Olanzapine Compositions and Methods of Use

Abstract

The present disclosure provides pharmaceutical compositions for subcutaneous administration comprising olanzapine, an organic solvent, and a triblock copolymer and a diblock copolymer, and methods of treating psychiatric diseases and disorders using such compositions.

Description

[Technical Field]

[0001] (Technical field) The present disclosure relates to pharmaceutical compositions for subcutaneous administration comprising olanzapine, an organic solvent, and triblock and diblock copolymers, and to methods of treating psychiatric diseases and disorders responsive to olanzapine using such compositions. [Background technology]

[0002] (background) Schizophrenia is a severely debilitating psychotic disorder characterized by positive symptoms (e.g., delusions, hallucinations, and severely disorganized behavior) and negative symptoms (e.g., flat affect, alogia, and amotivation) (New York State Office of Mental Health, 2019; Stefan et al., 2002).

[0003] The worldwide lifetime risk of developing this disorder is approximately 1% across diverse geographic, cultural, and socioeconomic regions. In most patients, the disease follows a chronic course with long-lasting disability, and long-term treatment with antipsychotic medications is usually required.

[0004] Nonadherence and high discontinuation rates are particularly problematic in patients with schizophrenia. Premature discontinuation of antipsychotic therapy is a common phenomenon; in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 74% of patients discontinued their medication within 18 months due to either poor tolerability or lack of efficacy, patient choice (i.e., nonadherence / study dropout), or investigator reasons (Lieberman et al., 2005). Nonadherence to long-term oral drug regimens, even among those who do not explicitly discontinue medication, is one of the most significant treatment problems in the treatment of schizophrenia and related disorders (Kane et al., 2013). As a result, many of these patients never receive the full benefit of antipsychotic therapy and frequently experience relapses or exacerbations requiring readmission (Carbon and Correll, 2014), often in the context of a psychiatric emergency department (Rainer, 2008).

[0005] Thus, the availability of long-acting injectable (LAI) antipsychotics has the potential to increase medication adherence in patients with schizophrenia (Barnes and Curson, 1994; Hughes, 2008; Keith and Kane, 2003; Kishimoto et al., 2021; Walburn et al., 2001), and has been shown in randomized, cohort, and mirror-image trials to significantly reduce relapse and readmission and improve many clinically meaningful outcomes to a much greater extent than oral antipsychotics.

[0006] Olanzapine is a well-characterized and commonly prescribed atypical antipsychotic approved for the treatment of schizophrenia and available in oral and intramuscular formulations. Olanzapine is currently marketed in the United States (US) as ZYPREXA tablets (2.5, 5, 7.5, 10, 15, and 20 mg); ZYPREXA INTRAMUSCULAR (10 mg / mL) for immediate-acting injection; and ZYPREXA ZYDIS® orally disintegrating tablets (5, 10, 15, and 20 mg) (ZYPREXA, ZYPREXA ZYDIS, ZYPREXA INTRAMUSCULAR U.S. Package Insert [USPI] 2021). ZYPREXA RELPREVV®, a vehicle for sustained-release olanzapine pamoate powder and suspension, is administered by deep intramuscular gluteal injection either every two weeks (150, 210, and 300 mg) or every four weeks (300 and 405 mg), depending on the target oral olanzapine dose (10, 15, or 20 mg / day). ZYPREXA RELPREVV® (ZYPREXA RELPREVV® PI, 2021) is currently approved and commercially available in the United States for the treatment of schizophrenia; however, it is only available through a limited distribution program. ZypAdhera® is an additional olanzapine pamoate product with the same composition as ZYPREXA RELPREVV®.

[0007] ZYPREXA RELPREVV® should be administered at a registered healthcare facility with easy access to emergency response services. After each procedure, healthcare professionals must continuously observe the patient at the healthcare facility for at least three hours and ensure that the patient is alert for, oriented to, and free of signs and symptoms of post-injection delirium / sedation syndrome (PDSS), which may result from the route of administration, before discharge. PDSS is characterized by severe sedation (possibly including coma) and / or delirium after injection. During PDSS events, patients exhibit higher olanzapine plasma concentrations, leading to the assumption that unintentional partial intravascular injection or vascular injury during injection induces accelerated salt dissolution, which may contribute to PDSS. See, e.g., Heres S, Kraemer S, Bergstrom RF, Detke HC, "Pharmacokinetics of olanzapine long-acting injection: the clinical perspective," Int Clin Psychopharmacol. 2014.

[0008] All patients must be constantly vigilant for the symptoms of PDSS and must have access to emergency medical assistance at a facility capable of medical monitoring and resuscitation. Due to the extensive and inconvenient precautions required for the safe use of ZYPREXA RELPREVV®, the product is rarely used in routine clinical practice. As a result, the options available to psychiatrists for the clinical management of schizophrenia are limited. Alternative treatment options are needed.

[0009] WO2012090070 describes pharmaceutical formulations comprising biodegradable PLA-PEG-PLA triblock polymers and mPEG-PLA diblock polymers that are useful for the delivery of various active ingredients. Summary of the Invention

[0010] (overview) In some embodiments, the present disclosure provides a pharmaceutical composition for administration by subcutaneous injection, comprising: 20%-45% (w / w) olanzapine; 35% to 65% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; A diblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and a triblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together constitute 10% to 25% of the composition by weight (w / w).

[0011] In another aspect, the present disclosure provides a pharmaceutical composition for administration by subcutaneous injection, comprising essentially: 20%-45% (w / w) olanzapine; 35% to 65% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; A diblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and a triblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); It consists of The diblock copolymer and the triblock copolymer together constitute 10% to 25% of the composition by weight (w / w).

[0012] In some embodiments, the present disclosure provides a pharmaceutical composition for administration by subcutaneous injection, comprising: 20%-45% (w / w) olanzapine; 35% to 65% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; A diblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and a triblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); It consists of The diblock copolymer and the triblock copolymer together constitute 10% to 25% of the composition by weight (w / w).

[0013] The pharmaceutical compositions described above allow for the safe and effective treatment of schizophrenia, schizoaffective disorder, bipolar disorder, or depressive conditions in patients with a convenient, once-monthly dosing regimen. The compositions can be administered to patients and provide an olanzapine plasma C of less than 100 ng / mL. max Without being bound by theory, olanzapine plasma C max It is understood that treatment is clinically effective and can avoid PDSS when the serum creatine phosphate dehydrogenase (GPa) level is less than 100 ng / mL. Thus, the compositions of the present invention can be administered on a monthly basis with minimal to no physician monitoring or intervention during the intervention period.

[0014] Also provided are methods of preparing the compositions of the present disclosure, methods of administering olanzapine to a patient using the compositions of the present disclosure, and methods of treating a disease or disorder in a patient that is schizophrenia, schizoaffective disorder, bipolar disorder, or a depressive state using the compositions of the present disclosure.

[0015] The present disclosure also provides: a container containing 318 mg to 950 mg, optionally 550 mg to 950 mg, optionally 450 mg to 800 mg of olanzapine; and Also provided is a kit comprising: an organic solvent which is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), or a combination thereof; and a container containing 0.73 to 2.5 grams, optionally 1.3 to 2.5 grams, or optionally 0.9 to 2.1 grams of a mixture of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w).

[0016] Methods of treating patients using the kits of the present disclosure are also provided.

[0017] Also provided are methods for switching a patient from daily oral olanzapine therapy to a therapy comprising monthly administration of a composition of the present disclosure, and methods for switching a patient from a long-acting intramuscular injectable olanzapine formulation to a composition of the present disclosure.

[0018] There is also provided a pharmaceutical composition as defined above for use in medicine.

[0019] Also provided is a pharmaceutical composition as defined above for use in a method as defined above. [Brief explanation of the drawings]

[0020] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows the X-ray diffraction analysis (XRD) profile of olanzapine Form II.

[0021] [Figure 2]Figure 2 shows a plot of the mean (±SD) olanzapine plasma concentrations versus time after a single subcutaneous administration of different compositions at a 405 mg dose or after repeated intramuscular administration of ZYPADHERA product at a 300 mg dose twice every two weeks. This study is further described in Example 2. SD = standard deviation.

[0022] [Figure 3] Figure 3 shows plots of mean (+ / - SD) olanzapine plasma concentrations versus time to dosing on a linear scale (top) and semi-logarithmic scale (bottom): oral olanzapine concentrations at steady state after and during the washout period - safety analysis set from the study described in Example 5. SD = standard deviation.

[0023] [Figure 4] Figure 4 shows the mean (±SD) plasma olanzapine concentrations (ng / mL) on a linear scale (top) and semi-logarithmic scale (bottom) in healthy subjects after a single subcutaneous dose of Formulation 1 from the study described in Example 5. SD = standard deviation.

[0024] [Figure 5] Figure 5 shows the mean (±SD) plasma olanzapine concentrations (ng / mL) in patients on a linear scale (top) and semi-logarithmic scale (bottom) after a single subcutaneous dose of Formulation 1 from the study described in Example 5. SD = standard deviation.

[0025] [Figure 6] Figure 6 shows the mean (±standard deviation) olanzapine plasma concentrations on a linear scale versus time by cohort and dosing day: multiple-dose patient cohort after Formulation 1 (safety analysis set). The horizontal line represents the clinically relevant olanzapine plasma concentration of 10 ng / mL.

[0026] [Figure 7]Figure 7 shows mean (±standard deviation) olanzapine plasma concentrations on a semi-log scale versus time by cohort and dosing day: multiple-dose patient cohort after Formulation 1 (safety analysis set). The horizontal line represents the clinically relevant olanzapine plasma concentration of 10 ng / mL.

[0027] [Figure 8] 8 shows the observed median pharmacokinetic profiles and pharmacokinetic variability (5th and 95th percentiles) of olanzapine concentrations for oral olanzapine (left panel) and Formulation 1 (right panel) from the study described in Example 4. The top panel shows Cohort 8 (left panel: oral dose = 10 mg; right panel: Formulation 1 dose = 283 mg). The bottom panel shows Cohort 9 (left panel: oral dose = 20 mg; right panel: Formulation 1 dose = 566 mg).

[0028] [Figure 9]Figure 9 shows a schematic diagram of the study described in Example 6. Patients participating in this study who have not previously received oral olanzapine will receive two oral doses of olanzapine on two consecutive days during the screening phase (the second dose should be administered at least 24 hours prior to randomization) to assess patient tolerability (at least 10 mg / day of oral olanzapine [but not more than 20 mg / day], as determined by the investigator). Patients who have received olanzapine within the last year will not be required to receive these two oral doses. The investigator will verify the availability, tolerability, and duration of previous olanzapine treatment to confirm prior tolerability. To maintain the blinding in Period 1, all patients will be re-randomized between Periods 1 and 2; patients previously assigned to an active treatment group will retain their Period 1 treatment assignment (the re-randomization of patients in the Formulation 1 group is done solely to maintain the blinding in Period 1 and is effectively a deterministic assignment, not a randomization), and patients previously assigned to the placebo group will be randomized in a 1:1:1 ratio to one of the active treatment groups. Disclosure of Period 2 treatment assignment will occur for each patient only after the completion and reporting of appropriate study procedures related to the evaluation of efficacy and safety endpoints in Period 1. Disclosure of Period 2 treatment assignment will occur between Weeks 8 and 12 by the sponsor or its agent according to a predefined procedure in the relevant study plan, provided that all requirements specified in this procedure are met. Thus, the Week 8 dose, although assigned to Period 2, will be blinded by all parties in the same way as the Period 1 dose. q1m=once a month; R=randomized.

[0029] [Figure 10] Figure 10 shows the in vitro release results for Formulation 1 and Zyprexa Relprevv® in human plasma at 37°C. See Example 7. DETAILED DESCRIPTION OF THE INVENTION

[0030] DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0031] When a range of values ​​is specified, it is understood that the upper limit of the range, the lower limit of the range, and every value between the upper and lower limits of the range are encompassed within the disclosure.

[0032] As used herein, the term "about" refers to the indicated value and any number within ±10% of the indicated value. Thus, for example, the term "about 10%" refers to any value within the range of 9 to 11.

[0033] As used herein, the articles "a" and "an" refer to one or to more than one (e.g., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. For example, "a composition" means one composition or two or more compositions.

[0034] The term "olanzapine" refers to the chemical name 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine and the chemical structure: [ka] means a compound having the formula:

[0035] Pharmaceutically acceptable salts of olanzapine are also within the scope of this disclosure.

[0036] U.S. Patent Nos. 5,229,382 and 5,736,541 describe olanzapine Form I and Form II, respectively. U.S. Patent No. 7,323,459 describes olanzapine crystalline Forms H, G, Y, X, K, S, Q, Z, and J. As the free base or a salt, e.g., hydrochloride or pamoate, olanzapine is an active ingredient (API) in pharmaceuticals used to treat schizophrenia and other neuropsychiatric diseases and disorders.

[0037] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of the federal or state government in the United States or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., humans.

[0038] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure that is pharmaceutically acceptable and that retains the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or salts formed with acetic acid, pamoic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, oxalic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl Acid addition salts formed with organic acids such as bicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated to an organic base such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine.

[0039] "Pharmaceutically acceptable excipient" means a non-toxic, biologically tolerable substance, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug, that is otherwise biologically suitable for and compatible with administration to a subject.

[0040] The term "alkyl," when used alone or as part of a substituent group, refers to a straight- or branched-chain saturated hydrocarbon group having from 1 to 6 carbon atoms ("C1-C6") in the group. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, and n-hexyl. When a range of carbon atoms, e.g., C1-C6, is used herein, all ranges and individual numbers of carbon atoms are included. For example, "C1-C3" includes C1-C3, C1-C2, C2-C3, C1, C2, and C3.

[0041] The terms "patient" or "the / said patient" are used throughout this specification to describe a human to whom treatment (including prophylactic treatment) with a composition according to the present disclosure is provided. As used herein, the terms "patient" or "the / said patient" also refer to either an individual human, or, where the context allows, a population of humans. Thus, in some embodiments, a patient is an individual human. In other embodiments, a patient is a population of humans.

[0042] As used herein, the term "subject" or "the / said subject" refers to a human being to whom a composition according to the present disclosure is administered.

[0043] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (e.g., halting or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical or psychological parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder or its symptoms. In some embodiments, "treating" or "treatment" encompasses maintenance therapy, i.e., therapy aimed at maintaining the patient's improved state by reducing or eliminating adverse changes in the patient's clinical symptoms, or physical or psychological parameters.

[0044] The term "effective" when used to describe a treatment means a treatment that is effective, i.e., produces desired results, including, but not limited to, the achievement of primary and / or secondary clinical endpoints.

[0045] "Post-injection delirium / sedation syndrome" or "PDSS" shall be understood to be a symptom or a combination of symptoms and circumstances as defined in Detke, HC et al., BMC Psychiatry 2010, 10:43, incorporated herein by reference, or as a physician of ordinary skill in the art would understand the term. For example, delirium-related symptoms include disorientation, confusion, ataxia, and dysarthria. Sedation-related symptoms include, for example, somnolence, sedation, or other altered level of consciousness.

[0046] The number average molecular weight (Mn) is usually measured by gel permeation chromatography (GPC), usually using polystyrene standards. Polymers can also be characterized by their weight average molecular weight (Mw), which can also be measured by gel permeation chromatography (GPC), usually using polystyrene standards. The polydispersity index is defined as the ratio of Mw / Mn and is usually greater than 1 but less than 2.

[0047] Additionally, or as an alternative to defining a polymer in terms of its number average molecular weight, the polymer can be defined in terms of its theoretical molecular weight. The term "theoretical molecular weight" refers to the molecular weight of a copolymer determined by calculating the sum of the molar weights of the repeating units that make up the polymer. Theoretical molecular weight indicates the average length of the polymer chains in question.

[0048] As used herein, the terms "once monthly" or "qlm" or "once per month" refer to once per month and may be used interchangeably. In some embodiments, "once monthly" or "qlm" or "once per month" refers to once every 28 days ± 5 days, such as once every 23 days, once every 24 days, once every 25 days, once every 26 days, once every 27 days, once every 28 days, once every 29 days, once every 30 days, once every 31 days, once every 32 days, or once every 33 days. In some embodiments, "once per month," or "qlm," or "once per month" means once every 28 days ± 3 days, e.g., once every 25 days, once every 26 days, once every 27 days, once every 28 days, once every 29 days, once every 30 days, or once every 31 days, etc. The "once per month," "qlm," or "once per month" administration can be administered on any day of the month, e.g., day 1, day 2, day 3, etc. A subsequent administration of the "once per month," "qlm," or "once per month" formulation is then administered one month later, e.g., 28 days ± 5 days, or 28 days ± 3 days later.

