In some embodiments, administration includes administering about 75 μL to about 200 μL of the composition to each nostril of the individual. In some embodiments, administration includes administering about 100 μL of the composition to each nostril of the individual.

[0134] In another embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising: administering intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at an interval between about 0.136 hours and 0.204 hours (T0.05). max The concentration of C10 reached between approximately 25.816 ng / ml and approximately 38.724 ng / ml. maxIn some embodiments, the composition is administered to achieve an AUC between about 370.76 ng·h / ml and about 556.14 ng·h / ml. 0-t In some embodiments, the composition is administered to achieve an AUC between about 379.93 ng·h / ml and about 569.89 ng·h / ml. ∞ In some embodiments, the AUC achieved by reacting the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%. In some embodiments, the AUC achieved by reacting the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ The composition comprises approximately 85% to approximately 90%. In some embodiments, the composition further comprises one or more non-aqueous solvents. In some embodiments, the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methylparaben, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, caprylic triglyceride, or any combination thereof. In some embodiments, the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof. In some embodiments, glycols or glycol derivatives may include, but are not limited to, propylene glycol, glycerol (anhydrous glycerol), or any combination thereof. In some embodiments, esters may include, but are not limited to, ethyl acetate, methylparaben, or combinations thereof. In some embodiments, the oil may include cottonseed oil, sesame oil, olive oil, soybean oil, castor oil, hydrogenated derivatives (e.g., Cremphor), eucalyptol, medium-chain triglycerides (MCT oil), or any combination thereof. In some embodiments, the ether may include, but is not limited to, diethylene glycol monoethyl ether (e.g., Transcutol). In some embodiments, the dimethyl or alkyl derivative may include, but is not limited to, dimethyl sulfoxide (DMSO), dimethyl isosorbide, or any combination thereof. In some embodiments, the alkane may include, but is not limited to, isopropyl myristate and isopropyl palmitate. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition. In some embodiments, the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition. In some embodiments, administration comprises administering about 75 μL to about 200 μL of the composition to each nostril of the individual. In some embodiments, administration comprises administering about 100 μL of the composition to each nostril of the individual.

[0135] In some embodiments, administration of a therapeutically effective amount of olanzapine via one or more doses of the intranasal olanzapine composition described herein results in a reduction in chemotherapy-induced nausea and vomiting in an individual compared to baseline. In some embodiments, treatment or management of chemotherapy-induced nausea and vomiting in an individual in need may comprise administration of a therapeutically effective amount of olanzapine to the individual's nasal mucosa via a single daily dose of the intranasal olanzapine composition described herein.

[0136] Chemotherapy-induced nausea and vomiting can be treated by administering a therapeutically effective amount of olanzapine via intranasal olanzapine composition at least once a day (e.g., once, twice, or three times a day). In any embodiment, a first dose, such as about 5 mg of olanzapine, may be administered to an adult individual on the first day, followed by higher doses of olanzapine, such as 7.5 mg 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 intranasal olanzapine composition may comprise spraying one or more volumes of intranasal olanzapine composition into each nostril, such as spraying a first volume of intranasal olanzapine composition into a first nostril, followed by spraying a second volume of intranasal olanzapine composition into a second nostril. Optionally, a third and / or fourth volume of intranasal olanzapine composition may be administered after the first and second volumes. In any embodiment, one or more doses may be administered to achieve a therapeutically effective amount of olanzapine.

[0137] Other usage methods

[0138] The intranasal olanzapine compositions disclosed herein can also be used to treat one or more of the following: depression; agitation associated with neurodevelopmental disorders such as autism spectrum disorder; anger episodes associated with obsessive-compulsive disorder (OCD), Tourette's syndrome, and / or autism spectrum disorder. Therefore, this disclosure provides a method for inhibiting or reducing one or more of these conditions or symptoms in an individual in need (e.g., diagnosed with OCD, Tourette's syndrome, or autism spectrum disorder), the method comprising administering a therapeutically effective amount of olanzapine to the nasal mucosa of an individual via one or more doses of the intranasal olanzapine composition disclosed herein. In some embodiments, the intranasal olanzapine composition may be non-aqueous, a solution, or both. In some embodiments, a therapeutically effective amount of olanzapine or a pharmaceutically acceptable salt thereof is about 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof). In some embodiments, the intranasal olanzapine composition further comprises about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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. For example, a therapeutically effective dose of about 75 μL to about 150 μL of the intranasal olanzapine composition disclosed herein may comprise about 2.5 mg to about 10 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20 mg to about 0.50 mg of dodecyl maltodextrin, 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, the dose of the intranasal olanzapine composition may comprise about 2.5 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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, a therapeutically effective dose of intranasal olanzapine composition of about 75 μL to about 150 μL may contain about 2.5 mg to about 10 mg of olanzapine (or a pharmaceutically acceptable salt thereof), about 0.20% w / v to about 0.50% w / v of dodecyl maltodextrin, 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 from about 4:1 to about 1:4. In some embodiments, the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:2.

[0139] Therapeutic effects

[0140] Intranasal administration of a therapeutically effective amount of olanzapine to an individual in need via the olanzapine composition described herein can effectively alleviate one or more measurable symptoms of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, delirium, TRD, or chemotherapy-induced nausea and vomiting. In any embodiment, the therapeutically effective amount of the intranasal olanzapine composition may comprise: about 1 mg to about 15 mg of olanzapine; about 0.1 mg to about 1 mg of dodecyl maltodextrin; 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, or both. In some embodiments, the ratio of the polyethylene glycol to the 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. Intranasal administration of such compositions containing a therapeutically effective amount of olanzapine can provide an individual with one or more therapeutic benefits, some of which can be quantitatively or semi-quantitatively measured according to various assessments described below.

[0141] For example, in any embodiment, administering a therapeutically effective amount of olanzapine intranasally to an individual via an intranasal olanzapine composition as disclosed herein can reduce an individual's positive score, negative score, or overall (combined) PANSS (Positive and Negative Syndrome 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 point, and therefore, the minimum total score a patient will receive is 30.

[0142] Table 1

[0143]

[0144] In another instance, in any embodiment, intranasal administration of a therapeutically effective amount of olanzapine to an individual with schizophrenia via an intranasal olanzapine composition can reduce the individual's score on the Clinical Global Impression-Schizophrenia (CGI-S) scale. The CGI-S scale is a rating scale for the severity of symptoms, treatment response, and efficacy of treatment studies in patients with mental disorders. The scale comprises a three-item observer rating scale assessing the severity of the disorder, overall improvement, and an efficacy index. The severity scale is a 7-point scale ranking patients from 1 (normal, no disease at all) to 7 (among the most severely ill patients). The improvement scale ranks patients from 1 (significantly improved) to 7 (significantly worsened). The efficacy index is a 4×4 rating scale that assesses treatment effects and associated side effects, ranging from significant / great improvement to no change / worse, where side effects range from none to better than the treatment effect.

[0145] In yet another instance, and in any embodiment, intranasal administration of a therapeutically effective amount of olanzapine via the intranasal olanzapine composition disclosed herein to an individual experiencing agitation can improve the individual's scores on the Agitation Calmness Evaluation Scale (ACES) and / or the Agitated Behavior Scale (ABS). The ACES consists of individual items rating overall agitation and sedation at the time of evaluation, and its range is from 1 (significant agitation) to 9 (unable to be aroused), where 7 indicates significant calmness. The ABS measures the behavioral aspects of agitation and is calculated on a 56-point scale, summing the response values ​​for each of 14 questions, each describing the form of agitated behavior. The values ​​for each question range from 1 (absent) to 4 (extremely present).

[0146] In yet another instance, and in any embodiment, intranasal administration of a therapeutically effective amount of olanzapine via the intranasal olanzapine composition disclosed herein reduces the overall score on the Brief Psychiatric Rating Scale (BPRS). The BPRS rates a range of symptoms on a scale from 1 (absent) to 7 (extremely severe): physical problems, anxiety, emotional withdrawal, conceptual confusion, guilt, tension, behavior / posture, grandiosity, depressed mood, hostility, paranoia, hallucinatory behavior, tardiness, noncooperation, unusual thinking, emotional blunting, agitation, and disorientation.

[0147] In another instance, and in any embodiment, a therapeutically effective amount of olanzapine is administered intranasally to an individual experiencing a bipolar depressive episode via an intranasal olanzapine composition as disclosed herein, to reduce the individual's score on the Hamilton Depression Rating Scale. The Hamilton Depression (HAM-D) is a multi-item questionnaire assessing a variety of symptoms such as: 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-point or 5-point scale, where 0 represents normal or absent, and higher numbers indicate increased severity of symptoms.

[0148] In another instance, and in any embodiment, intranasal administration of a therapeutically effective amount of olanzapine via the intranasal olanzapine composition disclosed herein to an individual experiencing a bipolar depressive episode can improve the individual's scores on one or more of the following: the Loss of Motivated Behavior HAM-D factor, the HAM-D Suicide Item, the Hamilton Anxiety Scale, and the Beck's Depression Inventory. Each of these tests is familiar to those generally skilled in the art.

[0149] In another instance, and in any embodiment, intranasal administration of a therapeutically effective dose of olanzapine via the intranasal olanzapine composition disclosed herein to an individual experiencing a bipolar depressive episode improved the individual's Young's Mania Rating Scale (YMRS) score. The YMRS has 11 items and is based on the individual's subjective report of their own clinical condition in the preceding 48 hours.

[0150] Manufacturing method

[0151] In any embodiment, the intranasal olanzapine composition may be substantially free of olanzapine micron particles, nanoparticles, or combinations thereof. The order of addition of any component of the intranasal olanzapine composition is not particularly critical, the limiting factor being that olanzapine is completely or at least substantially dissolved in the composition. For example, in any embodiment, an intranasal olanzapine composition, which may be non-aqueous, a solution, or both, as disclosed herein, can be prepared by dissolving an alkyl glycoside (e.g., dodecyl maltodextrin) in DMA, followed by the addition and dissolution of olanzapine. Polyethylene glycol may then be added, and the resulting mixture may be stirred.

[0152] The formulation method can be adjusted to account for variations in the intranasal olanzapine composition. For example, the intranasal olanzapine composition can be prepared by first combining DMA and olanzapine and mixing until the components are homogeneous, then adding dodecyl maltodextrin and mixing until the dodecyl maltodextrin dissolves and the solution is homogeneous. The mixture can be brought to a final target weight of the intranasal olanzapine composition by adding a sufficient amount of polyethylene glycol. Intranasal olanzapine compositions prepared according to this method 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. The intranasal olanzapine compositions disclosed herein are suitable for administration to the nasal mucosa and can be formulated into sprayable olanzapine compositions comprising 1 mg to about 15 mg of olanzapine (or a pharmaceutically acceptable salt thereof) in an intranasal administerable volume, such as about 25 μL, 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.

[0153] Therefore, in another aspect, this disclosure provides a device suitable for intranasal delivery of any of the intranasal olanzapine compositions disclosed herein. Such devices may be provided or supplied as pre-activated devices, or may be activated by an individual prior to use. The device may be a metered device and / or a single-dose device, a dual-dose device, or a multi-dose device. Such devices typically include a piston, a vortex chamber, an actuator, and deliver a spray formed when the composition in the reservoir is forced out through the vortex chamber. An individual may actuate the device by holding it between a second and third finger and placing their thumb on the actuator. The device may additionally include a pressure point mechanism to ensure reproducibility of the actuation force and the characteristics of the emitted smoke / spray.

[0154] Administering device

[0155] Another aspect of this disclosure relates to a device suitable for nasal delivery of a composition as described above to an individual, the device comprising a reservoir configured to contain any one of the intranasal olanzapine compositions as described above. Specifically, such compositions may contain from about 1% w / v to about 15% w / v olanzapine, from about 0.1% w / v to about 1% w / v dodecyl maltodextrin, 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, the composition may contain from about 2.5% w / v to about 12% w / v olanzapine, from about 0.20% w / v to about 0.50% w / v, from about 30% w / v to about 40% w / v DMA, and from about 44% w / v to about 66% 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 from about 3:2. Such devices may optionally be supplied as pre-activated devices. Such devices may optionally be multi-dose devices having one or more reservoirs; in the latter case, each contains a single dose of intranasal olanzapine composition. Each single-dose reservoir may contain, for example, 25 μL to about 200 μL of intranasal olanzapine composition. Each multi-dose reservoir may contain up to 20 mL or more of intranasal olanzapine composition, depending on its therapeutic use.

[0156] As used herein, the term "pre-primed" refers to a device, such as a nasal spray, that delivers a pharmaceutical composition to a patient in need upon first actuation of the spray pump, i.e., without requiring activation of the pump prior to administration, such as by actuating the pump once or multiple times until the spray appears. As used herein, the term "actuate" refers to the operation of the device that causes the pharmaceutical composition to be delivered therefrom.