[0049] In some embodiments, the present disclosure provides a pharmaceutical composition for administration by subcutaneous injection, comprising: 20% to 45% (w / w) olanzapine; 35% to 65% (w / w) organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); wherein the diblock copolymer and the triblock copolymer together constitute 10% to 25% of the composition by weight (w / w).

[0050] The pharmaceutical composition of the present disclosure is administered by subcutaneous injection. Subcutaneous injection can be performed at any suitable site on the skin of the subject to which the composition is administered. Exemplary sites include the abdomen, arms, lower back, thighs, etc.

[0051] In some embodiments, the compositions of the present disclosure comprise 20% to 45%, optionally 22% to 34%, optionally 30% to 32% olanzapine by weight (w / w), such as 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 40.5%, 41.0%, 41.5%, 42.0%, 42.5%, 43.0%, 43.5%, 44.0%, 44.5%, 45.0%, 45.5%, 46.0%, 46.5%, 47.0%, 47.5%, 48.0%, 48.5%, 49.0%, 49.5%, 50.0%, 50.5%, 51.0%, 51.5%, 52.0%, 52.5%, 53.0%, 53.5%, 54.0%, 54.5%, 55.0%, 55.5%, 56.0%, 56.5%, 57.0%, 57.5%, 5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 41.0%, 41.5%, 42.0%, 42.5%, 43.0%, 43.5%, 44.0%, 44.5%, or 45.0% of the olanzapine.

[0052] In some embodiments, the compositions of the present disclosure comprise about 20% to about 45% olanzapine by weight (w / w), such as about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41.0%, about 41.5%, about 42.0%, about 42.5%, about 43.0%, about 43.5%, about 44.0%, about 44.5%, or about 45.0% olanzapine by weight (w / w).

[0053] In some embodiments, the compositions of the present disclosure contain 22% to 34% olanzapine by weight (w / w), such as 22.0%, 22.5%, 23%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, or 34.0% olanzapine by weight (w / w).

[0054] In another embodiment, the compositions of the present disclosure contain about 22% to about 34% olanzapine by weight (w / w), such as about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, or about 34% olanzapine by weight (w / w).

[0055] In some embodiments, the compositions of the present disclosure contain 20% to 24% olanzapine by weight (w / w), such as 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23%, 23.5%, or 24.0% olanzapine by weight (w / w).

[0056] In another embodiment, the compositions of the present disclosure comprise about 20% to 24% olanzapine by weight (w / w), such as about 20.0%, about 20.5%, about 21.0%, about 21.5%, about 22.0%, about 22.5%, about 23%, about 23.5%, or about 24.0% olanzapine by weight (w / w).

[0057] In some embodiments, the compositions of the present disclosure comprise 20.5% olanzapine by weight (w / w).

[0058] In another embodiment, the compositions of the present disclosure comprise about 20.5% olanzapine by weight (w / w).

[0059] In some embodiments, the compositions of the present disclosure comprise 22.0% olanzapine by weight (w / w).

[0060] In another embodiment, the compositions of the present disclosure comprise about 22.0% olanzapine by weight (w / w).

[0061] In some embodiments, the compositions of the present disclosure comprise 23.5% olanzapine by weight (w / w).

[0062] In another embodiment, the compositions of the present disclosure comprise about 23.5% olanzapine by weight (w / w).

[0063] In some embodiments, the compositions of the present disclosure comprise 30% to 32% olanzapine by weight (w / w), such as 30.0%, 30.5%, 31%, 31.5%, or 32.0% olanzapine by weight (w / w).

[0064] In another embodiment, the compositions of the present disclosure comprise about 30% to about 32% olanzapine by weight (w / w), such as about 30%, about 31%, or about 32% olanzapine by weight (w / w).

[0065] In some embodiments, the compositions of the present disclosure comprise 26.5% olanzapine by weight (w / w).

[0066] In another embodiment, the compositions of the present disclosure comprise about 26.5% olanzapine by weight (w / w).

[0067] In some embodiments, the compositions of the present disclosure comprise 29.0% olanzapine by weight (w / w).

[0068] In another embodiment, the compositions of the present disclosure comprise about 29.0% olanzapine by weight (w / w).

[0069] In some embodiments, the compositions of the present disclosure comprise 30.5% olanzapine by weight (w / w).

[0070] In another embodiment, the compositions of the present disclosure comprise about 30.5% olanzapine by weight (w / w).

[0071] In some embodiments, the compositions of the present disclosure comprise 32.0% olanzapine by weight (w / w).

[0072] In another embodiment, the compositions of the present disclosure comprise about 32.0% olanzapine by weight (w / w).

[0073] In some embodiments, the compositions of the present disclosure comprise 33.5% olanzapine by weight (w / w).

[0074] In another embodiment, the compositions of the present disclosure comprise about 33.5% olanzapine by weight (w / w).

[0075] In some embodiments, the compositions of the present disclosure contain 40% to 45% olanzapine by weight (w / w), such as 40.0%, 40.5%, 40.7%, 41.0%, 41.5%, 42.0%, 42.5%, 43.0%, 43.5%, 44.0%, 44.5%, or 45.0% olanzapine by weight (w / w).

[0076] In another embodiment, the compositions of the present disclosure comprise about 40% to about 45% olanzapine by weight (w / w), such as about 40.0%, about 40.5%, about 40.7%, about 41.0%, about 41.5%, about 42.0%, about 42.5%, about 43.0%, about 43.5%, about 44.0%, about 44.5%, or about 45.0% olanzapine by weight (w / w).

[0077] In some embodiments, the compositions of the present disclosure comprise 40.7% olanzapine by weight (w / w).

[0078] In another embodiment, the composition of the present disclosure comprises about 40.7% olanzapine by weight (w / w).

[0079] In some embodiments, the compositions of the present disclosure comprise 42.0% olanzapine by weight (w / w).

[0080] In another embodiment, the compositions of the present disclosure comprise about 42.0% olanzapine by weight (w / w).

[0081] In some embodiments, the compositions of the present disclosure comprise 43.5% olanzapine by weight (w / w).

[0082] In another embodiment, the compositions of the present disclosure comprise about 43.5% olanzapine by weight (w / w).

[0083] In some embodiments, the compositions of the present disclosure contain about 220 mg to about 340 mg of olanzapine per gram of composition, e.g., about 220 mg, about 221 mg, about 222 mg, about 223 mg, about 224 mg, about 225 mg, about 226 mg, about 227 mg, about 228 mg, about 229 mg, about 230 mg, about 231 mg, about 232 mg, about 233 mg, about 234 mg, about 235 mg, about 236 mg, about 237 mg, about 238 mg, about 239 mg, about 240 mg, about 241 mg, about 242 mg, about 243 mg, about 244 mg, about 245 mg, about 246 mg, about 247 mg, about 248 mg, about 249 mg, about 250 mg, about 251 mg, about 252 mg, about 253 mg, about 254 mg, about 255 mg, about 256 mg, about 257 mg, about 258 mg, about 259 mg, about 260 mg, about 261 mg, about 262 mg, about 263 mg, about 264 mg, about 265 mg, about 266 mg, about 267 mg, about 268 mg, about 269 mg, about 270 mg, about 271 mg, about 272 mg, about 273 mg, about 274 mg, about 275 mg, about 276 mg, about 277 mg, about 278 mg, about 279 mg, about 280 mg, about 281 mg, about 282 mg, about 283 mg, about 284 mg, about 285 mg, about 286 mg, about 3mg, about 244mg, about 245mg, about 246mg, about 247mg, about 248mg, about 249mg, about 250mg, about 251mg, about 252mg, about 253mg, about 254mg, about 255mg, about 256mg, about 257mg, about 258mg, about 259mg, About 260mg, about 261mg, about 262mg, about 263mg, about 264mg, about 265mg, about 266mg, about 267mg, about 268mg, about 269mg, about 270mg, about 271mg, about 272mg, about 273mg, about 274mg, about 275mg, about 276m g, approx. 277 mg, approx. 278 mg, approx. 279 mg, approx. 280 mg, approx. 281 mg, approx. 282 mg, approx. 283 mg, approx. 284 mg, approx. 285 mg, approx. 93mg, about 294mg, about 295mg, about 296mg, about 297mg, about 298mg, about 299mg, about 300mg, about 301mg, about 302mg, about 303mg, about 304mg, about 305mg, about 306mg, about 307mg, about 308mg, about 309mg, The dosage contains about 310 mg, about 311 mg, about 312 mg, about 313 mg, about 314 mg, about 315 mg, about 316 mg, about 317 mg, about 318 mg, about 319 mg, about 320 mg, about 321 mg, about 322 mg, about 323 mg, about 324 mg, about 325 mg, about 326 mg, about 327 mg, about 328 mg, about 329 mg, about 330 mg, about 331 mg, about 332 mg, about 333 mg, about 334 mg, about 335 mg, about 336 mg, about 337 mg, about 338 mg, about 339 mg, or about 340 mg of olanzapine.

[0084] In some embodiments, the compositions of the present disclosure contain 265 mg of olanzapine per gram of composition. In some embodiments, the compositions of the present disclosure contain about 265 mg of olanzapine per gram of composition.

[0085] In some embodiments, the compositions of the present disclosure contain 290 mg of olanzapine per gram of composition. In some embodiments, the compositions of the present disclosure contain about 290 mg of olanzapine per gram of composition.

[0086] In some embodiments, the compositions of the present disclosure contain 305 mg of olanzapine per gram of composition. In some embodiments, the compositions of the present disclosure contain about 305 mg of olanzapine per gram of composition.

[0087] In some embodiments, the compositions of the present disclosure contain 320 mg of olanzapine per gram of composition. In some embodiments, the compositions of the present disclosure contain about 320 mg of olanzapine per gram of composition.

[0088] In some embodiments, the compositions of the present disclosure contain 335 mg of olanzapine per gram of composition. In some embodiments, the compositions of the present disclosure contain about 335 mg of olanzapine per gram of composition.

[0089] In some embodiments, the composition of the present disclosure comprises an organic solvent.The organic solvent suitable for use in the composition of the present disclosure includes benzyl alcohol, benzyl benzoate, diethylene glycol dimethyl ether (diglyme), diethylene glycol monoethyl ether (DEGMEE), dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, ethylene glycol monoethyl ether acetate, glycerin formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2, tetraglycol, triacetin, tributyrin, tripropionin, or triethylene glycol dimethyl ether (triglyme), or a mixture of the above-mentioned solvents.

[0090] In some embodiments, the compositions of the present disclosure comprise 35% to 65% by weight (w / w), optionally 50% to 55% of said organic solvent, for example, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 40.5%, 41.0%, 41.5%, 42.0%, 42.5%, 43.0%, 43.5%, 44.0%, 44.5%, 45.0%, 45.5%, 46.0%, 46.5%, 47.0%, 47.5% by weight (w / w) of said organic solvent. , 48.0%, 48.5%, 49.0%, 49.5%, 50.0%, 50.5%, 51.0%, 51.5%, 52.0%, 52.5%, 53.0%, 53.5%, 54.0%, 54.5%, 55.0%, 55.5%, 56.0%, 56.5%, 57.0%, 57.5%, 58.0%, 58.5%, 59.0%, 59.5%, 60.0%, 60.5%, 61.0%, 61.5%, 62.0%, 62.5%, 63.0%, 63.5%, 64.0%, 64.5%, or 65.0% organic solvent.

[0091] In some embodiments, the compositions of the present disclosure comprise about 35% to about 65% by weight (w / w) of the organic solvent, such as about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, or about 65% by weight (w / w).

[0092] In some embodiments, the organic solvent comprises dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof.

[0093] In some embodiments, the organic solvent comprises dimethyl sulfoxide (DMSO). In some embodiments, the organic solvent is preferably dimethyl sulfoxide (DMSO).

[0094] In another embodiment, the organic solvent comprises N-methyl-2-pyrrolidinone (NMP). In another embodiment, the organic solvent is N-methyl-2-pyrrolidinone (NMP).

[0095] In yet another embodiment, the organic solvent is a mixture of dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidinone (NMP). In such an embodiment, the DMSO and the NMP may be present in any ratio. In yet another embodiment, the DMSO is preferably present in a higher weight ratio than the NMP.

[0096] In some embodiments, the compositions of the present disclosure comprise 35% to 40% organic solvent by weight (w / w), such as 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, or 40.0% by weight (w / w).

[0097] In another embodiment, the composition of the present disclosure comprises about 35% to about 40% organic solvent by weight (w / w), such as about 35.0%, about 35.5%, about 36.0%, about 36.5%, about 37.0%, about 37.5%, about 38.0%, about 38.5%, about 39.0%, about 39.5%, or about 40.0% by weight (w / w).

[0098] In some embodiments, the compositions of the present disclosure comprise 35% by weight (w / w) of said organic solvent.

[0099] In another embodiment, the composition of the present disclosure comprises about 35% by weight (w / w) of said organic solvent.

[0100] In some embodiments, the compositions of the present disclosure comprise 37.1% by weight (w / w) of said organic solvent.

[0101] In another embodiment, the composition of the present disclosure comprises about 37.1% by weight (w / w) of said organic solvent.

[0102] In some embodiments, the compositions of the present disclosure comprise 38% by weight (w / w) of said organic solvent.

[0103] In another embodiment, the composition of the present disclosure comprises about 38% by weight (w / w) of said organic solvent.

[0104] In some embodiments, the compositions of the present disclosure comprise 50% to 55% organic solvent by weight (w / w), such as 50.0%, 50.5%, 51.0%, 51.5%, 52.0%, 52.5%, 53.0%, 53.5%, 54.0%, 54.5%, or 55.0% of the organic solvent by weight (w / w).

[0105] In another embodiment, the composition of the present disclosure comprises about 50% to about 55% by weight (w / w) of the organic solvent, such as about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% by weight (w / w).

[0106] In some embodiments, the compositions of the present disclosure comprise 50% by weight (w / w) of said organic solvent.

[0107] In another embodiment, the composition of the present disclosure comprises about 50% by weight (w / w) of said organic solvent.

[0108] In some embodiments, the compositions of the present disclosure comprise 52% by weight (w / w) of said organic solvent.

[0109] In another embodiment, the composition of the present disclosure comprises about 52% by weight (w / w) of said organic solvent.

[0110] In some embodiments, the compositions of the present disclosure comprise 53.5% by weight (w / w) of said organic solvent.

[0111] In another embodiment, the composition of the present disclosure comprises about 53.5% by weight (w / w) of said organic solvent.

[0112] In some embodiments, the compositions of the present disclosure comprise 54% by weight (w / w) of said organic solvent.

[0113] In another embodiment, the composition of the present disclosure comprises about 54% by weight (w / w) of said organic solvent.

[0114] In some embodiments, the compositions of the present disclosure comprise 55% by weight (w / w) of said organic solvent.

[0115] In another embodiment, the composition of the present disclosure comprises about 55% by weight (w / w) of said organic solvent.

[0116] In some embodiments, the compositions of the present disclosure comprise 58% to 62% organic solvent by weight (w / w), such as 58.0%, 58.5%, 59.0%, 59.5%, 60.0%, 60.5%, 61.0%, 61.5%, or 62.0% of the organic solvent by weight (w / w).

[0117] In another embodiment, the composition of the present disclosure comprises about 58% to about 62% organic solvent by weight (w / w), such as about 58.0%, about 58.5%, about 59.0%, about 59.5%, about 60.0%, about 60.5%, about 61.0%, about 61.5%, or about 62.0% by weight (w / w).

[0118] In some embodiments, the compositions of the present disclosure comprise 58.5% by weight (w / w) of said organic solvent.

[0119] In another embodiment, the composition of the present disclosure comprises about 58.5% by weight (w / w) of said organic solvent.

[0120] In some embodiments, the compositions of the present disclosure comprise 60.0% by weight (w / w) of said organic solvent.

[0121] In another embodiment, the composition of the present disclosure comprises about 60.0% by weight (w / w) of said organic solvent.

[0122] In some embodiments, the compositions of the present disclosure comprise 61.5% by weight (w / w) of said organic solvent.

[0123] In another embodiment, the composition of the present disclosure comprises about 61.5% by weight (w / w) of said organic solvent.

[0124] In some embodiments, the compositions of the present disclosure comprise a diblock copolymer and a triblock copolymer.

[0125] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises polylactic acid (PLA) and polyethylene glycol (PEG).

[0126] In some embodiments, the polylactic acid (PLA) in the diblock copolymer is composed of randomly distributed D-lactic acid and L-lactic acid monomer units.