[0157] Pre-activated single-dose and multi-dose devices, consisting of a reservoir, piston, and vortex chamber, are suitable for delivering intranasal olanzapine compositions as described herein. A spray is formed when 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 incorporated into some devices ensures reproducibility of the actuation force and the characteristics of the emitted smoke stream. Currently, this type of device is used to deliver commercially available nasal migraine medications such as IMITREX® (GlaxoSmithKline, Brentford, UK) and ZOMIG® (Pfeiffer / Aptar single-dose device), the commercially available flu vaccine Flu-Mist (Becton Dickinson single-dose spray device), and the intranasal preparation of naloxone for opioid overdose resuscitation, NARCAN NASAL® (narcan.com; AdaptPharma).

[0158] For medications intended for single-dose or occasional use where strict control of dosage and composition is important, single-dose or dual-dose spray devices are preferred, such as those available from Apta (Crystal Lake, IL, USA). Other suitable devices that can be used to deliver the compositions described herein include, but are not limited to, simple variations of the single-dose spray device (MAD™) supplied by LMA Corporation (Salt Lake City, UT, USA). The nasal component with the spray tip is fitted onto a standard syringe. The liquid medication to be delivered is first drawn into the syringe, and then the spray tip is fitted onto the syringe. Another suitable device is a pre-filled device based on the same principle capable of delivering one or two doses (ACCUSPRAY™, Becton Dickinson Technologies, Research Triangle Park, NC, USA). The device disclosed herein can alternatively comprise a conventional, simple metered-dose spray pump, which requires startup and some degree of overfilling to maintain the dose at the labeled number. These designs are well-suited for daily drug administration over extended periods.

[0159] Embodiments of this disclosure:

[0160] In a first embodiment, this disclosure provides a composition comprising: about 1% w / v to about 15% w / v olanzapine or a pharmaceutically acceptable salt thereof; about 0.1% w / v to about 1% w / v dodecyl maltodextrin; 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.

[0161] The first embodiment may optionally include one or more of the following elements.

[0162] Element 1: The composition according to the first embodiment comprises about 2.5% w / v to about 12% w / v of olanzapine or a pharmaceutically acceptable salt thereof.

[0163] Element 2: The composition according to the first embodiment comprises about 0.20% w / v to about 0.50% w / v of the dodecyl maltodextrin, and optionally comprises Element 1.

[0164] Element 3: The composition according to the first embodiment contains about 34% w / v to about 38% w / v of the N,N-dimethylacetamide, and optionally contains Element 1 or Element 2.

[0165] Element 4: The composition according to the first embodiment, wherein the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da, and optionally includes one or more of elements 1 to 3.

[0166] Element 5: The composition according to the first embodiment, wherein the polyethylene glycol has an average molecular weight of about 600 Da, and optionally includes one or more of elements 1 to 4.

[0167] Element 6: The composition according to the first embodiment comprises about 44% w / v to about 66% w / v of the polyethylene glycol, and optionally comprises one or more of elements 1 to 5.

[0168] Element 7: The composition according to the first embodiment, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is from about 4:1 to about 1:4, and optionally includes one or more of elements 1 to 6.

[0169] Element 8: The composition according to the first embodiment, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is about 3:2, and optionally includes one or more of elements 1 to 7.

[0170] Element 9: The composition according to the first embodiment, wherein the amount of olanzapine or a pharmaceutically acceptable salt thereof is from about 2.5 mg to about 10 mg, and optionally contains one or more of elements 1 to 8.

[0171] Element 10: The composition according to the first embodiment, wherein the composition contains less than 0.1% w / v of water and optionally contains one or more of elements 1 to 9.

[0172] Element 11: The composition according to the first embodiment comprises about 2.5% w / v to about 12% w / v of the olanzapine or a therapeutically equivalent amount of olanzapine salt, about 0.20% w / v to about 0.50% w / v of the dodecyl maltodextrin, about 34% w / v to about 38% w / v of the N,N-dimethylacetamide and about 44% w / v to about 66% w / v of the polyethylene glycol, and optionally comprises one or more of elements 1 to 10.

[0173] In a second embodiment, this disclosure provides a disposable spray device comprising the composition according to Example 1, optionally combined with one or more of elements 1 to 11, the disposable spray device being configured to dispense a volume of the composition corresponding to 2.5 mg to 15 mg olanzapine upon actuation of the device.

[0174] In a third embodiment, this disclosure provides a quantitative, reusable spray device comprising the composition according to Example 1, optionally combined with one or more of elements 1 to 11, wherein the disposable spray device is configured to dispense a volume of the composition corresponding to 2.5 mg to 15 mg olanzapine upon actuation of the device.

[0175] In a fourth embodiment, this disclosure provides a method for treating acute agitation in an individual in need of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising administering intranasal administration of a composition comprising: about 1% w / v to about 15% w / v olanzapine or a pharmaceutically acceptable salt thereof, about 0.1% w / v to about 1% w / v dodecyl maltodextrin, 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.

[0176] Optionally, the method of the fourth embodiment further includes element 10: the severity of the individual's acute agitation decreases within approximately 20 minutes after administration.

[0177] In a fifth embodiment, this disclosure provides a method for treating depression associated with type I bipolar disorder, the method comprising administering intranasal administration to the nasal mucosa of an individual a composition comprising: about 1 mg to about 15 mg of olanzapine or a therapeutically equivalent amount of olanzapine salt, about 0.1 mg to about 1 mg of dodecyl maltodextrin, about 30 mg to about 40 mg of N,N-dimethylacetamide and about 40 mg to about 70 mg of polyethylene glycol, wherein said composition is a non-aqueous solution containing less than about 3% w / v of water.

[0178] In a sixth embodiment, this disclosure provides a method for treating mania associated with type I bipolar disorder, the method comprising administering intranasal administration of a composition comprising: about 1% w / v to about 15% w / v olanzapine or a therapeutically acceptable salt thereof, about 0.1% w / v to about 1% w / v dodecyl maltodextrin, 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.

[0179] In a seventh embodiment, this disclosure provides a method for treating mixed episodes associated with type I bipolar disorder, the method comprising administering intranasal administration of a composition comprising: about 1% w / v to about 15% w / v olanzapine or a therapeutically equivalent amount of olanzapine salt, about 0.1% w / v to about 1% w / v dodecyl maltodextrin, 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.

[0180] In an eighth embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting, the method comprising administering intranasal administration of a composition comprising: about 1 mg to about 15 mg of olanzapine or a therapeutically equivalent amount of olanzapine salt, about 0.1 mg to about 1 mg of dodecyl maltodextrin, 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 containing less than about 3% w / v of water.

[0181] Any of the fourth, fifth, sixth, seventh, or eighth embodiments may optionally include one or more of the following elements:

[0182] Element 12: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition comprises about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v of N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, and optionally comprises one or more of elements 1 to 11.

[0183] Element 13: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered for approximately 0.08 hours (4.8 minutes) (T) max The concentration of C reached approximately 31.513 ng / ml. max It may optionally include one or more of elements 1 to 12.

[0184] Element 14: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max It may optionally include one or more of elements 1 to 13.

[0185] Element 15: The method according to any one of the embodiments in the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC of approximately 509.81 ng·h / ml. 0-t It may optionally include one or more of elements 1 to 14.

[0186] Element 16: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC between about 323.9 ng·h / ml and about 695.72 ng·h / ml. 0-t It may optionally include one or more of elements 1 to 15.

[0187] Element 17: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to an AUC of approximately 526.47 ng·h / ml. ∞ It may optionally include one or more of elements 1 to 16.

[0188] Element 18: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC between about 329.22 ng·h / ml and about 723.72 ng·h / ml. ∞ It may optionally include one or more of elements 1 to 17.

[0189] Element 19: The method according to any of the embodiments in the fourth to eighth embodiments, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t It comprises approximately 85% to approximately 90%, and optionally includes one or more of elements 1 to 18.

[0190] Element 20: The method according to any one of the embodiments in the fourth to eighth embodiments, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ It comprises approximately 85% to approximately 90%, and optionally includes one or more of elements 1 to 19.

[0191] Element 21: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition comprises about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v of N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, and optionally comprises one or more of elements 1 to 20.

[0192] Element 22: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered at approximately 0.17 hours (10.2 minutes) (T max The concentration of C reached approximately 32.270 ng / ml. max and optionally includes one or more of elements 1 to 21.

[0193] Element 23: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. max It may optionally include one or more of elements 1 to 22.

[0194] Element 24: The method according to any one of the embodiments in the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC of about 463.45 ng·h / ml. 0-t It may optionally include one or more of elements 1 to 23.

[0195] Element 25: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC between about 388.89 ng·h / ml and about 538.01 ng·h / ml. 0-t It may optionally include one or more of elements 1 to 24.

[0196] Element 26: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC of approximately 474.91 ng·h / ml. ∞ It may optionally include one or more of elements 1 to 25.

[0197] Element 27: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC between about 399.14 ng·h / ml and about 550.68 ng·h / ml. ∞ It may optionally include one or more of elements 1 to 26.

[0198] Element 28: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition comprises an equivalent amount of olanzapine or a salt thereof of about 2.5% w / v to about 12% w / v, and optionally comprises one or more of elements 1 to 27.

[0199] Element 29: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition comprises an equivalent amount of olanzapine or a salt thereof at about 2.5% w / v to about 10% w / v, and optionally comprises one or more of elements 1 to 28.

[0200] Element 30: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition comprises about 0.20% w / v to about 0.50% w / v of the dodecyl maltodextrin, and optionally comprises one or more of elements 1 to 29.

[0201] Element 31: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition comprises about 34% w / v to about 38% w / v of the N,N-dimethylacetamide, and optionally comprises one or more of elements 1 to 30.

[0202] Element 32: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da, and optionally includes one or more of elements 1 to 31.

[0203] Element 33: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition comprises about 44% w / v to about 66% w / v of the polyethylene glycol, and optionally comprises one or more of elements 1 to 32.

[0204] Element 34: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition comprises about 2.5 mg to about 12 mg of the olanzapine or a therapeutically equivalent amount of olanzapine salt, about 0.20 mg to about 0.50 mg of dodecyl maltodextrin, about 34 mg to about 38 mg of the N,N-dimethylacetamide and about 44 mg to about 66 mg of polyethylene glycol, and optionally comprises one or more of elements 1 to 33.

[0205] Element 35: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition, and optionally includes one or more of elements 1 to 34.

[0206] Element 36: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual, and optionally comprises one or more of elements 1 to 35.

[0207] Element 37: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the depression, mania, mixed episodes or chemotherapy-induced nausea and vomiting are characterized by recurrent episodes, and wherein one or more of the frequency, duration and severity of the recurrent episodes are reduced, and optionally includes one or more of elements 1 to 36.

[0208] Element 38: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the individual is less likely to discontinue use of the composition after administration compared to the likelihood of discontinuing use of the intramuscular or oral olanzapine composition, and optionally includes one or more of elements 1 to 37.

[0209] Element 39: The method according to any of the embodiments of the fourth to eighth embodiments, wherein the composition contains less than about 1% w / v of water and optionally contains one or more of elements 1 to 38.

[0210] Element 40: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is about 4:1 to about 1:4, and optionally includes one or more of elements 1 to 39.

[0211] Element 41: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is about 3:2, and optionally further comprises one or more of elements 1 to 40.

[0212] In a ninth embodiment, this disclosure provides a method for treating acute agitation in an individual in need of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v water.

[0213] In a tenth embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

[0214] Any of the ninth or tenth embodiments may optionally include one or more of the following elements:

[0215] Element 42: The method according to any embodiment of the ninth or tenth embodiment, wherein the composition is administered at approximately 0.08 hours (4.8 minutes) (T) after administration. max The concentration of C reached approximately 31.513 ng / ml. max It may optionally include one or more of elements 1 to 41.

[0216] Element 43: The method according to any embodiment of the ninth or tenth embodiment, wherein the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max It may optionally include one or more of elements 1 to 42.

[0217] Element 44: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC of about 509.81 ng·h / ml. 0-t And optionally include one or more of elements 1 to 43.

[0218] Element 45: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC between about 323.9 ng·h / ml and about 695.72 ng·h / ml. 0-t And optionally include one or more of elements 1 to 44.

[0219] Element 46: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to an AUC of about 526.47 ng·h / ml. ∞ It may optionally include one or more of elements 1 to 45.

[0220] Element 47: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC between about 329.22 ng·h / ml and about 723.72 ng·h / ml. ∞ It may optionally include one or more of elements 1 to 46.

[0221] Element 48: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t It comprises approximately 85% to approximately 90%, and optionally includes one or more of elements 1 to 47.

[0222] Element 49: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ It comprises approximately 85% to approximately 90%, and optionally includes one or more of elements 1 to 48.

[0223] Element 50: The method according to any embodiment of the ninth or tenth embodiment, wherein the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da, and optionally includes one or more of elements 1 to 49.

[0224] Element 51: The method according to any embodiment of the ninth or tenth embodiment, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is from about 4:1 to about 1:4, and optionally includes one or more of elements 1 to 50.

[0225] Element 52: The method according to any embodiment of the ninth or tenth embodiment, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is about 3:2, and optionally includes one or more of elements 1 to 51.