[0127] In some embodiments, the polyethylene glycol (PEG) in the diblock copolymer is end-capped with a C1-C6 alkyl group, such as -CH3, -CH2CH3, etc. That is, the terminal hydroxyl group at one end of the polyethylene glycol (PEG) chain is end-capped with a C1-C6 alkyl group, and the terminal hydroxyl group at the other end of the PEG chain forms an ester bond to the polylactic acid (PLA) chain.

[0128] In some embodiments, the polyethylene glycol (PEG) in the diblock copolymer is end-capped with -CH3. Such a capped PEG may also be referred to as mPEG. That is, the terminal hydroxyl group at one end of the polyethylene glycol (PEG) chain is capped with -CH3, and the terminal hydroxyl group at the other end of the PEG chain forms an ester bond to the polylactic acid (PLA) chain. Typically, the diblock copolymer can be obtained by ring-opening polymerization of D,L-lactide initiated by the terminal hydroxyl group of the mPEG chain.

[0129] In some embodiments, the diblock copolymer in the composition of the present disclosure has the structure: [ka] (where n is the number of ethylene oxide units in PEG, and m is the number of lactic acid units in PLA). The theoretical molecular weight of the diblock copolymer can be calculated using the molar mass of the lactic acid unit (M(LA)=72 g / mol) and the molar mass of the ethylene oxide unit (M(EO)=44 g / mol) and the number of repeating units in each block as follows: MW(mPEG-PLA)=n×44+m×72+32. Typically, the diblock copolymer in the composition of the present disclosure has a theoretical molecular weight of 6 to 15 kg / mol. In one embodiment, the diblock copolymer has a theoretical molecular weight of 8.0 to 12.5 kg / mol or 6.0 to 9.5 kg / mol.

[0130] In some embodiments, the diblock copolymer in the composition of the present disclosure has a number average molecular weight of 6 to 15 kg / mol and comprises 70% to 90% polylactic acid by weight (w / w).

[0131] In some embodiments, the diblock copolymer in the composition of the present disclosure has a molecular weight of 6 to 15 kg / mol, optionally 6.5 to 13.5 kg / mol, e.g., 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, or 15.0 kg / mol.

[0132] In some embodiments, the diblock copolymer in the composition of the present disclosure has a molecular weight of about 6 to about 15 kg / mol, e.g., about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, about 10.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.7, about 10.8, about 10.9, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, about 11.6, about 11.7, about 11.8, about 11.9, about 12.1, about 12.2, about 12.3, about 12.4, about 12.5, about 12.6, about 12.7, about 12.8, about 12.9, about 13.1, about 13.1, about 13.2, about 13.3, about 13.4, about 1 .8, approximately 7.9, approximately 8.0, approximately 8.1, approximately 8.2, approximately 8.3, approximately 8.4, approximately 8.5, approximately 8.6, approximately 8.7, approximately 8.8, approximately 8.9, approximately 9.0, approximately 9.1, approximately 9.2, approximately 9.3, approximately 9.4, approximately 9.5, approximately 9.6, approximately 9.7, approximately 9.8, approximately 9.9, approximately 10.0, approximately 10.1, approximately 10.2, approximately 10.3, approximately 10.4, approximately 10.5, approximately 10.6, about 10.7, about 10.8, about 10.9, about 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, about 11.6, about 11.7, about 11.8, about 11.9, about 12.0, about 12.1, about 12.2, about 12.3, about 12.4, about 12.5, about 12.6, about 12.7, about 12.8, about 12.9, about 1 and the like. The number average molecular weight is about 3.0, about 13.1, about 13.2, about 13.3, about 13.4, about 13.5, about 13.6, about 13.7, about 13.8, about 13.9, about 14.0, about 14.1, about 14.2, about 14.3, about 14.4, about 14.5, about 14.6, about 14.7, about 14.8, about 14.9, or about 15.0 kg / mol.

[0133] In some embodiments, the diblock copolymer has a number average molecular weight of 7.0 to 12.5 kg / mol. In other embodiments, the diblock copolymer has a number average molecular weight of 7.0 to 11.0 kg / mol. In some embodiments, the diblock copolymer has a number average molecular weight of about 10.0 kg / mol. In other embodiments, the diblock copolymer has a number average molecular weight of about 9.0 kg / mol.

[0134] In some embodiments, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 1.9 to 4.0, such as 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0.

[0135] In some embodiments, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 1.9 to about 3.5, optionally about 1.9 to about 2.9, such as about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, or about 3.5.

[0136] In some embodiments, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 2.4.

[0137] In another embodiment, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 2.4.

[0138] In another embodiment, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 2.8.

[0139] In another embodiment, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 2.8.

[0140] In some embodiments, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 3.2.

[0141] In another embodiment, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 3.2.

[0142] In some embodiments, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 3.5.

[0143] In another embodiment, the diblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 3.5.

[0144] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 70% to 90%, optionally 75% to 84%, optionally 84% to 88% polylactic acid by weight (w / w), such as 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% polylactic acid by weight (w / w).

[0145] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises about 70% to about 90% polylactic acid by weight (w / w), such as about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90% polylactic acid by weight (w / w).

[0146] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 75% to 84% polylactic acid by weight (w / w), such as 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, or 84% polylactic acid by weight (w / w).

[0147] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 75% to about 84% polylactic acid by weight (w / w), such as about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, or about 84% polylactic acid by weight (w / w).

[0148] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 76% polylactic acid by weight (w / w).

[0149] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 76% polylactic acid by weight (w / w).

[0150] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 80% polylactic acid by weight (w / w).

[0151] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 80% polylactic acid by weight (w / w).

[0152] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 82% polylactic acid by weight (w / w).

[0153] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 82% polylactic acid by weight (w / w).

[0154] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 73% to 77% polylactic acid by weight (w / w), such as 73%, 74%, 75%, 76%, or 77% polylactic acid by weight (w / w).

[0155] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 73% to about 77% polylactic acid by weight (w / w), such as about 73%, about 74%, about 75%, about 76%, or about 77% polylactic acid by weight (w / w).

[0156] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 73% polylactic acid by weight (w / w).

[0157] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 73% polylactic acid by weight (w / w).

[0158] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 75% polylactic acid by weight (w / w).

[0159] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 75% polylactic acid by weight (w / w).

[0160] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 77% polylactic acid by weight (w / w).

[0161] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 77% polylactic acid by weight (w / w).

[0162] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 84% ​​to 88% polylactic acid by weight (w / w), such as 84%, 85%, 86%, 87%, or 88% polylactic acid by weight (w / w).

[0163] In another embodiment, the diblock copolymer in the composition of the present disclosure comprises about 84% to 88% polylactic acid by weight (w / w), such as about 84%, about 85%, about 86%, about 87%, or about 88% polylactic acid by weight (w / w).

[0164] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 84% ​​polylactic acid by weight (w / w).

[0165] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises about 84% polylactic acid by weight (w / w).

[0166] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 86% polylactic acid by weight (w / w).

[0167] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises about 86% polylactic acid by weight (w / w).

[0168] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises 88% polylactic acid by weight (w / w).

[0169] In some embodiments, the diblock copolymer in the composition of the present disclosure comprises about 88% polylactic acid by weight (w / w).

[0170] In some embodiments, the weight ratio of the diblock copolymer to the triblock copolymer is from 6:1 to 2:1, optionally about 4:1.

[0171] In some embodiments, the compositions of the present disclosure comprise 10% to 18%, optionally 10 to 15%, optionally 12 to 17% by weight (w / w) of the diblock copolymer, such as 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, or 18% by weight (w / w) of the diblock copolymer.

[0172] In some embodiments, the compositions of the present disclosure comprise about 10% to about 17% by weight (w / w) of the diblock copolymer, such as about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, or about 18% by weight (w / w) of the diblock copolymer.

[0173] In some embodiments, the composition of the present disclosure comprises 17.8% by weight (w / w) of said diblock copolymer.

[0174] In another embodiment, the composition of the present disclosure comprises about 17.8% by weight (w / w) of said diblock copolymer.

[0175] In some embodiments, the compositions of the present disclosure comprise 10% to 15% by weight (w / w) of the diblock copolymer, for example, 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1% by weight (w / w). , 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, 15.0%, and the like.

[0176] In some embodiments, the compositions of the present disclosure comprise about 10 to about 15% by weight (w / w) of the diblock copolymer, such as about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight (w / w) of the diblock copolymer.

[0177] In some embodiments, the composition of the present disclosure comprises 12.2% by weight (w / w) of said diblock copolymer.

[0178] In another embodiment, the composition of the present disclosure comprises about 12.2% by weight (w / w) of said diblock copolymer.

[0179] In some embodiments, the composition of the present disclosure comprises 12.8% by weight (w / w) of said diblock copolymer.

[0180] In another embodiment, the composition of the present disclosure comprises about 12.8% by weight (w / w) of said diblock copolymer.

[0181] In some embodiments, the composition of the present disclosure comprises 13.2% by weight (w / w) of said diblock copolymer.

[0182] In another embodiment, the composition of the present disclosure comprises about 13.2% by weight (w / w) of said diblock copolymer.

[0183] In some embodiments, the composition of the present disclosure comprises 13.6% by weight (w / w) of said diblock copolymer.

[0184] In another embodiment, the composition of the present disclosure comprises about 13.6% by weight (w / w) of said diblock copolymer.

[0185] In some embodiments, the composition of the present disclosure comprises 14.0% by weight (w / w) of said diblock copolymer.

[0186] In another embodiment, the composition of the present disclosure comprises about 14.0% by weight (w / w) of said diblock copolymer.

[0187] In some embodiments, the composition of the present disclosure comprises 14.4% by weight (w / w) of said diblock copolymer.

[0188] In another embodiment, the composition of the present disclosure comprises about 14.4% by weight (w / w) of said diblock copolymer.

[0189] In some embodiments, the triblock copolymer in the composition of the present disclosure comprises polylactic acid (PLA) and polyethylene glycol (PEG).

[0190] In some embodiments, the polylactic acid (PLA) in the triblock copolymer is composed of randomly distributed D-lactic acid and L-lactic acid monomer units.

[0191] In some embodiments, the triblock copolymer in the composition of the present disclosure is an ABA copolymer, where the A group is polylactic acid and the B group is polyethylene glycol (PEG). In these embodiments, the terminal hydroxyl groups at either end of the polyethylene glycol (PEG) chain form an ester bond to the polylactic acid (PLA) chain. Typically, the triblock copolymer can be obtained by ring-opening polymerization of D,L-lactide initiated by the terminal hydroxyl groups of the PEG chain.

[0192] In some embodiments, the triblock copolymer in the composition of the present disclosure has the structure: [ka] (where n is the number of ethylene oxide units in PEG, and each m is the number of lactic acid units in the PLA group to which it refers). The theoretical molecular weight of the triblock copolymer can be calculated using the molar mass of the lactic acid unit (M(LA), 72 g / mol) and the molar mass of the ethylene oxide unit (M(EO), 44 g / mol) and the number of repeating units in each block as follows: MW(PLA-PEG-PLA) = n x 44 + 2 x m x 72 + 18. The triblock copolymer in the composition of the present disclosure has a theoretical molecular weight of 6 to 19 kg / mol. In one embodiment, the triblock copolymer has a theoretical molecular weight of 6.5 to 9.0 kg / mol or 10.0 to 17.0 kg / mol.

[0193] In some embodiments, the triblock copolymer in the composition of the present disclosure has a number average molecular weight of 6 to 19 kg / mol and comprises 80% to 90% polylactic acid by weight (w / w).

[0194] In some embodiments, the triblock copolymer in the composition of the present disclosure has a viscosity of 6 to 19 kg / mol, optionally 6 to 13 kg / mol, optionally 9 to 18 kg / mol, optionally 7 to 12 kg / mol, optionally 10 to 17 kg / mol, e.g., 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.10, 8.11, 8.12, 8.13, 8.14, 8.15, 8.16, 8.17, 8.18, 8.19, 8.20, 8.21, 8.22, 8.23, 8.24, 8.25, 8.26, 8.27, 8.28, 8.29, 8.30, 8.31, 8.32, 8.33, 8.34, 8.35, 8.36, 8.37, 8.38, 8.39, 8.40, 8.41, 8.42, 8.43, 8.44, 8.45, 8.46, 8.47, 8.48, 8.49, 8.50, 8.51, 8.52, 8.53, 8.54, 8.55, 8.56, 8.57, 8.58, 8.59, 8.60, 8.61, 8.62, 8.63, 8. .6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, or 19.0 kg / mol.

[0195] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molecular weight of about 6 to about 19 kg / mol, optionally about 6 to about 13 kg / mol, optionally about 9 to about 18 kg / mol, optionally about 7 to about 12 kg / mol, optionally about 10 to about 17 kg / mol, e.g., about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, about 10.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.7 7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, about 10.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.7, about 10.8, about 10.9, about 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, Approximately 11.6, approximately 11.7, approximately 11.8, approximately 11.9, approximately 12.0, approximately 12.1, approximately 12.2, approximately 12.3, approximately 12.4, approximately 12.5, approximately 12.6, approximately 12.7, approximately 12.8, approximately 12.9, approximately 13.0, approximately 13.1, approximately 13.2, approximately 13.3, approximately 13.4, approximately 13.5, approximately 13.6, approximately 13.7, approximately 13.8, approximately 13.9, approximately 14.0, approximately 14.1, approximately 14.2, approximately 14.3, approximately 14.4, approximately 14.5, approximately 14.6, approximately 14.7, approximately 14.8, approximately 14.9, approximately 15. and the like.

[0196] The triblock copolymer may have a number average molecular weight of about 6 to about 13 kg / mol, optionally about 7 to about 12 kg / mol. The triblock copolymer may have a number average molecular weight of 9 to 18 kg / mol, optionally 10 to 17 kg / mol. The triblock copolymer may have a number average molecular weight of about 9.5 kg / mol. The triblock copolymer may have a number average molecular weight of about 14 kg / mol.

[0197] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 2.8 to 4.5, such as 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0198] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 2.8 to about 4.5, such as about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5.

[0199] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 3.5 to 4.5, such as 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0200] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 3.5 to about 4.5, such as about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5.

[0201] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 3.6.

[0202] In another embodiment, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 3.6.

[0203] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 3.8.

[0204] In another embodiment, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 3.8.

[0205] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 4.0.

[0206] In another embodiment, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 4.0.

[0207] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 4.2.

[0208] In another embodiment, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 4.2.

[0209] In some embodiments, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of 4.4.

[0210] In another embodiment, the triblock copolymer in the composition of the present disclosure has a molar ratio of lactic acid to ethylene oxide of about 4.4.

[0211] In some embodiments, the triblock copolymer in the composition of the present disclosure comprises 80% to 90% polylactic acid by weight (w / w), such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% polylactic acid by weight (w / w).

[0212] In some embodiments, the triblock copolymer in the composition of the present disclosure comprises about 80% to about 90% by weight (w / w), optionally 83% to 88%, optionally 85% to 88%, optionally about 88% polylactic acid, such as about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90% polylactic acid.

[0213] In some embodiments, the triblock copolymer in the composition of the present disclosure comprises 83% to 88% polylactic acid by weight (w / w), such as 83%, 84%, 85%, 86%, or 87% or 88% polylactic acid by weight (w / w).

[0214] In another embodiment, the triblock copolymer in the composition of the present disclosure comprises about 83% to about 88% polylactic acid by weight (w / w), such as about 83%, about 84%, about 85%, about 86%, about 87%, or about 88% polylactic acid by weight (w / w).

[0215] In some embodiments, the triblock copolymer in the composition of the present disclosure comprises 85% to 88% polylactic acid by weight (w / w), such as 85%, 86%, 87%, or 88% polylactic acid by weight (w / w).

[0216] In some embodiments, the triblock copolymer in the composition of the present disclosure comprises about 85% to about 88% polylactic acid by weight (w / w), such as about 85%, about 86%, about 87%, or about 88% polylactic acid by weight (w / w).

[0217] In some embodiments, the triblock copolymer in the composition of the present disclosure preferably comprises about 85% polylactic acid by weight (w / w).

[0218] In some embodiments, the triblock copolymer in the composition of the present disclosure preferably comprises about 87% polylactic acid by weight (w / w).

[0219] In some embodiments, the triblock copolymer in the composition of the present disclosure comprises 82% to 87% polylactic acid by weight (w / w), such as 82%, 83%, 84%, 85%, 86%, or 87% polylactic acid by weight (w / w). In some embodiments, the triblock copolymer in the composition of the present disclosure preferably comprises 85% polylactic acid by weight (w / w).

[0220] In some embodiments, the triblock copolymer in the composition of the present disclosure comprises about 82% to about 87% polylactic acid by weight (w / w), such as about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, or about 88% polylactic acid by weight (w / w). In some embodiments, the triblock copolymer in the composition of the present disclosure preferably comprises about 85% polylactic acid by weight (w / w).

[0221] In some embodiments, the compositions of the present disclosure comprise 3% to 5% by weight (w / w), optionally 3% to 4% of said triblock copolymer, such as 3%, 4%, or 5% by weight (w / w) of said triblock copolymer.

[0222] In some embodiments, the compositions of the present disclosure comprise about 3% to about 5% by weight (w / w) of the triblock copolymer, such as about 3%, about 4%, or about 5% by weight (w / w) of the triblock copolymer.

[0223] In some embodiments, the compositions of the present disclosure comprise 3% to 4% by weight (w / w) of the triblock copolymer, such as 3% or 4% by weight (w / w) of the triblock copolymer.

[0224] In some embodiments, the compositions of the present disclosure comprise about 3% to about 4% by weight (w / w) of the triblock copolymer, such as about 3% or about 4% by weight (w / w) of the triblock copolymer.

[0225] In some embodiments, the compositions of the present disclosure comprise 3.0% by weight (w / w) of said triblock copolymer.

[0226] In another embodiment, the composition of the present disclosure comprises about 3.0% by weight (w / w) of said triblock copolymer.

[0227] In some embodiments, the compositions of the present disclosure comprise 3.2% by weight (w / w) of said triblock copolymer.

[0228] In another embodiment, the composition of the present disclosure comprises about 3.2% by weight (w / w) of said triblock copolymer.

[0229] In some embodiments, the compositions of the present disclosure comprise 3.5% by weight (w / w) of said triblock copolymer.

[0230] In another embodiment, the composition of the present disclosure comprises about 3.5% by weight (w / w) of said triblock copolymer.

[0231] In some embodiments, the compositions of the present disclosure comprise 3.6% by weight (w / w) of said triblock copolymer.

[0232] In another embodiment, the composition of the present disclosure comprises about 3.6% by weight (w / w) of said triblock copolymer.

[0233] In some embodiments, the compositions of the present disclosure comprise 3.7% by weight (w / w) of said triblock copolymer.

[0234] In another embodiment, the composition of the present disclosure comprises about 3.7% by weight (w / w) of said triblock copolymer.

[0235] In some embodiments, the composition of the present disclosure comprises 4.5% by weight (w / w) of said triblock copolymer.

[0236] In another embodiment, the composition of the present disclosure comprises about 4.5% by weight (w / w) of said triblock copolymer.

[0237] In some embodiments, in the compositions of the present disclosure, the diblock copolymer and the triblock copolymer together constitute 10% to 25% of the composition by weight (w / w), optionally 10 to 20%, optionally 14 to 20%, such as 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the composition by weight (w / w).

[0238] In some embodiments, in a composition of the present disclosure, the diblock copolymer and the triblock copolymer together constitute about 10% to about 25% by weight (w / w) of the composition, optionally about 10 to about 20%, optionally about 14 to about 20%, such as about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% of the composition.

[0239] In some embodiments, in the compositions of the present disclosure, the diblock copolymer and the triblock copolymer together comprise 12% of the composition by weight (w / w).

[0240] In another embodiment, in the composition of the present disclosure, the diblock copolymer and the triblock copolymer together comprise about 12% of the composition by weight (w / w).

[0241] In some embodiments, in the compositions of the present disclosure, the diblock copolymer and the triblock copolymer together comprise 14% of the composition by weight (w / w).

[0242] In another embodiment, in the composition of the present disclosure, the diblock copolymer and the triblock copolymer together comprise about 14% of the composition by weight (w / w).

[0243] In some embodiments, in the compositions of the present disclosure, the diblock copolymer and the triblock copolymer together comprise 16% of the composition by weight (w / w).

[0244] In another embodiment, in the composition of the present disclosure, the diblock copolymer and the triblock copolymer together comprise about 16% of the composition by weight (w / w).

[0245] In some embodiments, in the compositions of the present disclosure, the diblock copolymer and the triblock copolymer together comprise 18% of the composition by weight (w / w).

[0246] In another embodiment, in the composition of the present disclosure, the diblock copolymer and the triblock copolymer together comprise about 18% of the composition by weight (w / w).

[0247] In some embodiments, in the compositions of the present disclosure, the diblock copolymer and the triblock copolymer together comprise 20% of the composition by weight (w / w).

[0248] In another embodiment, in the composition of the present disclosure, the diblock copolymer and the triblock copolymer together comprise about 20% of the composition by weight (w / w).

[0249] In some embodiments, in the compositions of the present disclosure, the diblock copolymer and the triblock copolymer together comprise 22% of the composition by weight (w / w).

[0250] In another embodiment, in the composition of the present disclosure, the diblock copolymer and the triblock copolymer together comprise about 22% of the composition by weight (w / w).

[0251] In one embodiment, the composition comprises: 20%-45% (w / w) olanzapine; 35% to 65% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 10% to 17% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and 3% to 5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 13% to 22% of the composition by weight (w / w).

[0252] In one embodiment, the composition comprises: 22%–34% (w / w) olanzapine; 50% to 55% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 10% to 15% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and 3% to 4% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 13% to 19% of the composition by weight (w / w).

[0253] In one embodiment, the composition comprises: 30%-32% (w / w) olanzapine; 52% to 54% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 15% to 17.5% of the composition by weight (w / w).

[0254] In one embodiment, the composition comprises: 20%-45% (w / w) olanzapine; 35% to 65% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 10% to 17% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 13.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 13 kg / mol, and comprising 83% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 13% to 22% of the composition by weight (w / w).

[0255] In one embodiment, the composition comprises: 22%–34% (w / w) olanzapine; 50% to 55% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 10% to 15% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 12.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 4% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 13 kg / mol, and comprising 83% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 13% to 19% of the composition by weight (w / w).

[0256] In one embodiment, the composition comprises: 30%-32% (w / w) olanzapine; 52% to 54% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 12.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 13 kg / mol, and comprising 83% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 15% to 17.5% of the composition by weight (w / w).

[0257] In one embodiment, the composition comprises: 30%-32% (w / w) olanzapine; 52%-54% (w / w) dimethyl sulfoxide; 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 12.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 13 kg / mol, and comprising 83% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 15% to 17.5% of the composition by weight (w / w).

[0258] In one embodiment, the composition comprises: 20%-45% (w / w) olanzapine; 35% to 65% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 10% to 17% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 13.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 9 to 18 kg / mol, and comprising 83% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 13% to 22% of the composition by weight (w / w).

[0259] In one embodiment, the composition comprises: 22%–34% (w / w) olanzapine; 50% to 55% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 10% to 15% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 12.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 4% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol and having a number average molecular weight of 9 to 18 kg / mol and comprising 83% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 13% to 19% of the composition by weight (w / w).

[0260] In one embodiment, the composition comprises: 30%-32% (w / w) olanzapine; 52% to 54% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 12.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 9 to 18 kg / mol, and comprising 83% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 15% to 17.5% of the composition by weight (w / w).

[0261] In one embodiment, the composition comprises: 20%-40% (w / w) olanzapine; 40% to 65% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 10% to 17% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 7.0 to 12.5 kg / mol, and comprising 78% to 81% polylactic acid by weight (w / w); and 3% to 5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 7.0 to 12.0 kg / mol, and comprising 85% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 13% to 22% of the composition by weight (w / w).

[0262] In one embodiment, the composition comprises: 22%–34% (w / w) olanzapine; 50% to 55% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 10% to 15% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 7.0 to 12.5 kg / mol, and comprising 78% to 81% polylactic acid by weight (w / w); and 3% to 4% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 7.0 to 12.0 kg / mol, and comprising 85% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 13% to 19% of the composition by weight (w / w).

[0263] In one embodiment, the composition comprises: 30%-32% (w / w) olanzapine; 52% to 54% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 7.0 to 12.5 kg / mol, and comprising 78% to 81% polylactic acid by weight (w / w); and 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 7.0 to 12.0 kg / mol, and comprising 85% to 88% polylactic acid by weight (w / w); Including, The diblock copolymer and the triblock copolymer together comprise 15% to 17.5% of the composition by weight (w / w).

[0264] In some embodiments, the disclosure provides a container containing 318 mg to 950 mg, optionally 550 mg to 950 mg, optionally 450 mg to 800 mg of olanzapine; and The kit includes a container containing 0.73 to 2.5 grams, optionally 1.3 to 2.5 grams, or optionally 0.9 to 2.1 grams of a mixture of an organic solvent, which is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), or a combination thereof, and a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w), and a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 7 to 15 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w).

[0265] In some embodiments, the kits of the present disclosure comprise a container containing olanzapine.

[0266] In some embodiments, the kits of the present disclosure contain 318 mg to 950 mg, optionally 550 to 950 mg, optionally 450 mg to 800 mg of olanzapine, e.g., 318 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 5mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525m g, 530mg, 531mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 637mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 695mg, 70 0mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 743mg, 745mg, 750mg, 755mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785m The container contains olanzapine such as 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, or 950 mg.

[0267] In some embodiments, the kit of the present disclosure contains about 318 mg to about 950 mg, optionally about 550 to 950 mg, optionally 450 mg to 800 mg of olanzapine, for example, about 318 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520m g, approx. 525 mg, approx. 530 mg, approx. 531 mg, approx. 535 mg, approx. 540 mg, approx. 545 mg, approx. 550 mg, approx. 555 mg, approx. 560 mg, approx. 5mg, about 610mg, about 615mg, about 620mg, about 625mg, about 630mg, about 635mg, about 637mg, about 640mg, about 645mg, about 650mg, about 655mg, about 660mg, about 665mg, about 670mg, about 675mg, about 680mg, about 685mg, About 690mg, about 695mg, about 700mg, about 705mg, about 710mg, about 715mg, about 720mg, about 725mg, about 730mg, about 735mg, about 740mg, about 743mg, about 745mg, about 750mg, about 755mg, about 760mg, about 765mg, about 770m g, approx. 775 mg, approx. 780 mg, approx. 785 mg, approx. 790 mg, approx. 795 mg, approx. 800 mg, approx. 805 mg, approx. 810 mg, approx. 815 mg, approx. 820 mg, approx. 60mg, about 865mg, about 870mg, about 875mg, about 880mg, about 885mg, about 890mg, about 895mg, about 900mg, about 905mg, about 910mg, about 915mg, about 920mg, about 925mg, about 930mg, about 935mg, about 940mg, about 945mg,or a container containing about 950 mg of olanzapine.

[0268] In some embodiments, the kit of the present disclosure comprises a container containing 318 mg of olanzapine.

[0269] In another embodiment, the kit of the present disclosure comprises a container containing about 318 mg of olanzapine.

[0270] In some embodiments, the kit of the present disclosure comprises a container containing 575 mg of olanzapine.

[0271] In another embodiment, the kit of the present disclosure comprises a container containing about 575 mg of olanzapine.

[0272] In some embodiments, the kit of the present disclosure comprises a container containing 600 mg of olanzapine.

[0273] In another embodiment, the kit of the present disclosure comprises a container containing about 600 mg of olanzapine.

[0274] In some embodiments, the kit of the present disclosure comprises a container containing 710 mg of olanzapine.

[0275] In another embodiment, the kit of the present disclosure comprises a container containing about 710 mg of olanzapine.

[0276] In some embodiments, the kit of the present disclosure comprises a container containing 815 mg of olanzapine.

[0277] In another embodiment, the kit of the present disclosure comprises a container containing about 815 mg of olanzapine.

[0278] In some embodiments, the kit of the present disclosure comprises a container containing 885 mg of olanzapine.

[0279] In another embodiment, the kit of the present disclosure comprises a container containing about 885 mg of olanzapine.

[0280] In some embodiments, the kits of the present disclosure comprise a container containing a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer.

[0281] In some embodiments, the kits of the present disclosure comprise a container containing 0.73 to 2.5 grams, optionally 1.3 to 2.5 grams, optionally 0.9 to 2.1 grams of a mixture of organic solvent, diblock copolymer, and triblock copolymer, such as 0.73, 0.8, 0.9, 1.0, 1.1, 1.2, 1.26, 1.3, 1.4, 1.5, 1.50, 1.6, 1.7, 1.74, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 grams of a mixture of organic solvent, diblock copolymer, and triblock copolymer.

[0282] In some embodiments, the kits of the present disclosure include a container containing about 0.73 to about 2.5 grams, optionally about 1.3 to about 2.5 grams, of a mixture of organic solvent, diblock copolymer, and triblock copolymer, such as about 0.73, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.26, about 1.3, about 1.4, about 1.5, about 1.50, about 1.6, about 1.7, about 1.74, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 grams of a mixture of organic solvent, diblock copolymer, and triblock copolymer.

[0283] In some embodiments, the kit of the present disclosure comprises a container containing 0.73 to 2.5 grams of a mixture of an organic solvent, which is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), or a combination thereof, and a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w), and a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 7 to 15 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w).

[0284] In some embodiments, the container containing the mixture of the organic solvent, the diblock copolymer, and the triblock copolymer contains about 0.73 grams of the mixture.

[0285] In some embodiments, the container containing the mixture of the organic solvent, the diblock copolymer, and the triblock copolymer contains about 1.4 grams of the mixture.

[0286] In some embodiments, the container containing the mixture of the organic solvent, the diblock copolymer, and the triblock copolymer contains about 1.5 grams of the mixture.

[0287] In some embodiments, the container containing the mixture of the organic solvent, the diblock copolymer, and the triblock copolymer contains about 1.7 grams of the mixture.

[0288] In some embodiments, the container containing the mixture of the organic solvent, the diblock copolymer, and the triblock copolymer contains about 2.0 grams of the mixture.

[0289] In some embodiments of the kits of the present disclosure, the olanzapine in the kit has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, or a tap density of about 0.35 g / ml to 0.44 g / ml, or any combination thereof. Olanzapine having such characteristics is described in U.S. Provisional Patent Application No. 63 / 301,202, filed January 20, 2022.

[0290] As used herein, the term "D(90)" means that 90% of the particles (by volume) have a diameter equal to or less than the indicated value. For example, a D(90) (or d(90)) of 25 μm means that 90% of the particles (by volume) have a diameter equal to or less than 25 μm. As used herein, the term "D(3,2)" means the surface area moment average (Sauter Mean Diameter, SMD), which may be relevant when surface area is important, e.g., in dissolution, and reflects the amount of fine particles in a sample. Particle size is usually determined by laser diffraction, optionally using a Malvern Instruments Mastersizer instrument.

[0291] As used herein, "tapped density" (TD) refers to the ability of a powder sample to compact when tapped, providing a measure of powder cohesion and packing performance that can be related to its flowability. Tapped density can be determined by methods known to those skilled in the art. For example, bulk density / tapped density can be determined by European Pharmacopoeia 2.9.34. Method 1 (https: / / www.drugfuture.com / Pharmacopoeia / EP7 / DATA / 20934E.PDF; download PDF on November 14, 2021). In particular, bulk density and tapped density can be determined using an ERWEKA tapped density tester SVM 122 equipped with a 100 mL glass cylinder. Approximately 30 g of powder is poured into a 100 mL graduated cylinder using a funnel. Bulk density is calculated by dividing the amount of powder (grams) by the measured volume (mL). Tapped density is then determined as follows: Step (i) Tap the sample 10 times to remove the volume V 10 Read; Step (ii) Tap the sample 500 times (10 + 490) to obtain a volume V 500 Read; Step (iii) Tap the sample 1250 times (500 + 750) to obtain a volume V 1250 Read; Step (iv) Tap the sample 2500 times (1250 + 1250) to obtain a volume V 2500 Read; Step (v) V 500 and V 1250 If the difference is more than 2 mL, repeat the tap: That is, tap the sample an additional 1250 times and repeat until the difference is less than 2 mL. Bulk density = sample weight / volume before tapping. Tapped density = weight / volume after tapping. Calculation: Bulk density = m (mg) / V0 (mL) Tap density = m(mg) / V 2500 (mL)

[0292] See also Example 1 below.

[0293] In some embodiments of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of 20 μm to 37 μm, e.g., 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, or 37 μm.

[0294] In another embodiment of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, e.g., about 20 μm, about 21 μm, about 22 μm, about 23 μm, about 24 μm, about 25 μm, about 26 μm, about 27 μm, about 28 μm, about 29 μm, about 30 μm, about 31 μm, about 32 μm, about 33 μm, about 34 μm, about 35 μm, about 36 μm, or about 37 μm.

[0295] In some embodiments of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of 24 μm to 35 μm, e.g., 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, or 35 μm.