[0226] Element 53: The method according to any embodiment of the ninth or tenth embodiment, wherein the composition contains less than 1% w / v water and optionally contains one or more of elements 1 to 53.

[0227] Element 54: The method according to any embodiment of the ninth or tenth embodiment, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition, and optionally includes one or more of elements 1 to 53.

[0228] Element 55: The method according to any embodiment of the ninth or tenth embodiment, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition, and optionally includes one or more of elements 1 to 54.

[0229] Element 56: The method according to any embodiment of the ninth or tenth embodiment, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual, and optionally comprises one or more of elements 1 to 55.

[0230] Element 57: The method according to any embodiment of the ninth or tenth embodiment, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual, and optionally comprises one or more of elements 1 to 56.

[0231] In an eleventh embodiment, this disclosure provides a method for treating acute agitation in an individual in need of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution comprising less than about 3% w / v water.

[0232] In a twelfth embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

[0233] Any of the eleventh or twelfth embodiments may optionally include one or more of the following elements:

[0234] Element 58: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the composition is administered at approximately 0.17 hours (10.2 minutes) (T max The concentration of C reached approximately 32.270 ng / ml. max It may optionally include one or more of elements 1 to 57.

[0235] Element 59: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the composition is administered at a time of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. max It may optionally include one or more of elements 1 to 58.

[0236] Element 60: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC of about 463.45 ng·h / ml. 0-t It may optionally include one or more of elements 1 to 59.

[0237] Element 61: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC between about 388.89 ng·h / ml and about 538.01 ng·h / ml. 0-t And optionally include one or more of elements 1 to 60.

[0238] Element 62: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC of approximately 474.91 ng·h / ml. ∞ It may optionally include one or more of elements 1 to 61.

[0239] Element 63: The method according to any one of the embodiments of the fourth to eighth embodiments, wherein the composition is administered to achieve an AUC between about 399.14 ng·h / ml and about 550.68 ng·h / ml. ∞ It may optionally include one or more of elements 1 to 62.

[0240] Element 64: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da, and optionally includes one or more of elements 1 to 63.

[0241] Element 65: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is from about 4:1 to about 1:4, and optionally includes one or more of elements 1 to 64.

[0242] Element 66: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is about 3:2, and optionally includes one or more of elements 1 to 65.

[0243] Element 67: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition, and optionally includes one or more of elements 1 to 66.

[0244] Element 68: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition, and optionally includes one or more of elements 1 to 67.

[0245] Element 69: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual, and optionally comprises one or more of elements 1 to 68.

[0246] Element 70: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual, and optionally comprises one or more of elements 1 to 69.

[0247] Element 71: The method according to any embodiment of the eleventh or twelfth embodiment, wherein the composition contains less than 1% w / v water and optionally contains one or more of elements 1 to 70.

[0248] In a thirteenth embodiment, in another embodiment, this disclosure provides a method for treating acute agitation in an individual in need of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising: intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.064 hours and 0.096 hours (T0.06). max The concentration of C10 was between approximately 25.210 ng / ml and approximately 37.816 ng / ml. max .

[0249] In a fourteenth embodiment, in another embodiment, this disclosure provides a method for treating acute agitation in an individual in need of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising: intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.136 hours and 0.204 hours (T0.05). max The concentration of C10 reached between approximately 25.816 ng / ml and approximately 38.724 ng / ml. max .

[0250] Any of the thirteenth or fourteenth embodiments may optionally include one or more of the following elements:

[0251] Element 72: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the composition is administered to achieve an AUC between about 407.85 ng·h / ml and about 611.772 ng·h / ml. 0-t And optionally include one or more of elements 1 to 71.

[0252] Element 73: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the composition is administered to achieve an AUC between about 421.18 ng·h / ml and about 631.76 ng·h / ml. ∞ And optionally include one or more of elements 1 to 72.

[0253] Element 74: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t It comprises approximately 85% to approximately 90%, and optionally includes one or more of elements 1 to 73.

[0254] Element 75: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ It comprises approximately 85% to approximately 90%, and optionally includes one or more of elements 1 to 74.

[0255] Element 76: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the composition further comprises one or more non-aqueous solvents and optionally comprises one or more of elements 1 to 75.

[0256] Element 77: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, benzoic acid methyl ester, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, capric triglyceride, or any combination thereof, and optionally includes one or more of elements 1 to 76.

[0257] Element 78: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof, and optionally comprises one or more of elements 1 to 77.

[0258] Element 79: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the diol or diol derivative may include, but is not limited to, propylene glycol, glycerol (anhydrous glycerol) or any combination thereof, and optionally includes one or more of elements 1 to 78.

[0259] Element 80: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the ester may include, but is not limited to, ethyl acetate, benzoic acid, or a combination thereof, and optionally includes one or more of elements 1 to 79.

[0260] Element 81: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the oil may include cottonseed oil, sesame oil, olive oil, soybean oil, castor oil, hydrogenated derivatives (e.g., Cremphor), eucalyptol, medium-chain triglycerides (MCT oil), or any combination thereof.

[0261] Element 82: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the ether may include, but is not limited to, diethylene glycol monoethyl ether (e.g., Transcutol) and optionally includes one or more of elements 1 to 81.

[0262] Element 83: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the dimethyl derivative or alkyl derivative may include, but is not limited to, dimethyl sulfoxide (DMSO), dimethyl isosorbide, or any combination thereof, and optionally includes one or more of elements 1 to 82.

[0263] Element 84: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the alkane may include, but is not limited to, isopropyl myristate and isopropyl palmitate, and optionally includes one or more of elements 1 to 83.

[0264] Element 85: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition, and optionally includes one or more of elements 1 to 84.

[0265] Element 86: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition, and optionally includes one or more of elements 1 to 85.

[0266] Element 87: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein administration comprises administering about 75 μL to about 200 μL of the composition to each nostril of the individual, and optionally comprising one or more of elements 1 to 86.

[0267] Element 88: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein administration comprises administering about 100 μL of the composition to each nostril of the individual, and optionally comprises one or more of elements 1 to 87.

[0268] Element 89: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the severity of the acute agitation of the individual decreases within approximately 5 minutes after administration, and optionally includes one or more of elements 1 to 88.

[0269] Element 90: The method according to any embodiment of the thirteenth or fourteenth embodiment, wherein the severity of the acute agitation of the individual decreases within approximately 20 minutes after administration, and optionally includes one or more of elements 1 to 89.

[0270] In a fifteenth embodiment, in another embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising: administering intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at a time between about 0.064 hours and 0.096 hours (T0.06). max The concentration of C10 was between approximately 25.210 ng / ml and approximately 37.816 ng / ml. max .

[0271] In a sixteenth embodiment, in another embodiment, this disclosure provides a method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising: administering intranasal administration of a composition comprising about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof to the nasal mucosa of the individual; wherein the composition is a non-aqueous solution comprising less than about 3% w / v water; and wherein the composition is administered at an interval between about 0.136 hours and 0.204 hours (T0). max The concentration of C10 reached between approximately 25.816 ng / ml and approximately 38.724 ng / ml. max .

[0272] Any of the fifteenth or sixteenth embodiments may optionally include one or more of the following elements:

[0273] Element 91: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the composition is administered to achieve an AUC between about 370.76 ng·h / ml and about 556.14 ng·h / ml. 0-t And optionally include one or more of elements 1 to 90.

[0274] Element 92: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the composition is administered to achieve an AUC between about 379.93 ng·h / ml and about 569.89 ng·h / ml.∞ It may optionally include one or more of elements 1 to 91.

[0275] Element 93: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t It comprises approximately 85% to approximately 90%, and optionally includes one or more of elements 1 to 92.

[0276] Element 94: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine ∞ It comprises approximately 85% to approximately 90%, and optionally includes one or more of elements 1 to 93.

[0277] Element 95: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the composition further comprises one or more non-aqueous solvents and optionally comprises one or more of elements 1 to 94.

[0278] Element 96: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, benzoyl benzoate, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, capric triglyceride, or any combination thereof, and optionally includes one or more of elements 1 to 95.

[0279] Element 97: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof, and optionally comprises one or more of elements 1 to 96.

[0280] Element 98: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the diol or diol derivative may include, but is not limited to, propylene glycol, glycerol (anhydrous glycerol) or any combination thereof, and optionally includes one or more of elements 1 to 97.

[0281] Element 99: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the ester may include, but is not limited to, ethyl acetate, benzoic acid, or a combination thereof, and optionally includes one or more of elements 1 to 98.

[0282] Element 100: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the oil may include cottonseed oil, sesame oil, olive oil, soybean oil, castor oil, hydrogenated derivatives (e.g., Cremphor), eucalyptol, medium-chain triglycerides (MCT oil) or any combination thereof, and optionally includes one or more of elements 1 to 99.

[0283] Element 101: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the ether may include, but is not limited to, diethylene glycol monoethyl ether (e.g., Transcutol), and optionally includes one or more of elements 1 to 100.

[0284] Element 102: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the dimethyl derivative or alkyl derivative may include, but is not limited to, dimethyl sulfoxide (DMSO), dimethyl isosorbide, or any combination thereof, and optionally includes one or more of elements 1 to 101.

[0285] Element 103: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the alkane may include, but is not limited to, isopropyl myristate and isopropyl palmitate, and optionally includes one or more of elements 1 to 102.

[0286] Element 104: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition, and optionally includes one or more of elements 1 to 103.

[0287] Element 105: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition, and optionally includes one or more of elements 1 to 104.

[0288] Element 106: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the administration comprises administering about 75 μL to about 200 μL of the composition to each nostril of the individual, and optionally comprising one or more of elements 1 to 105.

[0289] Element 107: The method according to any embodiment of the fifteenth or sixteenth embodiment, wherein the administration comprises administering about 100 μL of the composition to each nostril of the individual, and optionally comprises one or more of elements 1 to 106.

[0290] Example

[0291] Example 1: Blending ingredients

[0292] Various non-limiting examples of intranasal olanzapine compositions as described herein are provided in Table 2 below. Formulations represent 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 11 mg, 12 mg, and 15 mg of olanzapine. In any case, % 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 would contain approximately 2.38% w / w olanzapine. Similarly, 12 mg of olanzapine corresponds to 11.43% w / w olanzapine. In any embodiment, olanzapine may be present as a salt (e.g., a dicarboxylate, such as tartrate), a solvate (e.g., a hydrate), a polymorph, a eutectic, a complex, or any combination thereof. In any embodiment, the formulation may contain any amount of olanzapine, including amounts between those listed in Table 2. The composition may contain about 0.25 mg to about 0.5 mg of dodecyl maltodextrin, a constant amount of DMA (37.80 mg), and make-up to 105 mg of PEG-600. In any embodiment, the formulation may contain any amount of dodecyl maltodextrin, DMA, or PEG-600, including amounts between those listed in Table 2. It is worth noting that all compositions are solutions prepared in the absence of water and are non-aqueous. Each of these formulations yields approximately 100 μL of solution, and therefore each value also represents a weight / volume amount.

[0293] Table 2

[0294]

[0295] Example 2: Compound Development

[0296] The formulation development strategy is based on the need to develop formulations with appropriate quality characteristics for convenient single-dose delivery of nasal therapeutic doses, high patient acceptability and ease of use for self-administration or caregiver administration. Under this premise, an initial Quality Target Product Profile (QTPP) was developed (Table 2).

[0297] Table 3

[0298]

[0299] In addition to the elements detailed in Table 3, the elements of the potential delivery system (sprayer) are also important to QTPP. Table 4 describes the combined product quality attributes.

[0300] Table 4

[0301]

[0302] Table 5 summarizes the quality attributes of pharmaceutical products and details which attributes are classified as critical quality attributes (CQAs). For product, appearance, olanzapine content determination, and related substances, Intravail A3 content determination, particulate matter, moisture, and microbiological quality were identified as subsets of CQAs. These subsets can be influenced by raw materials and processing and are therefore assessed in initial formulation development studies. For initial studies, the focus is primarily on appearance, olanzapine content determination, and related substances, as these attributes guide the selection of solvent systems. Due to the non-aqueous composition and low residual moisture content of the formulation, microbiological quality is assumed to be low-risk at this stage.

[0303] During the initial phase, the combined product CQA (such as pump performance parameters (pump delivery, spray content uniformity, droplet size distribution, smoke geometry / spray pattern, and actuation force) and container closure integrity were not formally evaluated. The proven track record of using commercially available installations provides a high degree of assurance that these factors will not pose a problem for the development program. Informal assessments of compatibility with the closure were conducted and showed no issues.

[0304] Table 5

[0305]

[0306] As outlined above, the primary objective of the initial formulation development program is to achieve adequate solubility and stability of the drug substance in acceptable solvent systems, thereby allowing for the full dose to be administered in a single 100 μL actuation. Olanzapine exhibits poor aqueous stability and solubility. Some basic olanzapine physicochemical parameters include: Class 2 BCS, solubility of 0.02 mg / mL in water at pH 6.8, solubility of 0.034 mg / mL in water at 37°C, and pKa of 4.01 and 7.24. To achieve the highest desired dose, a target concentration of 100 mg / mL will be required to ensure a robust formulation, and therefore a water-based system would not meet some key QTPP attributes.