[0296] In another embodiment of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 24 μm to about 35 μm, e.g., about 24 μm, about 25 μm, about 26 μm, about 27 μm, about 28 μm, about 29 μm, about 30 μm, about 31 μm, about 32 μm, about 33 μm, about 34 μm, or about 35 μm.

[0297] In some embodiments of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of 5.5 μm to 7.5 μm, e.g., 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, or 7.5 μm.

[0298] In another embodiment of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, e.g., about 5.5 μm, about 5.6 μm, about 5.7 μm, about 5.8 μm, about 5.9 μm, about 6.0 μm, about 6.1 μm, about 6.2 μm, about 6.3 μm, about 6.4 μm, about 6.5 μm, about 6.6 μm, about 6.7 μm, about 6.8 μm, about 6.9 μm, about 7.0 μm, about 7.1 μm, about 7.2 μm, about 7.3 μm, about 7.4 μm, or about 7.5 μm.

[0299] In some embodiments of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of 5.8 μm to 7.0 μm, e.g., 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, or 7.0 μm.

[0300] In another embodiment of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.8 μm to about 7.0 μm, e.g., about 5.8 μm, about 5.9 μm, about 6.0 μm, about 6.1 μm, about 6.2 μm, about 6.3 μm, about 6.4 μm, about 6.5 μm, about 6.6 μm, about 6.7 μm, about 6.8 μm, about 6.9 μm, or about 7.0 μm.

[0301] In some embodiments of the kit of the present disclosure, the tap density of the olanzapine is 0.35 g / ml to 0.44 g / ml, such as 0.35 g / ml, 0.36 g / ml, 0.37 g / ml, 0.38 g / ml, 0.39 g / ml, 0.40 g / ml, 0.41 g / ml, 0.42 g / ml, 0.43 g / ml, or 0.44 g / ml.

[0302] In some embodiments of the kit of the present disclosure, the tap density of the olanzapine is about 0.35 g / ml to about 0.44 g / ml, such as about 0.35 g / ml, about 0.36 g / ml, about 0.37 g / ml, about 0.38 g / ml, about 0.39 g / ml, about 0.40 g / ml, about 0.41 g / ml, about 0.42 g / ml, about 0.43 g / ml, or about 0.44 g / ml.

[0303] In some embodiments of the kits of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm and a D(3,2) of about 5.5 μm to about 7.5 μm.

[0304] In another embodiment of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0305] In some embodiments of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0306] In another embodiment of the kit of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm and a D(3,2) of about 5.5 μm to about 7.5 μm, and has a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0307] In some embodiments of the kits of the present disclosure, the olanzapine comprises polymorphic Form II. In some embodiments of the kits of the present disclosure, the olanzapine is polymorphic Form II.

[0308] As used herein, Olanzapine Form II is the polymorphic form described in U.S. Patent No. 5,736,541. This Form II polymorph has an XRPD spectrum substantially as shown in Figure 1. The major typical peaks for Olanzapine Form II are defined as those at about 8.7, 12.5, 17.4, 19.9, 21.1, 21.6, 22.4, 24.0, 25.3, and 29.8±0.2 degrees 2θ.

[0309] In some embodiments of the kit of the present disclosure, the container containing olanzapine is a vial.

[0310] In some embodiments of the kit of the present disclosure, the container containing olanzapine is a glass vial.

[0311] In some embodiments of the kit of the present disclosure, the container containing olanzapine is a 10 mL glass vial.

[0312] In some embodiments of the kit of the present disclosure, the container containing olanzapine is a sterile glass vial.

[0313] In some embodiments of the kit of the present disclosure, the container containing olanzapine is a 10 mL sterile glass vial.

[0314] In some embodiments of the kit of the present disclosure, the container containing the mixture of organic solvent, diblock copolymer, and triblock copolymer is a syringe.

[0315] In some embodiments of the kit of the present disclosure, the container containing the mixture of the organic solvent, the diblock copolymer, and the triblock copolymer is a 2.0-2.5 mL syringe.

[0316] In some embodiments of the kit of the present disclosure, the container containing the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.25 mL syringe.

[0317] In some embodiments of the kit of the present disclosure, the container holding the mixture of organic solvent, diblock copolymer, and triblock copolymer is a sterile syringe.

[0318] In some embodiments of the kit of the present disclosure, the container containing the mixture of the organic solvent, diblock copolymer, and triblock copolymer is a 2.0-2.5 mL sterile syringe.

[0319] In some embodiments of the kit of the present disclosure, the container holding the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.25 mL sterile syringe.

[0320] In some embodiments of the kit of the present disclosure, the container containing the mixture of organic solvent, diblock copolymer, and triblock copolymer is a pre-filled syringe.

[0321] In some embodiments of the kit of the present disclosure, the container containing the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.0-2.5 mL pre-filled syringe.

[0322] In some embodiments of the kit of the present disclosure, the container holding the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.25 mL pre-filled syringe.

[0323] In some embodiments of the kit of the present disclosure, the container holding the mixture of organic solvent, diblock copolymer, and triblock copolymer is a sterile, pre-filled syringe.

[0324] In some embodiments of the kit of the present disclosure, the container containing the mixture of the organic solvent, diblock copolymer, and triblock copolymer is a 2.0-2.5 mL sterile pre-filled syringe.

[0325] In some embodiments of the kit of the present disclosure, the container holding the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.25 mL sterile pre-filled syringe.

[0326] In some embodiments, the kit of the present disclosure further comprises a needle. The needle is attachable to the syringe and allows for subcutaneous injection of the composition of the present disclosure. In some embodiments, the needle is a 21-gauge needle. These embodiments are advantageous compared to other formulations known in the art, such as ZYPREXA RELPREVV®, which require a significantly larger inner diameter, i.e., a 16-gauge needle. A smaller inner diameter, i.e., a 21-gauge needle, generally causes less injection site pain and less patient anxiety.

[0327] In some embodiments, the needle has a length of 5 / 8 inch (approximately 15.8 mm). These embodiments are advantageous compared to other formulations known in the art, such as ZYPREXA RELPREVV®, which utilize a 1.5 inch long needle. Shorter needles generally cause less injection site pain and create less patient anxiety.

[0328] In some embodiments, the kits of the present disclosure are used to prepare the pharmaceutical compositions of the present disclosure.

[0329] In some embodiments, the pharmaceutical composition of the present disclosure is prepared from the kit by 1) disposing the contents of the pre-filled syringe (organic solvent, diblock copolymer, and triblock copolymer) into the vial containing olanzapine; and 2) mixing the contents of the vial to form the pharmaceutical composition. The composition can then be administered to a patient by withdrawing all or a portion of the composition from the vial using the syringe and then subcutaneously injecting the composition into the patient.

[0330] In some aspects, the present disclosure is directed to a method of preparing the pharmaceutical composition of the present disclosure, the method comprising adding a mixture of the organic solvent, the diblock copolymer, and the triblock copolymer to solid olanzapine.

[0331] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, or a tap density of about 0.35 g / ml to 0.44 g / ml, or any combination thereof.

[0332] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of 20 μm to 37 μm, e.g., 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, or 37 μm.

[0333] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, e.g., about 20 μm, about 21 μm, about 22 μm, about 23 μm, about 24 μm, about 25 μm, about 26 μm, about 27 μm, about 28 μm, about 29 μm, about 30 μm, about 31 μm, about 32 μm, about 33 μm, about 34 μm, about 35 μm, about 36 μm, or about 37 μm.

[0334] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of 24 μm to 35 μm, e.g., 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, or 35 μm.

[0335] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 24 μm to about 35 μm, e.g., about 24 μm, about 25 μm, about 26 μm, about 27 μm, about 28 μm, about 29 μm, about 30 μm, about 31 μm, about 32 μm, about 33 μm, about 34 μm, or about 35 μm.

[0336] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of 5.5 μm to 7.5 μm, e.g., 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, or 7.5 μm.

[0337] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, e.g., about 5.5 μm, about 5.6 μm, about 5.7 μm, about 5.8 μm, about 5.9 μm, about 6.0 μm, about 6.1 μm, about 6.2 μm, about 6.3 μm, about 6.4 μm, about 6.5 μm, about 6.6 μm, about 6.7 μm, about 6.8 μm, about 6.9 μm, about 7.0 μm, about 7.1 μm, about 7.2 μm, about 7.3 μm, about 7.4 μm, or about 7.5 μm.

[0338] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of 5.8 μm to 7.0 μm, e.g., 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, or 7.0 μm.

[0339] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.8 μm to about 7.0 μm, e.g., about 5.8 μm, about 5.9 μm, about 6.0 μm, about 6.1 μm, about 6.2 μm, about 6.3 μm, about 6.4 μm, about 6.5 μm, about 6.6 μm, about 6.7 μm, about 6.8 μm, about 6.9 μm, or about 7.0 μm.

[0340] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the tap density of the olanzapine is 0.35 g / ml to 0.44 g / ml, such as 0.35 g / ml, 0.36 g / ml, 0.37 g / ml, 0.38 g / ml, 0.39 g / ml, 0.40 g / ml, 0.41 g / ml, 0.42 g / ml, 0.43 g / ml, or 0.44 g / ml.

[0341] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the tap density of the olanzapine is about 0.35 g / ml to about 0.44 g / ml, such as about 0.35 g / ml, about 0.36 g / ml, about 0.37 g / ml, about 0.38 g / ml, about 0.39 g / ml, about 0.40 g / ml, about 0.41 g / ml, about 0.42 g / ml, about 0.43 g / ml, or about 0.44 g / ml.

[0342] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm and a D(3,2) of about 5.5 μm to about 7.5 μm.

[0343] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0344] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0345] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm and a D(3,2) of about 5.5 μm to about 7.5 μm, and has a tap density of about 0.35 g / ml to about 0.44 g / ml.

[0346] In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine comprises polymorphic Form II. In some embodiments of the method of preparing a pharmaceutical composition of the present disclosure, the olanzapine is polymorphic Form II.

[0347] In some embodiments of the method of preparing the pharmaceutical composition of the present disclosure, the mixture of the organic solvent, the diblock copolymer comprising polylactic acid and polyethylene glycol, and the triblock copolymer comprising polylactic acid and polyethylene glycol is added via syringe to the solid olanzapine contained in a vial.

[0348] In some embodiments, the present disclosure is directed to a method of administering olanzapine to a patient comprising subcutaneously injecting the patient with a pharmaceutical composition of the present disclosure.

[0349] In some aspects, the present disclosure is directed to a method of treating a disease or disorder that is schizophrenia, schizoaffective disorder, bipolar disorder, or a depressive state in a patient in need thereof, comprising subcutaneously administering to the patient a pharmaceutical composition of the present disclosure.

[0350] In a specific embodiment, tolerance is established with oral olanzapine treatment before initiating treatment with said subcutaneous injection.

[0351] In some embodiments, the disclosed methods comprise subcutaneously injecting the patient with a pharmaceutical composition of the present disclosure. In such embodiments, the subcutaneous injection can be administered to any suitable site on the patient's body. In some embodiments, the subcutaneous injection is administered to the patient's abdomen. In another embodiment, the subcutaneous injection is administered to the patient's upper arm. In another embodiment, the subcutaneous injection is administered to the patient's thigh. In another embodiment, the subcutaneous injection is administered to the patient's back.

[0352] In some embodiments, the disease or disorder is schizophrenia.

[0353] In some embodiments, the disease or disorder is schizoaffective disorder.

[0354] In some embodiments, the disease or disorder is bipolar disorder.

[0355] In some embodiments, the disease or disorder is depression.

[0356] In some embodiments of the methods of treatment of the present disclosure, the patient has a PANSS total score of 80 or greater and 120 or less, prior to subcutaneous administration of a composition of the present disclosure (e.g., at the start of a single patient treatment, or at baseline (prior to randomization) for a patient population), along with a score of ≧4 on at least two of the following four PANSS positive subscale items: hallucinatory behavior, delusions, impaired conceptual integration, or suspiciousness / persecutory feelings.

[0357] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously contains 300 mg to 600 mg of olanzapine, e.g., 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg g, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg of olanzapine.

[0358] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously is 300-350 mg, optionally 310-320 mg, e.g., 300 mg, 301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306 mg, 307 mg, 308 mg, 309 mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315 mg, 316 mg, 317 mg, 318 mg, 319 mg, 320 mg, including olanzapine such as 321 mg, 322 mg, 323 mg, 324 mg, 325 mg, 326 mg, 327 mg, 328 mg, 329 mg, 330 mg, 331 mg, 332 mg, 333 mg, 334 mg, 335 mg, 336 mg, 337 mg, 338 mg, 339 mg, 340 mg, 341 mg, 342 mg, 343 mg, 344 mg, 345 mg, 346 mg, 347 mg, 348 mg, 349 mg, or 350 mg.

[0359] In some embodiments, the pharmaceutical composition administered subcutaneously comprises about 318 mg of olanzapine. In some embodiments, the pharmaceutical composition administered subcutaneously comprises about 323 mg of olanzapine. In some embodiments, the pharmaceutical composition administered subcutaneously comprises about 328 mg of olanzapine.

[0360] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously comprises 400-450 mg, optionally 415-435 mg, e.g., 400 mg, 401 mg, 402 mg, 403 mg, 404 mg, 405 mg, 406 mg, 407 mg, 408 mg, 409 mg, 410 mg, 411 mg, 412 mg, 413 mg, 414 mg, 415 mg, 416 mg, 417 mg, 418 mg, 419 mg, 420 mg, including olanzapine such as 421 mg, 422 mg, 423 mg, 424 mg, 425 mg, 426 mg, 427 mg, 428 mg, 429 mg, 430 mg, 431 mg, 432 mg, 433 mg, 434 mg, 435 mg, 436 mg, 437 mg, 438 mg, 439 mg, 440 mg, 441 mg, 442 mg, 443 mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449 mg, or 450 mg.

[0361] In some embodiments, the pharmaceutical composition administered subcutaneously comprises about 425 mg of olanzapine. In some embodiments, the pharmaceutical composition administered subcutaneously comprises about 430 mg of olanzapine. In some embodiments, the pharmaceutical composition administered subcutaneously comprises about 435 mg of olanzapine.

[0362] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously is 500-550 mg, optionally 520-540 mg, e.g., 500 mg, 501 mg, 502 mg, 503 mg, 504 mg, 505 mg, 506 mg, 507 mg, 508 mg, 509 mg, 510 mg, 511 mg, 512 mg, 513 mg, 514 mg, 515 mg, 516 mg, 517 mg, 518 mg, 519 mg, 520 mg, including olanzapine such as 521 mg, 522 mg, 523 mg, 524 mg, 525 mg, 526 mg, 527 mg, 528 mg, 529 mg, 530 mg, 531 mg, 532 mg, 533 mg, 534 mg, 535 mg, 536 mg, 537 mg, 538 mg, 539 mg, 540 mg, 541 mg, 542 mg, 543 mg, 544 mg, 545 mg, 546 mg, 547 mg, 548 mg, 549 mg, or 550 mg.

[0363] In some embodiments, the pharmaceutical composition administered subcutaneously comprises 531 mg of olanzapine. In some embodiments, the pharmaceutical composition administered subcutaneously comprises about 536 mg of olanzapine. In some embodiments, the pharmaceutical composition administered subcutaneously comprises about 541 mg of olanzapine.

[0364] In some embodiments of the disclosed methods of treatment, the subcutaneously administered composition contains about 300 mg to about 600 mg of olanzapine, e.g., about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, and about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, or about 600 mg of olanzapine.

[0365] In some embodiments of the disclosed methods of treatment, the subcutaneously administered composition comprises about 318 mg of olanzapine.

[0366] In some embodiments of the disclosed methods of treatment, the subcutaneously administered composition comprises about 425 mg of olanzapine.

[0367] In some embodiments of the disclosed methods of treatment, the subcutaneously administered composition comprises about 531 mg of olanzapine.

[0368] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of 0.5 mL to 2.0 mL, such as 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, or 2.0 mL.

[0369] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of about 0.5 mL to about 2.0 mL, such as about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, or about 2.0 mL.

[0370] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of 0.5 mL to 1.8 mL, such as 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, or 1.8 mL.

[0371] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of about 0.5 mL to about 1.8 mL, such as about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, or about 1.8 mL.

[0372] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of 0.9 mL to 1.5 mL.

[0373] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of 0.9 mL.

[0374] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of about 0.9 mL.

[0375] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of 1.2 mL.

[0376] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of about 1.2 mL.

[0377] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of 1.5 mL.

[0378] In some embodiments of the disclosed methods of treatment, the pharmaceutical composition administered subcutaneously has a volume of about 1.5 mL.

[0379] In some embodiments of the disclosed methods of treatment, the AUC ∞ AUC of oral olanzapine (after a single subcutaneous administration of the pharmaceutical composition) tau The dose-normalized ratios for the 28-day period ranged from 0.97 to 1.29.

[0380] In some embodiments of the disclosed methods of treatment, the AUC ∞ AUC of oral olanzapine (after a single subcutaneous administration of the pharmaceutical composition) tau The dose-normalized ratio for (calculated over a 28-day period) is approximately 1.1.

[0381] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an increase in olanzapine plasma C within 11 to 14 days after administration. max This results in the patient having

[0382] As used herein, "C max " refers to the peak plasma concentration of olanzapine.

[0383] Without intending to be bound by theory, it is believed that upon subcutaneous injection of the pharmaceutical composition of the present disclosure, the organic solvent diffuses away and the block copolymer (which is not soluble in aqueous media) precipitates, thereby forming a depot that entraps the olanzapine. Olanzapine is slowly released from this depot by drug diffusion and / or slow depot degradation to achieve and maintain therapeutic drug levels over a period of time. In some embodiments, the period is 28 days ± 5 days, e.g., 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the period is 30 days or about 30 days. In some embodiments, the period is 60 days or about 60 days.

[0384] In the method of the present disclosure, the pharmaceutical composition of the present disclosure is subcutaneously administered once a month. Thus, the treatment regimen using the composition of the present disclosure includes a series of monthly subcutaneous injections. Each monthly subcutaneous injection, for example, reaches a peak plasma concentration of olanzapine, C max , t max and are associated with pharmacokinetic parameters such as AUC.

[0385] In some embodiments of the disclosed methods of treatment, a patient reaches a steady state such that there is no significant change in the patient's olanzapine pharmacokinetic parameters with successive monthly subcutaneous injections. In some embodiments, the steady state is reached between the first and second monthly subcutaneous injections. In other embodiments, the steady state is reached between the second and third monthly subcutaneous injections.

[0386] In some embodiments of the disclosed methods of treatment, the patient receives olanzapine C in successive monthly subcutaneous injections. max A steady state C where there is no significant change in max In some embodiments, steady state is reached after the second monthly subcutaneous injection. In other embodiments, steady state is reached after the third monthly subcutaneous injection.

[0387] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 100 ng / mL. max This results in the patient having

[0388] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 100 ng / mL after a first subcutaneous injection. max This results in the patient having

[0389] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 100 ng / mL after a second subcutaneous injection. max This results in the patient having

[0390] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 100 ng / mL after the third subcutaneous injection. max This results in the patient having

[0391] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 90 ng / mL. max This results in the patient having

[0392] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 90 ng / mL after a first subcutaneous injection. max This results in the patient having

[0393] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 90 ng / mL after a second subcutaneous injection. max This results in the patient having

[0394] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 90 ng / mL after the third subcutaneous injection. max This results in the patient having

[0395] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 80 ng / mL. max This results in the patient having

[0396] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 80 ng / mL after a first subcutaneous injection. max This results in the patient having

[0397] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 80 ng / mL after a second subcutaneous injection. max This results in the patient having

[0398] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 80 ng / mL after the third subcutaneous injection. max This results in the patient having

[0399] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 70 ng / mL. max This results in the patient having

[0400] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 70 ng / mL after a first subcutaneous injection. max This results in the patient having

[0401] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 70 ng / mL after a second subcutaneous injection. max This results in the patient having

[0402] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 70 ng / mL after the third subcutaneous injection. max This results in the patient having

[0403] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 60 ng / mL. max This results in the patient having

[0404] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 60 ng / mL after a first subcutaneous injection. max This results in the patient having

[0405] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 60 ng / mL after a second subcutaneous injection. max This results in the patient having

[0406] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 60 ng / mL after the third subcutaneous injection. max This results in the patient having

[0407] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 50 ng / mL. maxThis results in the patient having

[0408] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 50 ng / mL after a first subcutaneous injection. max This results in the patient having

[0409] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 50 ng / mL after a second subcutaneous injection. max This results in the patient having

[0410] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 50 ng / mL after the third subcutaneous injection. max This results in the patient having

[0411] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 40 ng / mL. max This results in the patient having

[0412] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 40 ng / mL after a first subcutaneous injection. max This results in the patient having

[0413] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 40 ng / mL after a second subcutaneous injection. max This results in the patient having

[0414] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in an olanzapine plasma C of less than 40 ng / mL after the third subcutaneous injection. max This results in the patient having

[0415] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having an olanzapine plasma level of at least 10 ng / mL for at least 21 of a 30-day period following the injection. In these embodiments, the 21 days during which the olanzapine plasma level is at least 10 ng / mL are not necessarily the first 21 of the 30 days following the injection, and are not necessarily a period of 21 consecutive days.

[0416] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having an olanzapine plasma level of at least 20 ng / mL for at least 21 of a 30-day period following the injection. In these embodiments, the 21-day period during which the olanzapine plasma level is at least 20 ng / mL is not necessarily the first 21 days of the 30-day period following the injection, and is not necessarily a consecutive 21-day period.

[0417] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having an olanzapine plasma level of at least 10 ng / mL for at least 30 of the 30 days following the injection.

[0418] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having an olanzapine plasma level of at least 20 ng / mL for at least 30 of the 30 days following the injection.

[0419] In some embodiments, the present disclosure is directed to a method of treating a patient with olanzapine, comprising: a) preparing a kit of the present disclosure; b) withdrawing the mixture of the organic solvent, diblock copolymer, and triblock copolymer from the container in the kit containing the mixture; c) adding the mixture of b) to the container in the kit containing olanzapine and then mixing to form a subcutaneous olanzapine pharmaceutical composition; and d) subcutaneously administering the subcutaneous olanzapine pharmaceutical composition to the patient in need of olanzapine treatment; wherein the treatment is effective in treating the patient for about one month.

[0420] In some embodiments of the disclosed methods of treatment, administration of the pharmaceutical composition to the patient by subcutaneous injection results in the patient having a lower score on the Positive and Negative Syndrome Scale (PANSS) than the patient had before receiving the subcutaneous injection of the composition. In some embodiments, the disclosed methods of treatment are superior to placebo in reducing the PANSS total score, e.g., by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 points, preferably by at least 6 points, more preferably by at least 8 points, and most preferably by at least 10 points, relative to placebo.

[0421] The PANSS is a 30-item scale used to assess positive and negative schizophrenic symptoms (Kay SR, Fiszbein A, Opler LA, "The positive and negative syndrome scale (PANSS) for schizophrenia." Schizophr Bull 1987;13(2):261-76). The PANSS is used to identify the presence and severity of psychopathological symptoms, the interrelationships between these symptoms, and overall psychopathology. Each item is scored on a 7-point scale ranging from 1 (absent) to 7 (extremely severe). The positive symptom scale contains 7 items with a maximum score of 49; the negative symptom scale contains 7 items with a maximum score of 49; and the global psychopathology scale contains 16 items with a maximum score of 112.

[0422] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having a lower score on the Clinical Global Impression-Improvement (CGI-I) scale than the patient had before receiving the subcutaneous injection of the composition.

[0423] The CGI-I scale allows for a global assessment of the patient's overall improvement in their symptoms. The CGI-I scale assesses the patient's improvement relative to their own symptoms on a 7-point scale ranging from 1 (much improved) to 7 (much worse). See Guy, W., ECDEU Assessment Manual for Psychopharmacology, (Revised Edition), Rockville (Maryland): US Department of Health, Education, and Welfare; Public Health Service; Alcohol, Drug Abuse, and Mental Health Administration; National Institute of Mental Health, Psychopharmacology Research Branch. 1976b;218-22.

[0424] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having a lower score on the Clinical Global Impression-Severity (CGI-S) scale than the patient had before receiving the subcutaneous injection of the composition.

[0425] The CGI-S allows raters to rate the current severity of a patient's illness on a 1-7 scale, where 1 = normal / not at all impaired, 2 = borderline mentally impaired, 3 = mildly impaired, 4 = moderately impaired, 5 = markedly impaired, 6 = severely impaired, and 7 = most severely impaired patient. See Guy, W., ECDEU Assessment Manual for Psychopharmacology, (Revised Edition), Rockville (Maryland): US Department of Health, Education, and Welfare; Public Health Service; Alcohol, Drug Abuse, and Mental Health Administration; National Institute of Mental Health, Psychopharmacology Research Branch. 1976b;218-22.

[0426] In some embodiments of the disclosed methods of treatment, administration of the pharmaceutical composition to the patient by subcutaneous injection results in the patient having a lower score on a Patient Global Impression-Improvement (PGI-I) than the patient had before receiving the subcutaneous injection of the composition.

[0427] The PGI-I rating scale is a single-item patient-rated instrument that measures improvement in a patient's illness; patients rate the perceived change in their condition in response to therapy. Patients are instructed to select response options on a 1-7 rating scale, where 1 = very improved, 2 = much improved, 3 = slightly improved, 4 = no change, 5 = slightly worse, 6 = much worse, and 7 = very worse. See Steinert T, Eisele F, Langle G, Albani C, Flammer E, Borbe R. "PGI-I (patient's global impression) as an outcome and quality indicator of psychiatric in-patient treatment: results and concordance with doctor's assessments," Psychiatr Prax 2010;37(7):343-9.

[0428] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having a higher score on a Personal and Social Performance Scale (PSP) than the patient had prior to receiving the subcutaneous injection of the composition.

[0429] The PSP is a clinician-rated instrument measuring personal and social functioning in patients with schizophrenia. See Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R., "Development, reliability, and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning," Acta Psychiatr Scand 2000 Apr;101(4):323-9. The PSP is a single-item rating scale with 100 points divided into 10 equally spaced intervals. Scores are based on an assessment of the patient's functioning in four categories: 1) socially useful activities, including work and schoolwork; 2) personal and social relationships; 3) self-care; and 4) disruptive and aggressive behavior. Higher scores represent better personal and social functioning, a rating of 91-100 indicates more than adequate functioning, and a score below 30 indicates poor functioning requiring intensive monitoring.

[0430] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having a lower score on the Schizophrenia Quality of Life Scale (SQLS), Fourth Revision, than the patient had before receiving the subcutaneous injection of the composition.

[0431] The Schizophrenia Quality of Life Scale (SQLS), Fourth Revision (Martin CR, Allan R. Factor structure of the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4). Psychol Health Med 2007;12(2):126-34) is a 33-item measure generating three subscale scores: psychosocial, motivation / energy, and symptoms / side effects. See Wilkinson G, Hesdon B, Wild D, Cookson R, Farina C, Sharma V, et al. Self-report quality of life measure for people with schizophrenia: the SQLS. Br J Psychiatry 2000;177:42-6. Higher scores on the scale indicate lower quality of life.

[0432] In some embodiments of the disclosed methods of treatment, administering the pharmaceutical composition to the patient by subcutaneous injection results in the patient having a low score on the 3-stage EuroQol 5-item questionnaire (EQ-5D-3L).

[0433] The 3-point EuroQol 5-item questionnaire (EQ-5D-3L) is a standardized questionnaire assessing global health status. The EQ-5D-3L consists of two parts. In the first part, patients measure their health status in five domains (mobility, self-care, usual activities, pain / discomfort, and anxiety / depression) using a 1-3 rating scale, where 1 = no problems, 2 = some problems, and 3 = very problems. In the second part, patients measure their health status on a visual analog scale ranging from 0 to 100; a rating of 0 represents the worst imaginable health state and a rating of 100 represents the best imaginable health state. See EuroQol Group, "EuroQol - a new facility for the measurement of health-related quality of life," Health Policy 1990;16:199-208; Rabin R, de Charro F., "EQ-5D: a measure of health status from the EuroQol Group," Ann Med 2001;33(5):337-43.

[0434] In some embodiments of the disclosed methods of treatment, administration of the pharmaceutical composition results in the patient having a D2 receptor occupancy of 60-80%, optionally 65-80%, optionally 65-70%, as determined by positron emission tomography (PET).

[0435] The level of dopamine D2 receptor occupancy (D2RO) is recognized as one of the drivers of clinical efficacy and safety response to antipsychotic drugs. The currently accepted hypothesis is that for optimal antipsychotic activity and minimal side effects, striatal D2RO receptor occupancy should be between 60 and 80%; the lower threshold is necessary for clinical efficacy, while exceeding the upper threshold increases the risk of side effects, particularly extrapyramidal symptoms (EPS). The relationship between olanzapine concentration and striatal D2RO receptor occupancy can be calculated using the Emax model:

number

[0436] In some embodiments, the present disclosure is directed to a method of switching a patient from daily oral olanzapine therapy to a pharmaceutical composition of the present disclosure, comprising: i) administering a final dose of the daily oral olanzapine therapy orally, where the final dose is administered orally, after which no further oral olanzapine therapy is administered; and the next day, subcutaneously administering to the patient a pharmaceutical composition of the present disclosure; thereby switching the subject from daily oral olanzapine therapy to a long-acting injectable olanzapine formulation.

[0437] In some embodiments, the present disclosure is directed to a method of switching a patient from daily oral olanzapine therapy to a pharmaceutical composition of the present disclosure, comprising: i) administering a final dose of the daily oral olanzapine therapy orally, where no further oral olanzapine therapy is administered thereafter; and then, 2 to 7 days after the final oral dose, subcutaneously administering a pharmaceutical composition of the present disclosure to the patient; thereby switching the subject from daily oral olanzapine therapy to a long-acting injectable olanzapine formulation.

[0438] In another aspect, the present disclosure is directed to a method of switching a patient from a long-acting intramuscularly injectable olanzapine formulation to a pharmaceutical composition of the present disclosure without the need for additional oral olanzapine therapy, comprising administering a final dose of a long-acting intramuscularly injectable olanzapine formulation; and, at the time of the next dose, optionally one month after the previous dose if the previous dose was administered once a month, or optionally two weeks after the previous dose if the previous dose was administered once every two weeks, subcutaneously administering a pharmaceutical composition of the present disclosure, wherein the method is performed without administering additional oral olanzapine therapy to the patient.

[0439] Additionally, there is provided a method of switching a patient from a long-acting intramuscular olanzapine formulation to a pharmaceutical composition of the present disclosure, comprising: a) administering the final dose of the long-acting intramuscular olanzapine formulation; and b) administering to said patient at the next dose a pharmaceutical composition of the present disclosure. Includes: the final dose of the long-acting intramuscular olanzapine formulation contains 150 mg of olanzapine and the pharmaceutical composition of the present disclosure contains 318 mg of olanzapine; or the final dose of the long-acting intramuscular olanzapine formulation contains 300 mg of olanzapine and the pharmaceutical composition of the present disclosure contains 318 mg of olanzapine; or the final dose of the long-acting intramuscular olanzapine formulation contains 210 mg of olanzapine and the pharmaceutical composition of the present disclosure contains 425 mg of olanzapine; or the final dose of the long-acting intramuscular olanzapine formulation contains 405 mg of olanzapine and the pharmaceutical composition of the present disclosure contains 425 mg of olanzapine; or The method is provided wherein the final dose of the long-acting intramuscular injectable olanzapine formulation contains 405 mg of olanzapine and the pharmaceutical composition of the present disclosure contains 531 mg of olanzapine.

[0440] In an embodiment of the above method, after switching, there are no clinically meaningful changes from baseline in psychiatric, neurological, and clinical symptoms and the subject remains clinically stable.

[0441] As used in this context, the phrase "at the next dose" refers to the dosing event at which the next dose of the long-acting intramuscular olanzapine formulation would be administered if the long-acting intramuscular olanzapine formulation had not been discontinued. In some embodiments, the long-acting intramuscular olanzapine formulation is ZYPREXA RELPREVV®. In some embodiments, the long-acting intramuscular olanzapine formulation is administered once a month. In another embodiment, the long-acting intramuscular olanzapine formulation is administered once every two weeks.

[0442] In some embodiments, the present disclosure is directed to a method of treating an olanzapine-naive patient, comprising administering to the patient an oral daily dose of 10 mg to 20 mg of olanzapine for two consecutive days to assess the patient's tolerance of olanzapine, and if the patient tolerates the oral olanzapine, subcutaneously administering a pharmaceutical composition of the present disclosure. As used herein, an "olanzapine-naive patient" is a patient who has not previously been administered olanzapine.