[0307] Therefore, non-aqueous systems were explored. Solvent selection was limited to pharmaceutically acceptable excipients listed in the FDA Inactive Ingredient Database (IID). It should be understood that the solvent content in the olanzapine formulations described herein may exceed the levels listed as safe. Therefore, safety evidence for the solvent content presented in the olanzapine nasal spray was established, taking into account the use cases (e.g., patient population, dosage, and duration of exposure). To support the formulation evaluation, stability indication methods were reviewed in the literature, and one method was selected to provide an assessment of key degradation products.

[0308] As a starting point, non-aqueous solvents from the approved intranasal formulations were tested. Specifically, vitamin E, benzyl alcohol, and ethanol were evaluated. After two weeks at 40°C, significant incompatibility between olanzapine and individual solvents became apparent, as indicated by the increase in degradation products and color changes. The importance of the presence of oxygen for degradation was investigated using nitrogen headspace, and its effect on the stability of this formulation series was found to be minimal.

[0309] Other solvents, including cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, methyl benzoate, cyclodextrin, and sterile water for injection, were also tested, resulting in poor solubility, poor stability, or a combination thereof. Several of these solvents were also tested with micronized olanzapine, which also resulted in poor solubility, poor stability, or a combination thereof.

[0310] Subsequently, a broad screening approach was employed with and without nitrogen headspace using a range of solvents, including oils, glycols, nonionic surfactants, and terpenoids. After one week at 40°C, the relevant substances ranged from 1% to 12%, with results varying significantly between solvents, and glycols showing the most promise. Generally, nitrogen headspace did not provide significant improvement, even when the primary degradation products were oxidative degradation products. Except for polyethylene glycol, dimethylacetamide exhibited good stability during the initial screening. It should also be noted that several of the solvents evaluated (including PEG) did not possess sufficient solubility to meet the QTPP solubility criteria.

[0311] Next, dimethylacetamide and PEG400 were individually evaluated at approximately 5 mg / mL over a two-month period at 40°C. The concentration was relatively low relative to the high target of 100 mg / mL due to the poor solubility of PEG. The stability results for both solvents were encouraging, as there was no significant increase in USP-related compounds B and C (major hydrolysis / oxidative degradation products) compared to previously studied solvent systems. Dimethylacetamide exhibited better stability characteristics than PEG 400. Based on these data, a further series of experiments was initiated, including evaluating the viscosity of the dimethylacetamide / PEG 200 binary solvent system, as well as the solubility and stability of olanzapine.

[0312] An investigation into the solubility profile of olanzapine in PEG 200 / dimethylacetamide was conducted 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 the content was determined. Data from these experiments are tabulated in Table 6, and... Figure 1 The information is presented graphically. It also compares the impurity profiles, and... Figure 2 The chromatogram is provided.

[0313] Table 6

[0314]

[0315] Based on solubility and stability data, and the requirement for a maximum concentration of at least 100 mg / mL, it was determined that a robust formulation could be achieved using a composition containing more than approximately 40% dimethylacetamide. It should be noted that USP olanzapine-related compound C (EP impurity D) was detected in solutions containing higher amounts of PEG 200, which also supports increasing the dimethylacetamide content.

[0316] Additional freeze-thaw experiments were conducted using 180 mg / g solutions in 60 / 40 dimethylacetamide / PEG 200, 80 / 20 dimethylacetamide / PEG 200, and 100% dimethylacetamide. The solutions were subjected to five freeze-thaw cycles to confirm the robustness of the formulations. No changes in appearance were observed, thus confirming the absence of the possibility of crystallization due to freezing / seedling introduction.

[0317] The viscosity of the three formulations was also measured. The values ​​ranged from 1.9 cP (100% dimethylacetamide) to 8.3 cP (60 / 40 dimethylacetamide / PEG 200).

[0318] At this point, it was concluded that formulations consisting of a binary mixture of PEG and dimethylacetamide may be feasible for further development. Sufficient solubility has been demonstrated, and the viscosity is acceptable (although an increase would be desirable to enhance residence time in the nose after dosing), but further work is needed on the effects of stability and PEG content.

[0319] New stability studies were initiated using two formulations: 50 / 50 dimethylacetamide / PEG 200 containing 150 mg / mL olanzapine and PEG 200 containing 10 mg / mL olanzapine. Appearance, assays, and related substances were monitored for both formulations over a three-month period, with samples stored at 5°C, 25°C / 60% RH, and 40°C / 75% RH. The 50 / 50 dimethylacetamide / PEG 200 formulation was also evaluated at six months. Data are summarized in Table 7. Figure 3 and Figure 4 The software provides an overlay of three months' worth of chromatograms.

[0320] Table 7

[0321]

[0322] Several conclusions can be drawn from these data: the results showed degradation in both samples, but it was most pronounced in the PEG 200 sample containing 10 mg / mL olanzapine; temperature was a significant factor in the overall formulation stability. A series of peaks characterizing the polymer were observed in both samples, suggesting the reaction of olanzapine with different polymer chains or potential polymer self-degradation; these peaks were most prevalent in the 10 mg / mL formulation of 100% PEG 200.

[0323] These data indicate that stable formulations are possible, but further optimization of PEG content (and grade) is needed to maximize product stability.

[0324] As a first step, the solubility of mixtures of dimethylacetamide and different molecular weight grades of PEG was evaluated, which has two potential benefits. First, higher molecular weight PEG will impart a higher viscosity to the final formulation, potentially enhancing nasal retention time. Second, higher molecular weight polymers will have fewer residual hydroxyl groups, thus minimizing the suspected drug-excipient interaction observed in the case of PEG 200. PEG 600 and PEG 1000 were selected for this screening because their molecular weights are significantly higher than PEG 200 used to date, with 3 to 5 times fewer hydroxyl groups and higher viscosity. Higher molecular weight PEGs (>1000) were excluded because of their poor miscibility with dimethylacetamide (e.g., PEG 3350 is insoluble in 60–90% dimethylacetamide) and the need for heating to aid dissolution (PEG 600 melts in the range of 15–25 °C, PEG 1000 melts in the range of 37–40 °C, and PEG 3350 melts in the range of 50–54 °C). An overview of the solubility data is provided in Table 8.

[0325] Table 8

[0326]

[0327] Data shows that sufficient olanzapine solubility was achieved at PEG 600 concentrations as low as 40%, and olanzapine solubility was also higher than the maximum target concentration of 100 mg / mL in 70% PEG 600 and 30% dimethylacetamide. PEG 1000 was soluble in dimethylacetamide at 40% concentration, but insoluble at higher concentrations.

[0328] Based on this information, PEG 600 was selected for further evaluation. As a first step, a series of formulations containing olanzapine and Intravail A3 were prepared. The solubility and freeze-thaw characteristics of the formulations were evaluated. The composition of the formulations is detailed in Table 9, and the results of the solubility and freeze-thaw studies are detailed in Table 10.

[0329] Table 9

[0330]

[0331] The solvent ratio is by weight and is calculated using a PEG density of 1.15 and a dimethylacetamide density of 0.94.

[0332] Table 10

[0333]

[0334] These data narrowed the range of formulations to a maximum PEG 600 content of 60%. Subsequently, three-month stability studies were conducted at -20°C, 25°C / 60% RH, and 40°C / 75% RH. Formulations B through E, as well as equivalents to formulation B prepared with PEG 200 instead of PEG 600, were placed under stability conditions to allow for direct comparison between PEG grades. The evaluation of formulations B and E was extended to include 6-month and 12-month time points at 40°C / 75% RH and 25°C / 60% RH. Data are presented in Tables 11 through 15.

[0335] At the start of the stability study, the analytical method qualification had not yet been completed. For the initial time point (T-0), the correlated substance values ​​were high due to sample degradation after preparation and before analysis. The method was subsequently modified to address this issue, which explained the high initial correlated substance data at T-0 relative to later time points (particularly the peaks at RRT 1.61 and RRT 1.76).

[0336] Table 11

[0337]

[0338] ND = Not detected; NT = Not tested; RRT = Relative residence time; USP RB = USP olanzapine-related compound B; USP RC = USP olanzapine-related compound C

[0339] Table 12

[0340]

[0341] BLQ = Below quantification (0.1%); ND = Not detected; NT = Not tested; RRT = Relative residence time; USP RB = USP olanzapine-related compound B; USP RC = USP olanzapine-related compound C

[0342] Table 13

[0343]

[0344] BLQ = Below quantification (0.1%); ND = Not detected; NT = Not tested; RRT = Relative residence time; USP RB = USP olanzapine-related compound B; USP RC = USP olanzapine-related compound C

[0345] Table 14

[0346]

[0347] BLQ = Below quantification (0.1%); ND = Not detected; NT = Not tested; RRT = Relative residence time; USP RB = USP olanzapine-related compound B; USP RC = USP olanzapine-related compound C

[0348] Table 15

[0349]

[0350] BLQ = Below quantification (0.1%); ND = Not detected; NT = Not tested; RRT = Relative residence time; USP RB = USP olanzapine-related compound B; USP RC = USP olanzapine-related compound C

[0351] In summary, these initial data demonstrate that the product maintained its quality characteristics throughout the study period. PEG 600 showed improved compatibility compared to PEG 200, and the stability of related substances improved slightly as the PEG 600 content decreased. However, 12-month and 6-month data for a 60:40 PEG600:dimethylacetamide formulation containing 120 mg / mL olanzapine at 25°C / 60% RH and 40°C / 75% RH, respectively, demonstrate that the product has satisfactory quality characteristics. It should be noted that at the 6-month and 12-month time points, some individual related substances appeared to have decreased. This is likely due to secondary degradation of these related substances, even though formal studies have not yet begun at this stage of development. The solution darkening is due to a slight increase in degradation products. The degradation products at RRT 1.82 exhibit significant absorption in the visible spectrum and are likely the main cause of the color change. Other characteristics remained unchanged. Based on the stability data, a formulation using a 60:40 PEG 600:dimethylacetamide ratio was selected for further development.

[0352] The drug product is a true solution, and therefore the solubility of olanzapine in the solvent system is a key physicochemical parameter to ensure that it remains dissolved and can be delivered reproducibly according to dosage and spray characteristics.

[0353] To date, olanza has been used in an average of well-defined crystal forms, and formulation studies have identified solvent compositions with excess solubility exceeding the target maximum concentration of 100 mg / mL. Furthermore, freeze-thaw studies of the formulations have demonstrated their robustness to temperature fluctuations.

[0354] Example 3: A pilot, phase 1, single-dose, open-label, randomized, parallel-group study to characterize the pharmacokinetics, safety, and tolerability of intramuscular and intranasal formulations of olanzapine in healthy male individuals.

[0355] The primary objective of this study was to characterize the pharmacokinetic profile of olanzapine in healthy males following a single intramuscular (IM) injection of 7.5 mg (Zyprexa), a single nasal spray injection of 7.5 mg of a solution containing 0.25% Intravail® A3 absorption enhancer (NRL-4A), and a single nasal spray injection of 7.5 mg of a solution containing 0.50% Intravail A3 absorption enhancer (NRL-4B). A secondary objective was to evaluate the safety and tolerability of olanzapine administered in healthy males in the form of a single 7.5 mg nasal spray injection with 0.25% Intravail® A3 absorption enhancer (NRL-4A) and a single nasal spray injection with 0.50% Intravail® A3 absorption enhancer (NRL-4B), compared to a single IM injection of 7.5 mg olanzapine (Zyprexa).

[0356] During an acute agitation episode, commonly used pharmacological treatments include the delivery of benzodiazepines and antipsychotics via intramuscular or intravenous routes to facilitate rapid drug action. However, these administrations can result in injury to staff and / or individuals, especially when the individual is agitated, and are often considered humiliating. Furthermore, administration requires trained healthcare workers, and its use is limited to clinics, emergency rooms, hospitals, or psychiatric wards.

[0357] Intranasal (IN) drug delivery is a preferred alternative because it is a practical, non-invasive administration option that is easy to self-administer or administered by a healthcare provider or family member. It offers rapid onset of action (potentially equivalent to intranasal infusion), avoids first-pass metabolism, and has good bioavailability, potentially resulting in a better safety profile by reducing dose-related side effects. Agitated, often psychotic individuals living alone may not be able to wait several hours for the therapeutic effect of an oral formulation or travel to an emergency room or health center for an intranasal infusion; therefore, ready-to-use IN formulations are easy to carry and administer, making them an attractive option in any social setting other than an emergency room or health center.

[0358] This is a pilot phase 1, open-label, randomized, parallel-group clinical study designed to compare the pharmacokinetics, safety, and tolerability of olanzapine IM (Zyprexa) and IN (NRL-4A and NRL-4B) formulations in healthy male individuals.

[0359] The study will include screening, followed by baseline and an open-label treatment period. Individuals will be admitted to the Clinical Research Unit (CRU) on Day -1 (the day before administration) for evaluation to reconfirm their eligibility for the study. Individuals will remain in the CRU until Day 4 for post-administration evaluation and sample collection. The individual's discharge time from the CRU can be arranged with ward staff, but the individual must return for all designated PK samples and be observed at the scheduled time.

[0360] Approximately 24 healthy male individuals aged 18 to 55 years (inclusive) were randomized in a 1:1:1 ratio to three treatment groups and received a single dose of olanzapine via intramuscular (IM) injection (7.5 mg olanzapine (Zyprexa) via IM) or one of two intranasal preparations while lying down for up to 2 hours. Individuals were instructed to drink at least 8 ounces (oz.) of fluid prior to administration. The intranasal preparations were preparations 5 and 6 in Table 2: 7.5 mg olanzapine + 0.25 mg dodecyl maltodextrin or 7.5 mg olanzapine + 0.50 mg dodecyl maltodextrin. Safety assessments were performed after each administration and included physical examination, vital sign measurements (e.g., blood pressure, heart rate), ECG, and clinical laboratory tests. The incidence of self-reported dizziness or lightheadedness was noted. Objective evaluation of nasal irritation was assessed using a 6-point (0–5) scale after each intranasal administration. Trained observers scored the nasal mucosa based on assessments at baseline and 30 minutes (±5 min) and 1 hour (±10 min), 2 hours (±15 min), 4 hours (±30 min), 6 hours (±30 min), 8 hours (±30 min), and 24 hours (±30 min) after administration. Irritation was assessed by evaluating the degree of mucosal inflammation and bleeding. Individuals were required to report any bleeding or inflammatory events between the actual assessment time points.

[0361] Blood pressure (BP) and pulse were measured after each administration of the study drug. BP and pulse were obtained at baseline, before administration, and at 15 minutes (± 2 min), 30 minutes (± 2 min), and 45 minutes (± 5 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 were also collected while the individual was sitting and after standing for 3 minutes. Any sensations of dizziness or lightheadedness were also inquired about by trained observers.

[0362] Injection site reaction was assessed using a 6-point (0-5) scale after each IM administration. Trained observers assessed the IM injection site at baseline and at 30 minutes (±5 min) and 1 hour (±10 min), 2 hours (±15 min), 4 hours (±30 min), 6 hours (±30 min), 8 hours (±30 min), and 24 hours (±30 min) post-administration. Individuals were required to report any injection site reaction events between the actual assessment time points.

[0363] An objective assessment of pain will be conducted using an 11-point Numerical Rating Scale (NRS; 0 to 10), where 0 signifies “no pain” and 10 signifies “the worst imaginable pain.” Individuals will report pain scores at baseline (before administration) and at 15 minutes (±2 min), 30 minutes (±5 min), 1 hour (±10 min), 2 hours (±15 min), 4 hours (±30 min), 6 hours (±30 min), and 8 hours (±30 min) after administration.

[0364] Sedation was objectively assessed using a 6-point (0 to 5) sedation rating scale to evaluate the degree of drowsiness in individuals after each administration of the study drug. Sedation scores were reported by individuals (if awake) and trained observers using the same rating scale at baseline and at 15 minutes (± 2 min) and 30 minutes (± 5 min) and at 1 hour (± 10 min), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), and 8 hours (± 30 min) after administration. The trained observers also inquired about the degree of drowsiness in individuals.

[0365] Blood samples were collected before administration (0, before administration), and at 5, 10, 15, 30, and 45 minutes after administration, and at 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, 144 hours, 192 hours, and 240 hours after administration to measure the plasma concentration of olanzapine. Actual blood collection times may vary as follows: 1) ±1 minute for 5-minute and 10-minute samples; 2) ±2 minutes for 15-minute to 60-minute samples; 3) ±5 minutes for 1.25-hour to 8-hour samples; 4) ±15 minutes for 12-hour and 24-hour samples; 5) ±2 hours for 36-hour and 48-hour samples; 6) ±6 hours for 72-hour and 96-hour samples; and 7) ±24 hours for 144-hour, 192-hour, and 240-hour samples.

[0366] Suicidal tendencies were recorded using the Columbia Suicide Severity Rating Scale (C-SSRS), a measure of suicidal ideation and behavior, in order to classify suicide events using the Columbia Classification Algorithm of Suicide Assessment. Suicidal tendencies were assessed at screening, at baseline, and before discharge from the clinical research ward.

[0367] Inclusion criteria included (1) a weight of 51 kg to 111 kg and a body mass index of 18 to 35 kg / m². 2(1) Within the range, including the extreme values; (2) Male individuals aged 18 to 55 years, including the extreme values; (3) No clinically significant abnormalities found in medical history, physical examination, electrocardiogram (based on QTc values ​​obtained within a short recording period, with a corrected QT interval (QTcF) <450 ms; or for individuals with bundle branch block, a corrected QT interval <480 ms), or in clinical laboratory results during screening; (4) No clinically significant abnormalities (in the investigator's opinion) as assessed by review of medical and surgical history, physical examination, vital sign measurements, ECG, and laboratory evaluations conducted during screening and entry into the CRU; (5) Normal blood pressure (BP) (systolic BP 90 to 140 mmHg, including the extreme values, diastolic BP <90 mmHg) and pulse rate (50 to 100 beats / min, including the extreme values). Exclusion criteria include (1) unstable medical conditions; any clinical or laboratory measurements (including ECG, hematological, biochemical, and urinalysis) assessed by the researcher as clinically relevant; a current or prior clinically significant history of the following conditions as determined by the researcher: heart disease, cardiovascular or cerebrovascular disease, respiratory disease, gastrointestinal disease, endocrine disease, hematological disease, psychosis (specifically schizophrenia, schizoaffective disorder, type I bipolar disorder, or major depressive disorder), kidney disease, liver disease, lung disease, or neurological disease; use of drugs that may alter the absorption, metabolism, or elimination of IP, or cause danger, or other drugs or diseases that interfere with the interpretation of study data; (2) a history of the following: seasonal or non-seasonal allergies, nasal polyps, or any nasal passage abnormalities that may interfere with nasal spray administration, or any other condition that, in the researcher's opinion, may jeopardize the individual's safety or affect the validity of the study results; (3) The following are clear or suspected personal or family medical histories: (4) adverse reactions or hypersensitivity to IP or drugs with similar chemical structures (history of sensitivity to any IP or its components, or history of drug or other allergies that the researchers or medical monitors deem unsuitable for participation); (5) any clinically significant illness within 4 weeks prior to enrollment; (6) a lifetime history of alcohol or drug abuse, or a positive test for opioids, cocaine, benzodiazepines, barbiturate, or amphetamine, or a history of illicit drug use (intermittent cannabis use, defined as permitted more than once a week, but not occurring within 1 week prior to screening and during the duration of the study); (7) significant traumatic injury, major surgery, or open biopsy within 30 days prior to screening; (8) a history of major depressive disorder or suicide attempt.(8) At the time of screening, the researcher judged a significant risk of suicide, violence, or homicide (suicide risk is defined as answering 'yes' to item 4 or 5 on the suicidal ideation section of the Columbia Suicide Severity Rating Scale (C-SSRS), or having attempted suicide within 18 months prior to screening); (9) History of orthostatic tachycardia syndrome, or orthostatic hypotension when standing during the physical examination at the time of screening; (10) History of allergy or adverse reaction to any of the components of olanzapine or IP; (11) Participation in a clinical trial (excluding participation in an observational (non-invasive) study) within 30 days prior to the first dose of the study drug, provided there is no scheduling conflict with the study; (12) Use of over-the-counter products and natural health products (including herbs, homeopathic and traditional medicines, probiotics, food supplements (such as vitamins, minerals, amino acids, essential fatty acids, and protein supplements used in exercise)) and occasional use of paracetamol (up to 2 doses per day) within 14 days prior to IP administration. (g) except; (13) intravenous access that may affect the quality of PK samples or the time of collection is insufficient or difficult; (14) a positive blood screening for HIV, hepatitis B surface antigen (HbSAg), or hepatitis C at screening or baseline; (15) a positive urine screening for alcohol, drug abuse (excluding marijuana), or cotinine at screening or baseline; (16) incapacity, whether mental or legal; (17) unwillingness or inability to follow the procedures outlined in the protocol; (18) other conditions that, in the investigator's judgment, render the individual unfit for clinical research.

[0368] The primary endpoints of this study will include: plasma concentrations of olanzapine obtained from serial PK sampling after IM and IN administration; the observed maximum plasma concentration (Cmax); the time to reach the maximum plasma concentration (Tmax); the area under the concentration-time curve (AUC) in plasma from time zero to the last quantifiable concentration (AUC0-t); the AUC in plasma extrapolated from time zero to infinity (AUC0-∞); the terminal elimination half-life of olanzapine in plasma (t1 / 2); the terminal elimination rate constant (λz); the apparent clearance of olanzapine in plasma without correction for bioavailability (F) (CL / F); and the apparent volume of distribution of olanzapine in plasma during the terminal phase (Vz / F).

[0369] Safety endpoints will include the incidence of adverse events (AEs) and serious AEs; laboratory, vital signs and ECG values; concomitant medications; mental status assessment using the C-SSRS; and biometric assessments: nasal irritation, sedation and pain scores.

[0370] The analysis will include the entire population, the population that can be evaluated by PK, and the population that is safe.

[0371] PK complete population: All individuals who received a known amount of IP and had at least one quantifiable concentration of olanzapine in their plasma.

[0372] PK evaluable population: All individuals that have a known amount of IP and at least one estimable PK parameter.

[0373] Security Group: All individuals accepting any number of IPs. Security Assessment:

[0374] Adverse events will be collected and reviewed to evaluate the safety and tolerability of olanzapine nasal spray solution compared to intranasal injection. Other safety measures will include physical examination, vital sign measurement, ECG, and clinical laboratory testing.

[0375] Blood pressure, pulse rate, body temperature, and respiratory rate will be measured before administration (baseline) and at 15 (±2) minutes, 30 (±2) minutes, 45 (±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 will be collected while the individual is supine and 3 minutes after they have stood. Trained observers will also ask individuals about any feelings of dizziness or lightheadedness.

[0376] Objective assessments of nasal irritation will be conducted using a 6-point (0 to 4) rating system following administration of the intranasal injection (IN) to the intranasal injection (IP) (Groups 2 and 3). Training observers will score the nasal irritation based on assessments of the nasal mucosa at pre-administration (baseline), and at 5 (±1) minutes, 10 (±2) minutes, 30 (±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, as well as on day 14 (end of the study). Individuals will also be required to report any bleeding or inflammatory events between the actual assessment time points.

[0377] A 6-point (0 to 5) sedation rating system will be used to objectively assess sedation levels in individuals following administration of intravenous injection (IP). Sedation scores will be reported using the same rating scale by individuals (if awake) and by trained observers at baseline, and at 15 (±2) minutes, 30 (±5) minutes, 1 hour (±10) minutes, 2 hours (±15) minutes, 4 hours (±30) minutes, 6 hours (±30) minutes, and 8 hours (±30) minutes after administration. Trained observers will also inquire about the degree of sedation in individuals.

[0378] An 11-point NRS (0 to 10) will be used to assess the objective evaluation of pain, where 0 means "no pain" and 10 means "the worst imaginable pain". Pain scores will be reported by individuals before administration (baseline) and at 15 (±2) minutes, 30 (±5) minutes, 1 hour (±10) minutes, 2 hours (±15) minutes, 4 hours (±30) minutes, 6 hours (±30) minutes, and 8 hours (±30) minutes after administration.

[0379] The C-SSRS (a measure of suicidal ideation and behavior) will be used to record suicidal tendencies so that the Columbia Suicide Assessment Classification (CSCC) algorithm can be used to classify suicide events. Suicidal tendencies will be assessed at screening, at baseline, and before discharge from the CRU.

[0380] All safety assessments, demographic variables, and treatment data will be presented in the individual data list. Descriptive statistics will be used to list and summarize study results. Background and demographic characteristics will be presented. Continuous variables will be summarized using descriptive statistics (sample size, mean, standard deviation, median, minimum, and maximum). Discrete variables will be summarized using frequencies and percentages. Tabular summaries will be presented by treatment and time point where appropriate.

[0381] For statistical purposes, treatment will be defined by three treatment groups: a single dose of olanzapine 7.5 mg (Zyprexa) administered via intramuscular injection; a single dose of olanzapine 7.5 mg solution with 0.25% Intravail A3 absorption enhancer administered via nasal spray; and a single dose of olanzapine 7.5 mg solution with 0.50% Intravail A3 absorption enhancer administered via nasal spray.

[0382] Electrocardiogram, vital signs, and clinical laboratory test data (observed and relative to baseline) will be summarized by time points using appropriate descriptive statistics.

[0383] The table will show the deviations of chemical and hematological laboratory parameters relative to the baseline. Any ECG abnormalities should be confirmed by a trained cardiologist.