[0443] The methods of treatment disclosed herein provide safe and effective treatment for schizophrenia, schizoaffective disorder, bipolar disorder, or depression. The efficacy of the disclosed methods can be demonstrated by clinical measures described herein (e.g., PANSS, CGI-S, etc.). The safety of the disclosed methods can be demonstrated by one or more of the following: absence of serious adverse events, absence of extrapyramidal symptoms, absence of injection pain and other injection site reactions (local tolerability), vital signs (blood pressure, pulse and orthostatic changes, and temperature), weight, clinical tests, electrocardiogram, concomitant medication use, time to all-cause discontinuation, all-cause discontinuation rate and discontinuation rate due to adverse events (tolerability), and the following rating scales: Abnormal Involuntary Movements Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale, Columbia Suicide Severity Rating Scale, and Calgary Depression Rating Scale for Schizophrenia.

[0444] In some embodiments, the subject's weight increases by less than 10%, optionally less than 9%, optionally less than 8%, optionally less than 7%, optionally less than 6%, optionally less than 5% compared to the subject's weight at the beginning of the treatment method.The subject's weight is usually measured during the treatment method.The weight can be measured over a period of 8, 48 or 56 weeks.

[0445] The safety of the disclosed methods is such that in some embodiments of the disclosed methods, it is not necessary to monitor the patient for PDSS. In these embodiments, the administering physician is not required to monitor the patient for PDSS. [Example]

[0446] (Example) List of abbreviations [Table 1] TIFF2026501805000006.tif235170TIFF2026501805000007.tif236170TIFF2026501805000008.tif235170TIFF2026501805000009.tif57170

[0447] For reference, the pharmacokinetics and dose proportionality of IM olanzapine are listed:

[0448] Intramuscular olanzapine pharmacokinetics

[0449] Immediate-release intramuscular injection (Zyprexa Intramuscular) provides rapid absorption, with peak plasma concentrations occurring within 15 to 45 minutes. Based on pharmacokinetic studies in healthy volunteers, a 5 mg dose of intramuscular olanzapine produces, on average, a maximum plasma concentration approximately 5-fold higher than that produced by a comparable dose of oral olanzapine. The AUC achieved after an intramuscular dose is similar to that achieved after oral administration of the same dose. The half-life observed after intramuscular administration is similar to that observed after oral administration. The pharmacokinetic profile is linear over the clinical dosage range. The metabolic profile after intramuscular administration is qualitatively similar to that after oral administration.

[0450] The sustained-release (slow-dissolving) intramuscular injection (ZYPREXA RELPREVV® [olanzapine pamoate]) produces prolonged systemic olanzapine plasma concentrations over weeks to months. The fundamental pharmacokinetic properties of olanzapine are similar between ZYPREXA RELPREVV® and daily oral olanzapine. The alteration to the sustained-release and rate-controlled absorption process is the only fundamental pharmacokinetic difference between ZYPREXA RELPREVV® administration and oral olanzapine. ZYPREXA RELPREVV® injections every 2 or 4 weeks produce olanzapine plasma concentrations similar to those achieved by daily oral olanzapine administration. Steady-state plasma concentrations for ZYPREXA RELPREVV® at doses of 150 mg to 405 mg every 2 or 4 weeks are within the range of steady-state olanzapine plasma concentrations known to be associated with a once-daily oral dose of 5 to 20 mg of olanzapine. The effective half-life of olanzapine after intramuscular ZYPREXA RELPREVV® administration is approximately 30 days, in contrast to the half-life of approximately 30 hours after oral administration. Olanzapine exposure can persist for several months after ZYPREXA RELPREVV® injection. The long-term persistence of olanzapine systemic concentrations may be an important consideration in the long-term clinical management of patients. Typical systemic olanzapine plasma concentrations peak within the first week after injection, reaching trough levels immediately prior to the next injection. Olanzapine plasma concentration fluctuations between peak and trough are comparable to those associated with once-daily oral dosing.

[0451] Dose proportionality and oral dose correspondence

[0452] ZYPREXA RELPREVV® is available in the following dosing regimens: 150 mg / 2 weeks, 300 mg / 4 weeks, 210 mg / 2 weeks, 405 mg / 4 weeks, or 300 mg / 2 weeks. Higher dose injections result in a dose-proportional increase in systemic exposure. ZYPREXA RELPREVV® olanzapine exposure corresponds to the oral olanzapine dose and dosing regimen, as detailed in the table below: Recommended Dosing of ZYPREXA RELPREVV Based on Correspondence to Oral ZYPREXA Doses. [Table 2] Source: ZYPREXA RELPREVV® US Package Insert, 2018

[0453] Example 1: Materials Copolymers were synthesized by the method described in U.S. Pat. No. 6,350,812, incorporated herein by reference with minor modifications. Typically, the required amount of PEG (to give triblock copolymers) or methoxy-PEG (to give diblock copolymers) was heated to 65°C and dried under vacuum in a reaction vessel for 2 hours. D,L-lactide (corresponding to the desired lactic acid / ethylene oxide (LA / EO) molar ratio) and zinc lactate (1 / 1000 of the amount of lactide) were added. The reaction mixture was first dehydrated by three short vacuum / N2 cycles. The reaction mixture was heated to 140°C and rapidly degassed under vacuum. The reaction was carried out at 140°C for 4 days under a constant nitrogen flow (0.2 bar). The reaction was cooled to room temperature, and the contents were dissolved in acetone and then precipitated with ethanol. The resulting product was then dried under reduced pressure. Alternatively, the copolymers may be purchased from Corbion.

[0454] The resulting product was analyzed for its residual lactide content and for determination of the LA / EO molar ratio. 1 It was characterized by 1 H NMR. 1 H NMR spectroscopy was performed using a Brucker Advance 300 MHz spectrometer. 1For H NMR spectrograms, TopSpin software was used for integration of the characteristic peaks of PLA and PEG and their analysis. Chemical shifts were referenced to the solvent value of CDCl3 at δ = 7.26 ppm.

[0455] The resulting product was further characterized by gel permeation chromatography (GPC) to determine its molecular weight distribution. GPC was performed using an LC system equipped with a refractive index detector. The instrument was equipped with a series of Waters styragel columns selected from HR4, HR3, HR2, and HR1, maintained at constant temperature. Samples were analyzed in BHT-stabilized THF at a constant flow rate. Molecular weight distributions (Mn; Mw, and polydispersity index) were determined by conventional calibration using polystyrene calibration standards.

[0456] Olanzapine polymorph Form II was used. Characterization included X-ray diffraction analysis (XRD), particle size distribution, and bulk / tap density.

[0457] A typical XRD profile obtained is shown in Figure 1. The major typical peaks of olanzapine Form II are defined as those at about 8.7, 12.5, 17.4, 19.9, 21.1, 21.6, 22.4, 24.0, 25.3 and 29.8 ± 0.2 degrees 2θ.

[0458] For purposes herein, particle size distribution (PSD) is determined as percent volume, i.e., D(90) and D(3,2), and was measured by laser diffraction using a Malvern Mastersizer 2000 fitted with a Hydro 2000 S dispersion unit.

[0459] Measurements were carried out in saturated aqueous dispersion medium (refractive index = 1.22 (general purpose)). Samples were added as a thick suspension under stirring until a 10-20% obscuration ratio was reached. Results were derived from 10 measurement cycles with a 30 second recirculation time (after sonication). The following parameters were used: Dispersion unit: Hydro 2000 S Measurement range: 0.02 to 2000 μm Analytical models: general purpose, standard, Mie model Sensitivity: Standard ·Particle shape: irregular Sample refractive index: 1.709 Absorption: 0.01 Dispersant: Olanzapine saturated aqueous dispersion medium Dispersion medium refractive index: 1.330 ·Occupation: 10~20% Pump / agitator speed: 2500 rpm Level Sensor Threshold: 64% Sample measurement time: 10 seconds Background measurement time: 10 seconds Replicates (per aliquot): 10 Internal ultrasound: 30 seconds at 90% power Recirculation time (after sonication): 30 seconds Number of measurements (aliquots): 1

[0460] Sample preparation: Samples were prepared as thick suspensions. Approximately 50-100 mg of olanzapine sample was added to a small glass beaker using a spatula, and a few drops of saturated aqueous dispersion medium were added. A paste was obtained by gentle mixing to obtain a thick, homogeneous suspension, and an additional volume (1 ml) of saturated aqueous dispersion medium was added.

[0461] Bulk density / tapped density was determined by European Pharmacopoeia 2.9.34 method 1 (https: / / www.drugfuture.com / Pharmacopoeia / EP7 / DATA / 20934E.PDF; PDF downloaded on November 14, 2021).

[0462] Bulk density and tapped density were determined using an ERWEKA tapped density tester SVM 122 fitted with a 100 mL glass cylinder. Approximately 30 g of powder was carefully poured into a 100 mL graduated cylinder using a funnel. Bulk density was calculated by dividing the amount of powder (grams) by the measured volume (mL). Tapped density was then calculated as follows: 10 taps - volume reading (=V10) 500 (10 + 490) taps - volume reading (= V500) 1250 (500 + 750) taps - volume reading (=V1250) 2500 (1250 + 1250) taps - volume reading (= V2500) It was decided as follows.

[0463] If the difference between V500 and V1250 was more than 2 mL, the tap was repeated: 1250 more taps, and so on until the difference was less than 2 mL. Bulk density = sample weight / volume before tapping. Tapped density = weight / volume after tapping. Calculation: Bulk density = m (mg) / V0 (mL) Tap density = m (mg) / V2500 (mL)

[0464] Example 2 Pharmacokinetic studies were conducted with selected test articles in young, untreated female dogs weighing approximately 8 kg. Six animals were assigned to each treatment group and identified prior to the start of the study.

[0465] Animals in the control group (Group 1) received repeated intramuscular doses of ZYPADHERA (which is identical to ZYPREXA RELPREVV®, marketed in the United States) in the thigh muscle every two weeks for two months. The reference product was reconstituted according to the instructions in the SPC (Special Product Description) to a concentration of 150 mg / mL olanzapine. 300 mg olanzapine (2 mL) per injection per animal was administered via a 19G 1" tube. 1 The injection was administered using a 1 / 2 needle.

[0466] Animals in Groups 2-5 received a single subcutaneous injection of the corresponding test article. The olanzapine dose was fixed at 405 mg, and the administration volume was adjusted based on the test article composition. The test article was reconstituted immediately prior to administration and injected using a 21G 1" needle. Injection of the test article in Group 3 was reported to be more difficult than in the other groups and therefore less optimal.

[0467] Table 2.1 provides an overview of the PK study design. (Table 2.1) [Table 3] N / A: Not applicable f(PLA) - Fraction (wt%) of polymer that is polylactic acid

[0468] The diblock copolymers were composed of polylactic acid and polyethylene glycol, had a number average molecular weight of 6.5-15 kg / mol, and contained 70%-90% polylactic acid by weight (w / w). The triblock copolymers were composed of polylactic acid and polyethylene glycol, had a number average molecular weight of 6-15 kg / mol, and contained 80%-90% polylactic acid by weight (w / w). In these experiments, the diblock copolymer was kept constant, and two triblock copolymers with different number average molecular weights were tested.

[0469] The first day of treatment was designated as day 0 (D0), and blood samples were collected as follows:

[0470] Group 1: before each injection and 1 hour, 3 hours, 6 hours, 12 hours, 24 hours (D1), 48 hours (D2), 72 hours (D3), 144 hours (D6), 216 hours (D9), 288 hours (D12) after each IM administration;

[0471] Groups 2 to 5: before each injection and 1 hour, 3 hours, 6 hours, 12 hours, 24 hours (D1), 48 hours (D2), 72 hours (D3), 144 hours (D6), 216 hours (D9), 288 hours (D12), 360 hours (D15), 432 hours (D18), 504 hours (D21), 576 hours (D24), 648 hours (D27), 720 hours (D30), 792 hours (D33), 864 hours (D36), 936 hours (D39), 1008 hours (D42), 1080 hours (D45), 1152 (D48), 1224 (D51), 1296 (D54), 1368 (D57), and 1440 (D60) after subcutaneous administration. After centrifugation, plasma was collected into tubes containing K2-EDTA and stored at −80°C until analyzed by LC MS / MS.

[0472] The results of the test are shown in Figure 2 and Table 2.2. (Table 2.2) [Table 4] (1) T max Report the median (Min-Max) for (2);(3);(4) Mean ± SD (3) SC case C 30D ;IMC trough **AUC 0-28D

[0473] As seen in Figure 2, the mean PK profiles confirmed the ability of the four compositions tested to release olanzapine over the target period of one month. For all of the SC formulations tested, plasma concentrations were quantifiable after one month, with the C obtained after intramuscular injection. trough Furthermore, during this month, the mean plasma levels of olanzapine obtained after subcutaneous injection were generally within the range of the mean plasma levels in the two-dose control group. The mean plasma profiles of the various test articles maintained a near-constant exposure for nearly three weeks after injection, followed by a slow rate of decline in plasma levels. C after subcutaneous administration of the various formulations max The value is the reference of ZypAdhera C maxIt was less than.

[0474] Example 3 Effect of warming or rubbing the injection site on the PK of Formulation 1 in male SD-IGS rats

[0475] The objective of this study was to evaluate the effect of external factors, namely, warming and rubbing at the injection site under clinically-like conditions, on the olanzapine PK profile within the first 24-hour post-dose period after a single subcutaneous dose of Formulation 1 in male SD-IGS rats.

[0476] Test Item D is representative of Formulation 1, which is a pharmaceutical composition of the present disclosure comprising: 30% to 32% (w / w) olanzapine; 52% to 54% (w / w) dimethyl sulfoxide; 12% to 14% (w / w) diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 12.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 3.5% (w / w) triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 13 kg / mol, and comprising 83% to 88% polylactic acid by weight (w / w); wherein the diblock copolymer and the triblock copolymer collectively constitute 15% to 17.5% of the composition by weight (w / w).

[0477] The study included a total of three groups with six animals per group. The study design is shown in Table 3.1. (Table 3.1 Test-Experimental Design) [Table 5] sc=subcutaneous

[0478] All groups received 70 μL of Formulation 1 subcutaneously at a target dose of 80 mg / kg, the maximum dose of Formulation 1 tolerated in SD-IGS rats.

[0479] Blood samples were collected from the tail vein of all animals using a serial collection scheme at the following time points: pre-dose, 10 minutes (Groups 1 and 2 only), 30 minutes, and 1, 2, 4, 4.5, 5.5, 12, 24, 48, and 72 hours after administration (serial sampling).

[0480] Olanzapine was present in all post-dose plasma samples, beginning at 10 minutes and disappearing at 24 hours in all samples from the animal.

[0481] Low variability (14-35%) in exposure parameters was observed in all groups. In all groups, olanzapine plasma concentrations increased immediately, reaching Cmax within 10 minutes after administration, followed by a decline to a plateau concentration by 72 hours. In the majority of study animals, Cmax occurred before challenge, and therefore, any changes in Cmax cannot be related to the challenge. In some animals, a moderate increase in olanzapine plasma concentrations was observed after challenge, with no significant effect on exposure.

[0482] Small spikes in olanzapine plasma concentrations were observed in some animals, but none could be associated with the load and were followed by parallel elimination compared to the rest of the group, suggesting that dose dumping was not occurring.

[0483] All groups had the same exposure as indicated by similar AUC0-72h values.

[0484] In conclusion, extreme injection site manipulation of Formulation 1, i.e., either warming or rubbing at 0.5 or 4 hours after injection, had no effect on the PK or local injection site tolerability of olanzapine in rats, supporting the conclusion that dose dumping with Formulation 1 is unlikely to occur in humans. Dose dumping is a phenomenon that results in premature and excessive release of drug. This can significantly increase drug concentrations in plasma and can lead to side effects and potential drug-induced toxicity.

[0485] Example 4 Following the encouraging PK results from the studies described in Examples 2 and 3, further studies were conducted in humans using Formulation 1.

[0486] The pharmaceutical product is intended for reconstitution, and a vehicle containing excipients is used for reconstitution.

[0487] Phase 1 clinical trial materials include the following components: One single-use vial of olanzapine powder or one empty vial (for placebo administration) 1 single-use PFS containing vehicle (diluent) Two 16-gauge reconstitution needles, one for adding the vehicle to the vial and one for withdrawing the reconstituted drug product (Formulation 1) into a dosing syringe. One Luer Lock disposable syringe with a Luer Lock tip One 21-gauge 16mm hypodermic safety needle with needle protector for subcutaneous administration

[0488] The drug product olanzapine and vehicle for the extended-release injectable suspension (Formulation 1) should be stored at 2°C to 8°C. At the specified storage conditions, the API (olanzapine) is a yellow powder and the vehicle is a frozen, opaque solid. Prior to reconstitution, both components must be adjusted to room temperature, at which point the drug product is a yellow powder and the vehicle is a clear, colorless solution. After reconstitution of the drug product (i.e., the drug substance powder and vehicle), a yellow, opaque suspension is obtained.