[0384] Adverse events will be summarized by presenting the number and percentage of individuals experiencing any adverse event. The number and percentage of individuals reporting AEs during treatment will be tabulated by system organ class and preferred terminology (coded using the Medical Dictionary for Regulatory Activities). AEs during treatment will be further categorized by severity and relation to treatment.

[0385] Frequency tables will be used to summarize the safety measurements of sedation. Where data permits, frequency tables will be used to summarize C-SSRS results.

[0386] Individual plasma concentrations, actual sampling time, and PK parameters will be listed by treatment. Descriptive statistics for plasma concentrations and PK parameters will be calculated by treatment. Individual and mean plasma concentrations will be displayed graphically on linear and semi-logarithmic axes.

[0387] An analysis of variance (ANOVA) model will be used, with treatment as a fixed effect, and the natural logarithm of the PK parameters will be used to compare the PK parameters Cmax, AUC0-t, and AUC0-∞ of olanzapine between treatments. For each PK parameter, a confidence interval (CI; 90%) for the geometric mean ratio of olanzapine nasal (test) to olanzapine IM (reference) will be constructed using a two-tailed t-test procedure. Point estimates and confidence limits will be exponentially transformed to restore them to the original scale. The comparability between olanzapine nasal (test) and olanzapine IM (reference) will be assessed based on the geometric mean ratio and 90% CI of the responses to each PK parameter.

[0388] Approximately 24 healthy male individuals (8 individuals in each treatment group). An interim analysis is planned after 6 individuals in each treatment group have completed the observation period and PK results are available to determine if additional individuals are needed. Variance estimates obtained from an ANOVA model based on the primary endpoint (AUC, Cmax) of the previous batch of N=18 individuals will be used to examine the power of the statistical tests. Evidence of high variability in the PK parameters (coefficient of variation ≥30%) will suggest that at least N=24 individuals be enrolled as planned.

[0389] Each individual will participate in the study for up to 35 days, which includes a 21-day screening period and a 14-day treatment period, including a 4-day stay in the CRU and a 10-day follow-up period.

[0390] The mean pharmacokinetic characteristics of olanzapine after treatment with 7.5 mg solution of 0.25% Intravail® A3 absorption enhancer via nasal spray (NRL-4A) (Test Product I (Treatment A)), 7.5 mg solution of 0.50% Intravail A3 absorption enhancer via nasal spray (NRL-4B) (Test Product II (Treatment B)), and 7.5 mg via intramuscular (IM) injection (Zyprexa) (Reference Product (Treatment C)) are as follows:

[0391] Table 16 - Pharmacokinetic Parameters

[0392]

[0393] Median (range)

[0394] The bioequivalence confidence interval, power, and inter-individual CV% for olanzapine test product I (treatment A) relative to the reference product (treatment C) are as follows:

[0395] Table 17 - Comparison of bioequivalence of olanzapine

[0396]

[0397] %

[0398] The bioequivalence confidence interval, power, and inter-individual CV% for olanzapine test product II (treatment B) relative to the reference product (treatment C) are as follows:

[0399] Table 18 - Comparison of bioequivalence of olanzapine

[0400]

[0401]

[0402]

[0403] Twenty-four individuals experienced sedation while receiving olanzapine treatment A, B, or C during the study period, and 16 individuals experienced burning sensation while receiving olanzapine treatment A or B. These adverse events were mild in intensity and classified as possibly relevant. A total of 24 treatment-emergent adverse events (TEAEs) were reported in 24 individuals (100%) following treatment A, B, or C. At follow-up, no clinically significant changes were observed in laboratory tests or vital signs in all individuals, but all individuals experienced burning sensation while receiving olanzapine treatment A or B during the study period. No serious adverse events occurred during the study period. Both the test product and the reference product were well tolerated.

[0404] The pharmacokinetic parameters of olanzapine were compared between the intranasal spray and the intramuscular injection. The intranasal spray showed a higher absorption rate and faster absorption compared to the intramuscular injection, while the intramuscular injection showed greater absorption. During follow-up, no clinically significant changes were observed in any individual's study-treatment-related laboratory tests, vital signs, physical examination, ECG, and mental status assessment using the C-SSRS, indicating a favorable safety and tolerability profile for both the test and reference products. All individuals experienced a burning sensation when administered olanzapine treatment A or B during the study period. Clinical evaluations were performed on all individuals to assess their tolerance to the study drug. Study individuals demonstrated good tolerance to the study drug.

[0405] Example 4: A single-dose, randomized, open-label, parallel design study to characterize the pharmacokinetics of investigational olanzapine nasal spray compared to the reference dose of intramuscular olanzapine injection in healthy adult men.

[0406] summary

[0407] Objective: Injectable olanzapine for acute agitation in mental disorders is limited to delivery by healthcare professionals in a supervised setting. Intranasal (IN) administration provides a potential needle-free delivery route with favorable pharmacokinetics and patient experience, including the possibility of self-administration in a community setting. Two IN formulations of olanzapine containing the penetration enhancer dodecyl maltoside (DDM) were evaluated, with intramuscular (IM) olanzapine as a reference.

[0408] Methods: In this randomized phase I trial, healthy volunteers (N=24) were randomized 1:1:1 to receive one dose of olanzapine 7.5 mg + 0.25% DDM, olanzapine 7.5 mg + 0.50% DDM, or olanzapine 7.5 mg IM. Plasma olanzapine concentrations were measured over time, and safety and tolerability were assessed.

[0409] Results: The mean peak plasma concentrations of olanzapine administered via 0.25% and 0.50% DDM spray and IM were 31.5, 32.3, and 20.5 ng / mL, respectively. The median times to reach peak plasma concentration were 4.8, 10.2, and 37.8 minutes, respectively. Bioavailability following a single dose of 0.25% and 0.50% DDM formulations was 88.8% and 83.3% of a single IM dose, respectively. All reported adverse events were mild, transient, and considered potentially related to the study drug, the most common being sedation (n=24) and nasal discomfort lasting several seconds (n=16, IM treatment). Nasal irritation scores were grade 0 (no signs of nasal irritation or mucosal erosion), and suicide risk assessments were negative at all time points.

[0410] Conclusion: Two novel investigational IN formulations of olanzapine containing the penetration enhancer DDM demonstrated favorable pharmacokinetics and an acceptable safety profile, with no unexpected signals observed in healthy adults. Further research is warranted.

[0411] introduction

[0412] Acute agitation is a common clinical management problem, recently defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as “excessive motor activity associated with internal tension” and unproductive, repetitive behaviors. Acute agitation is a distinct state, but it can sometimes escalate into aggression or violence, thus requiring timely treatment to prevent escalation. It can also cause distress to the patient, who is at risk of harming themselves or others. Acute agitation can occur in a variety of settings, from emergency departments (EDs), inpatient psychiatric wards, long-term care facilities, to community settings. In the United States, an estimated 2 million ED visits per year involve agitation. In one urban county ED study, the overall prevalence of agitation was 2.6%, which was associated with alcohol and drug use, medical conditions, and psychotic symptoms. While most patients with mental disorders are not violent, schizophrenia and bipolar disorder can increase the risk of violence. In one psychiatric ED, 26% of patients exhibited aggression.

[0413] Treatment guidelines for acute agitation support a flexible approach that combines observation and speech de-escalation techniques with pharmacological intervention as needed, where patient consent is crucial. Currently, the U.S. Food and Drug Administration (FDA)-approved pharmacological formulations for agitation associated with schizophrenia (most of which are also approved for agitation associated with bipolar disorder) include intramuscular (IM) aripiprazole, olanzapine, and ziprasidone; inhaled loxapine; and dexmedetomidine sublingual film. These formulations provide rapid pharmacological action but require administration by trained personnel in a controlled environment, and some administration routes may be considered coercive, posing a risk of needlestick injury or other harm to healthcare workers or individuals. There remains an unmet clinical need for noninvasive treatment options that support speech de-escalation strategies and can be used by patients or caregivers in the community, potentially reducing ED visits and associated costs.

[0414] Intranasal (IN) delivery is currently used in clinical care for several acute therapies targeting the central nervous system. IN formulations offer relatively rapid onset of action, avoidance of first-pass metabolism, and good bioavailability, potentially leading to fewer dose-related side effects. 2 Potential patient benefits include non-invasive ease of delivery in a community setting and a positive patient experience, including the ability to self-administer. IN formulations are specifically designed to address the anatomical and physiological challenges of the nose, including the addition of excipients to increase drug solubility or mucosal absorption. One example is the alkyl sugar excipient dodecyl maltoside (DDM; Intravail). ® A3), its mechanism of action is to temporarily open tight cell junctions and disrupt cell membranes in the nasal mucosa, thereby promoting systemic bioavailability. It is generally recognized as safe (GRAS) for oral administration and has been shown to be generally non-irritating to the nose. It is a component of diazepam nasal spray, an immediate-use anti-epileptic drug used to treat cluster seizures in epilepsy; sumatriptan nasal spray, used for migraines; epinephrine, used for allergic reactions; and nalmefene nasal spray, used for opioid overdose.

[0415] To address the gap in a non-invasive, easy-to-use treatment for acute agitation with adequate safety and tolerability, and potentially faster onset of action, an intranasal (IN) formulation of olanzapine including the FDA-approved excipient DDM is being developed. The primary objective of this Phase I study is to characterize the pharmacokinetics of two intranasal formulations of olanzapine plus DDM relative to clinically available olanzapine IM formulations. Secondary objectives are to evaluate the safety and tolerability of the formulations.

[0416] method:

[0417] This study (NCT06600477) employed an open-label, randomized, single-dose, parallel design to evaluate the pharmacokinetics and safety of olanzapine 7.5 mg + 0.25% DDM and olanzapine 7.5 mg + 0.5% DDM in healthy adult men. The commercially available olanzapine 7.5 mg IM formulation (Zyprexa) was also discussed. ® IM) is used as a reference. DDM concentrations are determined based on previous preclinical and clinical studies.

[0418] Research participants and intervention

[0419] Participants were healthy men aged 18–55 years who were either non-smokers or had quit smoking, as olanzapine metabolism is mediated by CYP1A2, which is induced by polycyclic aromatic hydrocarbons found in cigarette smoke. Exclusion criteria included a history of major health conditions, including asthma, sinusitis, cardiovascular and psychiatric disorders, particularly schizophrenia, schizoaffective disorder, type I bipolar disorder, or major depressive disorder; a history of suicide attempts or a significant risk of suicide, violence, or homicide; and any acute (≥2 weeks) intranasal problems (such as the common cold or hay fever) or a history of nasal pathology, surgery, condition, or abnormality that may affect nasal spray delivery and absorption.

[0420] The study was conducted in October 2023 at the Clinical Centre of the International Pharmaceutical Research Center (IPRC, Amman, Jordan), in accordance with the Declaration of Helsinki and the International Committee on Harmonisation Tripartite Guideline. The IPRC Institutional Review Committee approved the study and obtained written informed consent from each participant prior to study screening.

[0421] Enrolled participants were randomly assigned in equal proportions to one of three treatments. On day 1 of the study, fasting participants were given a single dose. Nasal obstruction was checked before intranasal administration, and no drug solution dripping was observed after administration. The IN formulation was delivered as a single spray into one nostril. IM was administered intramuscularly to the gluteal muscles in this experimental setting. Nasal irritation, sedation, and pain associated with the injection were assessed at baseline and at fixed time intervals after drug administration. Blood samples were collected at 0 hours prior to administration (before administration) and at 5, 10, 15, 30, and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 4, 8, 12, 24, 36, 48, 72, 96, 144, 192, and 240 hours post-administration for plasma olanzapine concentration determination. Olanzapine plasma concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS) developed by the IPRC and validated according to FDA guidelines (Agilent, Waldbronn, Germany [LC]; Applied Biosystems Sciex, Toronto, Canada [MS]).

[0422] Treatment-interventional adverse events (TEAEs) were collected, summarized, and reviewed throughout the study, including any TEAE, serious TEAE (SAE), treatment-related TEAE, treatment-related SAE, discontinuation, and death. Nasal irritation of the IM formulation was assessed by trained professional observers using a 6-point nasal mucosal rating system (i.e., 0, no signs of nasal irritation or mucosal erosion; 1A, focal nasal mucosal irritation or inflammation; 1B, superficial mucosal erosion; 2, moderate mucosal erosion; 3, ulceration; 4, nasal septum perforation). Participants assessed pain induced by IM administration using an 11-point numerical rating scale (0-10), where 0 represents "no pain" and 10 represents "the most severe imaginable pain". For all preparations, sedation was assessed by participants (if conscious) and trained staff using a previously published 6-point system (i.e., 0: alert, not drowsy, normal conversation; 1: conscious, talking, but somewhat drowsy; 2: dozing or sleeping, but easily awakened; 3: sleeping, only awakened by loud talking or shaking; 4: sleeping, difficult to awaken, quickly falls asleep again; 5: sleeping, cannot be awakened). Suicidal ideation and behavior were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). Blood pressure and heart rate were assessed at baseline, hourly from 1 to 8 hours post-treatment, and at 11 and 24 hours; body temperature and respiratory rate were measured at baseline, 4 hours, and 24 hours. A comprehensive physical examination, clinical laboratory tests, and electrocardiogram were also performed at screening / baseline and day 11 follow-up.

[0423] Pharmacokinetic evaluation and statistical analysis

[0424] Pharmacokinetic parameters were estimated using standard non-compartmental methods, including the peak plasma concentration of olanzapine (C0.05). max ) and the time to reach peak concentration (T) max The data is taken directly from the measured data. The area under the curve (AUC) from time zero to the last measurable concentration is calculated using the linear trapezoidal rule. 0-t ), and will eliminate half-life (t 1 / 2 The linear regression slope is calculated as the plasma concentration after ln conversion at the terminal stage of the curve. Missing drug concentration data are not included in the calculation, and any value below the lower limit of quantitation is considered zero.

[0425] Statistical analysis was performed using WinNonlin statistical software v8.3.4 (Certara, Inc., Princeton, NJ, USA). Statistical evaluation of the PK parameters included C after ln transformation. max AUC 0-t Extrapolating to infinity, AUC (AUC 0-∞ Analysis of variance (ANOVA) was performed on the DDM concentration and the ratio of the compound (point estimate) was calculated to assess the effect of DDM concentration on PK parameters. The significance level of treatment effect was tested at 0.05. For the parametric analysis of bioavailability, such as the suggestions of Steinijans and Diletti (Steinijans VW, Diletti E, Statistical analysis of bioavailability studies: parametric and nonparametric confidence intervals), European Journal of Clinical Pharmacology (Eur J ClinPharmacol.) 1983;24(1):127-136. doi:10.1007 / BF00613939), for the ln-transformed C max (Reflects absorption rate), AUC 0-t (Definition of absorption degree) and AUC 0-∞ The 90% CI for the ratio of IN to IM formulations was calculated. No formal sample size determination was performed in this study; 24 participants were considered sufficient to obtain meaningful pharmacokinetic results.

[0426] result

[0427] Treatment and Demographics

[0428] A total of 39 participants were screened, of whom 13 did not pass the screening. Figure 7 Two participants were screened and enrolled as alternates. The remaining 24 participants were enrolled, administered medication, and completed the study. Alternate participants were excluded according to the protocol as they were not required to serve as replacements. All participants (N=24) were male, Middle Eastern, and non-smokers, with a mean age (SD) of 34.8 (7.0) years and a mean BMI (SD) of 26.2 (2.1) kg / m². 2 .

[0429] Pharmacokinetics

[0430] Mean plasma olanzapine concentration versus time curves (0-2 hours and 0-240 hours), Figure 8 The results showed that after nasal administration of the two DDM-containing formulations, plasma drug concentrations increased rapidly, and the mean peak plasma concentration (C0.05) was significantly higher. max The concentration was approximately 30 ng / mL (Table 19).

[0431] Table 19-2 PK parameters (mean ± SD) of intranasal olanzapine formulations and reference IM formulations.

[0432]

[0433] Abbreviation: AUC 0-t The area under the curve from time zero to the last measurable concentration; AUC 0-∞ Extrapolate to the area under the curve to infinity; C max Peak plasma concentration; DDM, dodecyl maltodextrin; IM, intramuscular; IN, intranasal; OLZ, olanzapine; T max The time to reach maximum plasma concentration; t 1 / 2 Eliminate half-life.

[0434] The average peak plasma concentration with IM administration was approximately 20 ng / mL. The median time to peak plasma concentration (T0) was [not specified] with 0.25% and 0.50% DDM formulations. max The timeouts were 0.08 hours (approximately 5 minutes) and 0.17 hours (approximately 10 minutes) respectively, while the timeout for IM-based investment was... max The median time was 0.63 hours (approximately 38 minutes). >2 hours after administration, olanzapine plasma concentrations were similar across all formulations. Bioequivalence assessments using parametric methods indicated that the IN formulation resulted in a faster absorption rate and approximately 1.5-fold higher mean C60 compared to IM olanzapine. max And shorter T max Median (Table 20).

[0435] Table 20 shows the bioequivalence (CI), potency, and inter-participant variability of the IN olanzapine formulation relative to the reference IM formulation.

[0436]

[0437] Abbreviation: AUC 0-t The area under the curve from time zero to the last measurable concentration; AUC 0-∞ The area under the curve is extrapolated to infinity; CI is the confidence interval; C max Peak plasma concentration; CV%, coefficient of variation (%); DDM, dodecyl maltodextrin; Geo LSM, geometric least squares mean; IM, intramuscular; OLZ, olanzapine.

[0438] For 0.25% and 0.50% DDM formulations, based on AUC 0-∞ The measured absorption rates were 88.8% and 83.3% of the absorption rates measured under IM administration, respectively.

[0439] Security

[0440] A total of 40 TEAEs were reported; 24 participants (100%) experienced ≥1 TEAE (Table 21).

[0441] Table 21 - Security Overview

[0442]

[0443] The data is n (%).

[0444] Abbreviations: DDM, dodecyl maltodextrin; IM, intramuscular; OLZ, olanzapine; TEAE, adverse events that occur during treatment.

[0445] TEAEs in ≥2 participants consisted of sedation and nasal discomfort. All TEAEs were mild in severity and researchers considered them potentially related to the study drug. No participants reported moderate or severe TEAEs. There were no deaths, no SAEs, and no TEAEs leading to study discontinuation.

[0446] All 24 participants experienced maximum sedation ranging from level 2 (drowsy or asleep, but easily awakened) to level 4 (sleeping, difficult to awaken, quickly returning to sleep), with no significant difference observed between the IN and IM groups. Figure 9 The highest rating among the 4 participants was Level 2 (16.7% overall), the highest rating among the 13 participants was Level 3 (54.2%), and the highest rating among the 7 participants was Level 4 (29.2%). Sedation subsided in all participants within 24 hours.

[0447] All 16 participants in the IN group reported mild, transient nasal discomfort lasting several seconds. All nasal discomfort TEAEs subsided upon discharge from the clinical study ward. At all assessed time points, all participants receiving the IN dose had a nasal irritation assessment score of 0 (no signs of nasal irritation or mucosal erosion). No epistaxis, nasal discharge, or sneezing was reported during the study.

[0448] No laboratory parameters showed clinically significant abnormalities or changes relative to baseline. There were also no clinically significant abnormal vital sign measurements, and no clinically significant changes relative to baseline, including any significant hypotension.

[0449] All participants had negative C-SSRS results at all time points.

[0450] discuss

[0451] Intranasal delivery of central nervous system drugs offers the potential for favorable pharmacokinetics and bioavailability, as well as a good safety profile and positive patient attributes (e.g., non-invasiveness, potential for self-administration), which may be beneficial during the treatment of acute agitation. We evaluated for the first time the pharmacokinetics and safety of a novel investigational nasal spray containing the atypical antipsychotic olanzapine plus the penetration enhancer DDM. When comparing the pharmacokinetic parameters of olanzapine nasal spray and the IM injection formulation, the IN formulation resulted in a higher absorption rate and a higher (approximately 1.5-fold) mean C60 compared to the IM injection formulation. max and shorter T max Median, supporting the possibility that intranasal formulations may be a favorable option. Absorption extent after a single dose (in AUC) of IN formulations with 0.25% DDM or 0.50% DDM. 0-∞ The results (measured) were comparable to the IM injectable formulation (approximately 89% and 83%, respectively), supporting the expectation that the IN and IM formulations have similar long-term safety profiles. The IN formulation was generally safe and well-tolerated, with no SAEs and no unexpected TEAEs.

[0452] Both nasal spray formulations produced favorable pharmacokinetics, with the 0.25% DDM formulation showing a faster Tg compared to the two IN formulations. max =Quite C max It was associated with a higher total exposure AUC. When testing for bioequivalence with olanzapine IM, the 0.25% DDM formulation caused C... maxHigher point estimates and better relative bioavailability. The slightly higher and faster drug absorption observed in the 0.25% DDM formulation is consistent with the 0.1% to 0.2% formulation range of alkyl sugar absorption enhancers reported elsewhere, and may indicate a dose-limiting effect of DDM on absorption. Meanwhile, alkyl sugars have been tested in the Draize test at concentrations up to 25% and have shown to be safe, non-toxic, and non-sensitizing.

[0453] The safety profile in this group of healthy volunteers was favorable, with TEAEs being mild, transient, and consistent with olanzapine and nasal delivery. The safety profile was comparable between the two 7.5 mg nasal spray formulations. No unexpected TEAEs were observed, and there were no serious or discontinuing TEAEs. Drowsiness was similar between the IN and IM formulations, and no nasal irritation was observed with IN administration. All TEAEs resolved by the end of the study. As expected in olanzapine-naïve individuals, sedation was reported in all patients, but there was no difference between those receiving IN and IM formulations. No significant hypotension was observed, and there were no signs of suicide risk. Nasal discomfort was mild and transient, as seen in long-term repeated-dose safety studies of diazepam nasal sprays with DDM, in which no evidence of olfactory changes was observed, and no effects of seasonal allergies / rhinitis were observed. No reports of nasal bleeding, nasal discharge, or sneezing were reported.

[0454] The pharmacokinetic profile of the intranasal olanzapine formulation showed improved absorption kinetics and similar overall drug exposure to olanzapine IM. These profiles reasonably suggest that the intranasal formulation offers a potentially improved therapeutic profile and comparable safety profile, including sustained effects over time, compared to studies using the IM formulation. In a pivotal trial, agitated hospitalized patients meeting the DSM-4 criteria for schizophrenia, schizophrenia-like disorder, or schizoaffective disorder received a single dose of olanzapine 10 mg IM or placebo. Two hours post-injection, olanzapine was statistically superior to placebo in reducing agitation, as measured by a decrease in the mean (SD) of the excitatory component of the Positive and Negative Syndrome Scale (PANSS-EC), which was -7.7 (6.1) and -3.6 (5.2); P < 0.05. Significant differences were observed starting 15 minutes post-administration. When tested in hospitalized patients with agitation meeting the DSM-4 criteria for type I bipolar disorder, a single 10 mg IM dose also showed a statistically superior reduction in PANSS-EC compared to placebo. Similarly, lower doses of 2.5 mg and 5 mg, tested in patients with acute agitation and dementia, were also statistically superior to placebo. In these studies, a repeat-dose rate of approximately 25% was reported with 10 mg IM administration.

[0455] Outpatients experiencing acute agitation may be treated at an ED, and parenteral medications may be used when nonpharmacological interventions are insufficient. These remain the most appropriate option for some patients, such as those with severe agitation who may be less receptive to participation. Meanwhile, most agitated episodes treated in psychiatric emergency departments involve restraint or isolation, suggesting an opportunity to treat certain episodes at an earlier, less acute stage with less coercion and needle-free intervention, possibly before arrival at an acute healthcare facility. In a study of community-dwelling patients with schizophrenia or bipolar disorder, 71% were always or sometimes aware of becoming agitated, and more than half (55% of schizophrenia patients and 66% of bipolar disorder patients) reported taking prescription medications to manage episodes.

[0456] The non-invasive, investigational olanzapine nasal spray formulation tested here represents a potentially substantial advance in treatment options for acute agitation. Olanzapine has been extensively studied and identified as one of the most effective and safest treatments for agitation in a systematic review and meta-analysis. The single-dose nasal delivery system used as part of the investigational formulation is familiar and widely used for the treatment of acute symptoms of the central nervous system, such as migraines, opioid overdose, and cluster seizures in epilepsy. The system is easy to learn and use for healthcare professionals and community members, and can be administered by self-administered or by caregivers / care partners in a community setting.

[0457] Studies of olanzapine powder formulations support our findings regarding favorable pharmacokinetics of intranasal delivery. Powdered olanzapine is being tested in a drug-device combination for intranasal delivery. The device is a handheld research dosing device that requires an air pump to manually activate and push the powder into the nasal cavity. A phase 1 pharmacokinetic dose-escalation study (5, 10, and 15 mg olanzapine) found similar exposures for the powder formulation and equivalent doses of the IM formulation. The Tg of powdered olanzapine... max The median duration of adverse events (TEAEs) was 9.5 to 15 minutes, with increased durations associated with lower doses. The incidence of TEAEs was 67% to 80%, with the most common (>2 patients in all groups receiving powdered olanzapine) being dizziness (including orthostatic dizziness), orthostatic symptoms, and nasal congestion.

[0458] As is common in Phase 1 pharmacokinetic studies involving healthy participants, the results observed here have limited generalizability to the potential target patient population of schizophrenia or bipolar disorder experiencing acute mania. Regarding safety, the study did not specifically assess orthostatic hypotension (i.e., no vital signs were measured under orthostatic stress). Orthostatic hypotension is associated with antipsychotic medication treatment and can occur in the case of olanzapine, particularly during initial dose titration. Further studies are needed to characterize the use of olanzapine nasal spray in patients with psychotic symptoms.

[0459] In summary, gaps remain in the availability of rapid, non-invasive, and non-mandatory treatment options for acute agitation that can be used in hospitals and the community. A novel investigational in-line formulation of olanzapine containing the penetration enhancer DDM exhibits favorable pharmacokinetics, with higher maximum plasma concentrations and a shorter time to reach maximal concentrations, suggesting a potentially advantageous therapeutic profile compared to commercially available in-line formulations. This, along with an acceptable safety profile in healthy adults, supports continued investigation of this in-line formulation of olanzapine with DDM.

[0460] All publications mentioned herein are incorporated herein by reference in their entirety. Nothing in this document should be construed as an admission that this disclosure is not entitled to precedence over such disclosure.

[0461] All features disclosed in this specification (including the abstract and drawings) and all steps of any disclosed method or process may be combined in any combination, except for at least some mutually exclusive combinations of such features and / or steps. Unless otherwise expressly stated, each feature disclosed in this specification (including the abstract and drawings) may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Therefore, unless otherwise expressly stated, each disclosed feature is merely one example of a general series of equivalent or similar features. In addition to those described herein, various modifications to this disclosure will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims

1. A method for treating acute agitation in an individual in need associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v water.

2. The method of claim 1, wherein the composition is administered about 0.08 hours (4.8 minutes) after administration (T max The concentration of C reached approximately 31.513 ng / ml. max .

3. The method of claim 1, wherein the composition is administered at a time interval of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max .

4. The method of claim 1, wherein the composition is administered at an AUC of approximately 509.81 ng·h / ml. 0-t .

5. The method of claim 1, wherein the composition is administered at an AUC between about 323.9 ng·h / ml and about 695.72 ng·h / ml. 0-t .

6. The method of claim 1, wherein the composition is administered at an AUC of about 526.47 ng·h / ml. ∞ .

7. The method of claim 1, wherein the composition is administered to achieve an AUC between about 329.22 ng·h / ml and about 723.72 ng·h / ml. ∞ .

8. The method of claim 1, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

9. The method of claim 1, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

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

11. The method of claim 1, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is from about 4:1 to about 1:

4.

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

2.

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

14. The method of claim 1, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition.

15. The method of claim 1, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition.

16. The method of claim 1, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual.

17. The method of claim 1, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual.

18. The method of claim 1, wherein the severity of the acute agitation in the individual decreases within approximately 5 minutes after administration.

19. A method for treating acute agitation in an individual in need associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide, and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v water.

20. The method of claim 19, wherein the composition is administered at approximately 0.17 hours (10.2 minutes) (T max The concentration of C reached approximately 32.270 ng / ml. max .

21. The method of claim 20, wherein the composition is administered at a time interval of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. max .

22. The method of claim 19, wherein the composition is administered at an AUC of about 463.45 ng·h / ml. 0-t .

23. The method of claim 19, wherein the composition is administered to achieve an AUC between about 388.89 ng·h / ml and about 538.01 ng·h / ml. 0-t .

24. The method of claim 19, wherein the composition is administered to an AUC of about 474.91 ng·h / ml. ∞ .

25. The method of claim 19, wherein the composition is administered to achieve an AUC between about 399.14 ng·h / ml and about 550.68 ng·h / ml. ∞ .

26. The method of claim 19, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

27. The method of claim 19, wherein the AUC achieved by administering the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

28. The method of claim 19, wherein the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da.

29. The method of claim 19, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is from about 4:1 to about 1:

4.

30. The method of claim 19, wherein the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:

2.

31. The method of claim 19, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition.

32. The method of claim 19, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition.

33. The method of claim 19, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual.

34. The method of claim 19, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual.

35. The method of claim 19, wherein the composition contains less than 1% w / v of water.

36. The method of claim 19, wherein the severity of the acute agitation in the individual decreases within approximately 20 minutes after administration.

37. A method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.25% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

38. The method of claim 37, wherein the composition is administered about 0.08 hours (4.8 minutes) after administration (T max The concentration of C reached approximately 31.513 ng / ml. max .

39. The method of claim 37, wherein the composition is administered at a time interval of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C10 within the range was between approximately 20.243 ng / ml and 42.783 ng / ml. max .

40. The method of claim 37, wherein the composition is administered at an AUC of about 509.81 ng·h / ml. 0-t .

41. The method of claim 37, wherein the composition is administered at an AUC between about 323.9 ng·h / ml and about 695.72 ng·h / ml. 0-t .

42. The method of claim 37, wherein the composition is administered at an AUC of about 526.47 ng·h / ml. ∞ .

43. The method of claim 37, wherein the composition is administered to achieve an AUC between about 329.22 ng·h / ml and about 723.72 ng·h / ml. ∞ .

44. The method of claim 37, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

45. The method of claim 37, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

46. ​​The method of claim 37, wherein the polyethylene glycol has an average molecular weight of about 200 Da to about 1000 Da.

47. The method of claim 37, wherein the ratio of the polyethylene glycol to the N,N-dimethylacetamide is from about 4:1 to about 1:

4.

48. The method of claim 37, wherein the ratio of polyethylene glycol to N,N-dimethylacetamide is about 3:

2.

49. The method of claim 37, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition.

50. The method of claim 37, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition.

51. The method of claim 37, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual.

52. The method of claim 37, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual.

53. The method of claim 37, wherein the composition contains less than 1% w / v of water.

54. A method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising administering intranasal administration of a composition comprising: about 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof, about 0.5% w / v dodecyl maltodextrin, about 34% w / v to about 38% w / v N,N-dimethylacetamide and about 44% w / v to about 66% w / v polyethylene glycol, wherein the composition is a non-aqueous solution containing less than about 3% w / v of water.

55. The method of claim 54, wherein the composition is administered at approximately 0.17 hours (10.2 minutes) (T max The concentration of C reached approximately 32.270 ng / ml. max .

56. The method of claim 54, wherein the composition is administered at a time interval of about 0.08 (4.8 minutes) to about 0.25 hours (15 minutes) (T). max The concentration of C within the range was between approximately 13.43 ng / ml and 51.11 ng / ml. max .

57. The method of claim 54, wherein the composition is administered at an AUC of about 463.45 ng·h / ml. 0-t .

58. The method of claim 54, wherein the composition is administered to achieve an AUC between about 388.89 ng·h / ml and about 538.01 ng·h / ml. 0-t .

59. The method of claim 54, wherein the composition is administered to an AUC of about 474.91 ng·h / ml. ∞ .

60. The method of claim 54, wherein the composition is administered to achieve an AUC between about 399.14 ng·h / ml and about 550.68 ng·h / ml. ∞ .

61. The method of claim 54, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

62. The method of claim 54, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

63. The method of claim 54, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition.

64. The method of claim 54, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition.

65. The method of claim 54, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual.

66. The method of claim 54, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual.

67. The method of claim 54, wherein the composition contains less than 1% w / v of water.

68. A method for treating acute agitation in an individual in need associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, said method comprising: Intranasal administration of a composition containing approximately 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof into the nasal mucosa of the individual; The composition is a non-aqueous solution containing less than about 3% w / v of water; The composition was added between approximately 0.064 hours and 0.096 hours (T) max The concentration of C10 was between approximately 25.210 ng / ml and approximately 37.816 ng / ml. max .

69. The method of claim 68, wherein the composition is administered to achieve an AUC between about 407.85 ng·h / ml and about 611.772 ng·h / ml. 0-t .

70. The method of claim 68, wherein the composition is administered to achieve an AUC between about 421.18 ng·h / ml and about 631.76 ng·h / ml. ∞ .

71. The method of claim 68, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

72. The method of claim 68, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

73. The method of claim 68, wherein the composition further comprises one or more non-aqueous solvents.

74. The method according to claim 73, wherein the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, benzoyl benzoate, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, capric triglyceride, or any combination thereof.

75. The method of claim 74, wherein the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof.

76. The method of claim 74, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition.

77. The method of claim 74, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition.

78. The method of claim 74, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual.

79. The method of claim 74, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual.

80. The method of claim 74, wherein the severity of the acute agitation in the individual decreases within approximately 5 minutes after administration.

81. A method for treating acute agitation in an individual in need associated with one or more of schizophrenia, schizoaffective disorder, type I bipolar disorder, Alzheimer's disease, autism spectrum disorder, post-traumatic stress disorder (including irritability and episodic outbursts), attention deficit disorder, hyperactivity disorder, or delirium, said method comprising: Intranasal administration of a composition containing approximately 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof into the nasal mucosa of the individual; The composition is a non-aqueous solution containing less than about 3% w / v of water; The composition was added between approximately 0.136 hours and 0.204 hours (T). max The concentration of C10 reached between approximately 25.816 ng / ml and approximately 38.724 ng / ml. max .

82. The method of claim 81, wherein the composition is administered to achieve an AUC between about 370.76 ng·h / ml and about 556.14 ng·h / ml. 0-t .

83. The method of claim 81, wherein the composition is administered to achieve an AUC between about 379.93 ng·h / ml and about 569.89 ng·h / ml. ∞ .

84. The method of claim 81, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

85. The method of claim 81, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

86. The method of claim 81, wherein the composition further comprises one or more non-aqueous solvents.

87. The method according to claim 86, wherein the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, benzoic acid methyl ester, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, capric triglyceride, or any combination thereof.

88. The method of claim 81, wherein the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof.

89. The method of claim 81, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition.

90. The method of claim 81, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition.

91. The method of claim 81, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual.

92. The method of claim 81, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual.

93. The method of claim 81, wherein the severity of the acute agitation in the individual decreases within approximately 20 minutes after administration.

94. A method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising: Intranasal administration of a composition containing approximately 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof into the nasal mucosa of the individual; The composition is a non-aqueous solution containing less than about 3% w / v of water; The composition was added between approximately 0.064 hours and 0.096 hours (T) max The concentration of C10 was between approximately 25.210 ng / ml and approximately 37.816 ng / ml. max .

95. The method of claim 94, wherein the composition is administered to achieve an AUC between about 407.85 ng·h / ml and about 611.772 ng·h / ml. 0-t .

96. The method of claim 94, wherein the composition is administered to achieve an AUC between about 421.18 ng·h / ml and about 631.76 ng·h / ml. ∞ .

97. The method of claim 94, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

98. The method of claim 94, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

99. The method of claim 94, wherein the composition further comprises one or more non-aqueous solvents.

100. The method according to claim 99, wherein the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, benzoyl benzoate, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, capric triglyceride, or any combination thereof.

101. The method of claim 99, wherein the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof.

102. The method of claim 99, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition.

103. The method of claim 99, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition.

104. The method of claim 99, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual.

105. The method of claim 99, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual.

106. A method for treating chemotherapy-induced nausea and vomiting in an individual in need, the method comprising: Intranasal administration of a composition containing approximately 7.5 mg of olanzapine or a pharmaceutically acceptable salt thereof into the nasal mucosa of the individual; The composition is a non-aqueous solution containing less than about 3% w / v of water; The composition was added between approximately 0.136 hours and 0.204 hours (T). max The concentration of C10 reached between approximately 25.816 ng / ml and approximately 38.724 ng / ml. max .

107. The method of claim 106, wherein the composition is administered to achieve an AUC between about 370.76 ng·h / ml and about 556.14 ng·h / ml. 0-t .

108. The method of claim 106, wherein the composition is administered to achieve an AUC between about 379.93 ng·h / ml and about 569.89 ng·h / ml. ∞ .

109. The method of claim 106, wherein the AUC achieved by dispensing the composition is... 0-t The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

110. The method of claim 106, wherein the AUC achieved by dispensing the composition is... ∞ The AUC of an intramuscularly administered equivalent dose of olanzapine 0-t Approximately 85% to approximately 90%.

111. The method of claim 106, wherein the composition further comprises one or more non-aqueous solvents.

112. The method according to claim 106, wherein the one or more non-aqueous solvents are selected from vitamin E, benzyl alcohol, ethanol, cottonseed oil, eucalyptol, polysorbate 20, polysorbate 80, triethanolamine, sesame oil, benzoyl benzoate, dimethylacetamide, polyethylene glycol, alcohol, glycol, glycol derivatives, esters, oils, ethers, dimethyl derivatives and alkyl derivatives, alkanes, triacetin (glyceryl triacetate), N-methyl-2-pyrrolidone (NMP), caprylic triglyceride, capric triglyceride, or any combination thereof.

113. The method of claim 106, wherein the composition further comprises cyclodextrin, dodecyl maltodextrin, or any combination thereof.

114. The method of claim 106, wherein the composition is provided in a pre-activated disposable delivery device containing about 75 μL to about 200 μL of the composition.

115. The method of claim 106, wherein the composition is provided in a pre-activated disposable delivery device containing about 100 μL of the composition.

116. The method of claim 106, wherein the dosing comprises dosing about 75 μL to about 200 μL of the composition into each nostril of the individual.

117. The method of claim 106, wherein the dosing comprises dosing about 100 μL of the composition into each nostril of the individual.

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