[0489] Example 5 This study is an open-label, SAD and MAD study evaluating the safety, tolerability, and PK of Formulation 1 in healthy subjects and patients diagnosed with schizophrenia or schizoaffective disorder. Healthy subjects will receive a maximum subtherapeutic dose of Formulation 1 of 105 mg, and patients will receive a maximum therapeutic dose of 566 mg. Patients will be clinically stable and not receiving antipsychotic treatment other than oral olanzapine at the time. Subjects and patients who met screening eligibility were assigned to one of eight active cohorts or a vehicle cohort, as detailed in Table 5.1 below.

[0490] Table 5.1 Study Treatment Assignment [Table 6] N / A=not applicable; sc=subcutaneous; q1m=once a month.

[0491] All cohorts included assessments of safety, tolerability, and intensive PK sampling.

[0492] With the exception of the 70 mg starting dose, the study followed an adaptive design in which the decision to increase the dose for Formulation 1 was based on a review of PK and safety data from the preceding lower dose of Formulation 1.

[0493] (Test results) All cohort subjects and patients received treatment as listed in Table 5.1; none of the protocol stopping rules were met.

[0494] (demographic characteristics) One hundred twenty-seven healthy subjects and patients met the inclusion criteria and were considered eligible for enrollment in the first phase of the study (the oral olanzapine treatment period).

[0495] A total of 36 healthy subjects and 91 patients (54 patients randomized to the single-dose formulation and 37 patients randomized to the multiple-dose formulation) were enrolled during the first phase of the study.

[0496] During Phase 2, a total of 30 healthy subjects and 71 patients received at least one dose of Formulation 1 and were included in the enrollment, safety, and pharmacokinetic analysis sets, respectively. An additional 6 healthy subjects were randomized to the vehicle treatment group in Phase 2 of the study.

[0497] (Pharmacokinetics) During the study, dosing was reduced from 7 days to 2 days in the single-dose patient cohorts (4 and 5) and the multiple-dose cohorts (8 and 9) during which a washout period was performed between the last oral dose of oral olanzapine and Formulation 1. No adjustment for the carryover effect of oral olanzapine concentration residues on Formulation 1 was performed for the noncompartmental analysis. This approach was considered reasonable because any olanzapine residues remaining after the last oral dose are expected to be eliminated within several hours after dosing with Formulation 1. Therefore, its impact on the PK parameters of Formulation 1 is expected to be minimal.

[0498] (Oral Olanzapine Pharmacokinetics) Oral olanzapine (Zyprexa®) was administered for 7 days at subtherapeutic doses (2.5 and 5 mg / day) to healthy subjects and at therapeutic doses (10, 15, and 20 mg / day) to patients. After the final oral dose, a comprehensive PK sampling scheme was applied to fully characterize steady-state PK.

[0499] The resulting oral data PK parameters are summarized in Figure 3. The PK parameters and inter-individual variability are consistent with published data for oral olanzapine (Zyprexa®).

[0500] The systemic exposure of olanzapine (i.e., C max , AUC τ,ss ) increased with dose proportionally over the range of 2.5 to 20 mg.

[0501] (Pharmacokinetics of Formulation 1, single dose (healthy subjects and patients)) The olanzapine PK profiles following administration of single ascending doses of Formulation 1 by subcutaneous injection are shown in Figure 4 for healthy subjects and in Figure 5 for patients.

[0502] In general, the PK profile of Formulation 1 was qualitatively similar in healthy subjects and patients. Formulation 1 induced an initial, rapid increase in olanzapine plasma concentrations, which reached clinically relevant levels (≥10 ng / mL; Meyer and Stahl, 2021) within 1–2 days after administration of Formulation 1 to patients enrolled in Cohorts 4–6. The profile demonstrated an initial immediate-release character with a slow increase in plasma concentrations and no sudden spikes or unexplained increases in olanzapine exposure. No dose dumping occurred after subcutaneous injection of Formulation 1, consistent with preclinical studies.

[0503] Olanzapine plasma levels gradually increased and reached a maximum (C ) within 11 to 14 days (i.e., 264 to 336 hours) after dosing at doses of 318 mg to 531 mg. max ) was achieved. The slow absorption of olanzapine after subcutaneous administration of Formulation 1 reflects its long apparent terminal half-life (flip-flop kinetics). The arithmetic mean t of the therapeutic Formulation 1 single-dose cohorts (Cohorts 4–6) 1 / 2 Values ​​ranged from 11 to 17 days (264 to 406 hours) depending on dose. Therapeutic levels were maintained over a 28-day dosing interval at clinically relevant doses; concentrations then declined in an apparently polyphasic manner until the last sampling time of 84 days (Cohorts 1-4) or 42 days (Cohorts 5 and 6).

[0504] (Injection site may be changed) In this study, exposure equivalence was investigated using a 105 mg dose of Formulation 1 administered subcutaneously in the abdomen (Cohort 2) and upper arm (Cohort 3). These two injection sites demonstrated similar PK profiles. The absorption rate of olanzapine in the abdomen was similar to that in the arm, with a median t max The values ​​were 263 and 264 hours, respectively. C maxand AUC 0-28d The mean ratios of AUC and AUC were approximately 38% and 20%, respectively, higher than their corresponding values ​​after subcutaneous injection in the abdomen. 0-t and AUC 0-∞ showed similar exposure levels for the two injection sites. Therefore, exposure to Formulation 1 after administration via these two injection sites was considered to be comparable.

[0505] (Pharmacokinetics of Formulation 1 multiple doses (patients)) The multiple-dose PK of olanzapine was evaluated in patients (Cohorts 8 and 9, respectively) after administration of either 283 or 566 mg Formulation 1 in three consecutive q1m injections. The mean concentration versus time plots for olanzapine after the third subcutaneous injection are shown in Figures 6 and 7.

[0506] In the multiple dose cohort, three doses of Formulation 1 were administered on days 1, 29 (week 4), and 57 (week 8), respectively.

[0507] The median time to peak plasma concentration after three q1m subcutaneous doses was 11 and 10 days (262 and 236 hours) for Cohort 8 and Cohort 9, respectively. After reaching peak concentrations, olanzapine levels declined slowly until the final sampling. Increases in olanzapine exposure appeared proportional to increasing dose in the multiple-dose cohorts. After the final Formulation 1 dose (3rd dose), the arithmetic mean t 1 / 2 The data used to calculate the values ​​ranged from 22 to 25 days (539 to 589 hours) between cohorts 8 and 9. AUC 0-tau The accumulation ratio (injection 3 / injection 1) for Cmax and AUC 0-tau Regarding 1.30 and 1.14 and C max The C showed only moderate accumulation of 1.09 and 0.90. trough , AUC tauBoth NCA and popPK analysis by validation of Cmax were reliable in estimating steady-state achievement. Steady-state was determined once a stable value, either observed or simulated, was reached. As previously noted, Formulation 1 showed minimal olanzapine accumulation after the second or third dose in Cohort 8 and Cohort 9. It was concluded that steady-state was rapidly reached within two injections by the end of the second dose on Day 57 (Week 8) (Figures 6 and 7).

[0508] Beta elimination half-life

[0509] The use of a plausible beta-elimination half-life instead of the observed terminal elimination half-life (observed best-fit lambda Z) can be beneficial for estimating the time to steady state in cases of sustained release with multicompartment kinetics (Gidal et al., 2017; Krause et al., 2021). The validity of using the terminal half-life may be limited in cases where drug concentrations decline slowly at low concentrations at the end of the tested pharmacokinetic profile, contributing only slightly to overall drug exposure.

[0510] The beta elimination half-life showed better correlation to steady state for Formulation 1 compared to the terminal elimination (observed best fit lambda Z) half-life due to the multiphasic profile of Formulation 1. The mean beta half-life values ​​for Formulation 1 ranged from 5 to 7 days in the single-dose patient cohort and from 8 to 10 days in the multiple-dose patient cohort (Table 5.2).

[0511] (Table 5.2 Estimated terminal (lambda Z) elimination half-lives and beta half-lives) [Table 7]

[0512] Further characterization of Formulation 1 at steady-state exposure was investigated with Pop PK modeling and simulation.

[0513] (dose proportionality) Systemic exposure assessed by Cmax and AUC was 0-28d and AUC 0-∞ increased approximately dose-proportionally across the therapeutic dose range from 283 mg to 566 mg in patients except for Cohort 6 (531 mg Formulation 1 subcutaneously), where exposure was slightly lower than expected based on exposure at other dose levels; however, this change was not clinically significant and is most likely related to the small number of cases and individuals with faster olanzapine clearance after oral olanzapine and Formulation 1 administration.

[0514] Although this study was not powered to assess dose proportionality and significant variability was observed in PK parameters, a clear trend toward dose proportionality exists. This finding is also supported by popPK analysis. The observed median olanzapine PK profiles and PK variability for oral olanzapine and Formulation 1 are shown in Figure 8. Furthermore, PK / PD simulations correlated olanzapine concentrations with D2 receptor occupancy and determined the dose at which D2 receptor occupancy occurred. The simulations also confirmed that the selected doses targeted a resulting D2 receptor occupancy range of 60% to 80%, which is associated with a balance between antipsychotic efficacy and minimal side effects.

[0515] (Equivalence to Formulation 1 oral olanzapine) After the third injection of Formulation 1 (Day 57), when olanzapine plasma levels were considered to be at steady state for the 283 and 566 mg doses, the range of systemic exposure over a 28-day period (Cmax,ss, trough plasma drug concentration at Day 28 [C28d / C trough ,ss] and mean plasma concentrations [Cavg,ss]) were similar to the systemic exposure observed at steady state after oral olanzapine administration over the dose range of 10 to 20 mg.

[0516] Median concentrations, including the 5th and 95th percentiles, for olanzapine concentrations observed after the third dose of Formulation 1 (q1m; 283 mg) versus the seventh dose of oral olanzapine (10 mg / day), and after Formulation 1 (q1m; 566 mg) versus oral olanzapine (20 mg / day), both of which are considered to be at steady state, are shown in Figure 8.

[0517] Overall, the panels of Figure 8 show that the pharmacokinetic variability of Formulation 1 over a 28-day dosing interval was comparable to that of oral olanzapine over a 24-hour dosing interval for the 5th and 95th percentiles. Similarly, total exposure (i.e., AUC) was comparable and had similar variability.

[0518] (Relative Bioavailability) The relative bioavailability of Formulation 1 to oral olanzapine is shown in Table 5.3. The steady-state relative bioavailability is calculated as the AUC of oral olanzapine. tau (AUC at steady state) divided by (calculated for 28 days) tau The relative bioavailability of the subcutaneous formulation of olanzapine after a single dose of Formulation 1 (as a surrogate for olanzapine) was calculated as a dose-normalized ratio of AUC inf after a single dose of Formulation 1 in patient cohorts (Cohorts 4-6) was 112%, with a 90% confidence interval (CI) close to the bioequivalence acceptance criteria (0.969, 1.291). After multiple doses in patient cohorts (Cohorts 8 and 9), the relative bioavailability of Formulation 1 compared with oral olanzapine was 95%, with a 90% CI (0.855, 1.059). Although the study size was not sufficiently powered to support a bioavailability analysis, these results support the overall similarity of Formulation 1 to oral olanzapine when administered at similar doses.

[0519] Table 5.3 Dose-normalized relative bioavailability of Formulation 1 compared to oral olanzapine [Table 8] a Relative bioavailability was assessed in terms of dose-normalized olanzapine AUC (ln-transformed AUC for Formulation 1). 0-∞ and ln-transformed AUC for oral olanzapine 0-tau and both are treated as a single result). b Relative bioavailability was assessed in terms of olanzapine dose-normalized AUC (ln-transformed AUC for the interval between multiple doses of Formulation 1 for the third time point). 0-tau Dose-normalized ln-transformed AUC calculated for Formulation 1 and oral olanzapine 0-tau28d and both reflect the steady-state AUC over the 28-day dosing interval and are treated as a single outcome). AUC = area under the plasma drug concentration-time curve; AUC0-∞ = area under the plasma drug concentration-time curve extrapolated to infinity; AUC0- tau = area under the plasma drug concentration-time curve until the end of the dosing period; CI = confidence interval; Geo = geometric; GMR = geometric mean ratio; LS = least squares; Ref = reference. NOTE: Calculation of GMR: Dose-normalized AUC0- of oral olanzapine tau Ratio of dose-normalized AUC0-∞ (based on pooled data from single-dose cohorts) for Formulation 1 divided by (multiplied by 28 days)

[0520] (Safety Assessment) Safety was assessed during the study by evaluating AEs, clinical laboratory results (serology, hematology, urinalysis, and prolactin), vital sign measurements, ECG, physical examination, injection site pain, local tolerability, and leakage assessment. In addition, psychiatric, neurological, and clinical symptom assessments were performed: ·Abnormal Involuntary Movement Scale (AIMS) Barnes Akathisia Rating Scale (BARS) Clinical Global Impression Scale-Illness Severity (CGI-S) Columbia-Suicide Severity Rating Scale (C-SSRS) Extrapyramidal Symptom Rating Scale (ESRS) Epworth Sleepiness Scale (ESS) Positive and Negative Symptom Scale (PANSS) It was composed of:

[0521] The severity of AEs was graded according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 guidelines, from grade 1 (mild, asymptomatic, or mildly symptomatic) to grade 5 (AE-related death).

[0522] (Summary of the study on Formulation 1) The safety and risk-benefit profile of Formulation 1 were evaluated using clinical safety data available from this study to date. All study cohorts were completed. The data cutoff included all safety and PK data from the single-dose cohorts (Cohorts 1–6). For the multiple-dose cohorts (Cohorts 8 and 9), partial PK and safety data after the third dose were available because all patients had received Formulation 1 for three consecutive q1m injections and completed the treatment period (Day 85). For Cohort 8, 11 patients entered the full-time period, and one patient completed the study. For Cohort 9, six patients entered the full-time period, six completed the study, and one patient terminated early during the full-time period.

[0523] Results of clinical laboratory tests, vital signs, ECGs, clinical rating scales, and AEs did not suggest any systemic safety signals for the new formulation 1 and were consistent with the well-characterized safety profile of olanzapine. No PDSS events or suspected PDSS events were observed during the study.

[0524] The injection site reactions observed in the study were related to the route of administration and do not appear to significantly alter the benefit-risk profile of Formulation 1.

[0525] (Safety conclusion) Safety endpoints in this study included the incidence of adverse events, changes from baseline in ECG parameters, selected laboratory values ​​(including prolactin) and vital signs, and changes in neurological and clinical symptom assessments (e.g., PANSS, ESRS, AIMS, BARS, CGI-S, C-SSRS), and other safety measures assessed throughout the study.

[0526] Overall, single ascending and multiple doses of olanzapine extended-release injectable suspension (Formulation 1) administered subcutaneously to healthy subjects and patients diagnosed with schizophrenia or schizoaffective disorder were well tolerated. The safety profile, with the exception of ISR, was similar to oral olanzapine.

[0527] No deaths or treatment-related serious adverse events occurred in this study. During the washout period after oral olanzapine administration, 4 / 127 (3.1%) participants withdrew from the study due to adverse events (2 events of elevated low-density lipoprotein and 1 event of neutropenia and rash); all of these participants were healthy subjects. During the second period of the study, only one patient receiving a clinically significant dose of Formulation 1 (Cohort 4; Formulation 1 425 mg) withdrew from the study due to a Grade 3 serious adverse event of psychotic disorder, and one patient in Cohort 9 (multiple doses of Formulation 1 566 mg q1m) experienced a Grade 2 serious adverse event of schizophrenia during the study. Both of these serious adverse events were deemed unrelated to Formulation 1 by the investigator and sponsor.

[0528] In all Phase 2 treatment cohorts, at least one healthy subject or patient experienced at least one treatment-related adverse event. The incidence of treatment-related adverse events was slightly higher in the single-dose healthy subject cohort (30.0%) compared with the single-dose patient cohort (23.8%), with the multiple-dose patient cohort having the highest incidence of treatment-related adverse events (44.8%). The most frequently reported treatment-related adverse events (occurring in more than 4% of healthy subjects or patients overall) in the single-dose healthy subject cohort were injection site erythema (6.7%) and headache (6.7%); in the single-dose patient cohort, they were headache (4.8%), somnolence (4.8%), increased appetite (4.8%), or weight gain (4.8%); and in the multiple-dose patient cohort, they were obesity (13.8%) and injection site pruritus (10.3%). Treatment-related adverse events were generally grade 1 or grade 2 in severity, with only three healthy subjects or patients experiencing grade 3 treatment-related events (one healthy subject in Cohort 3 [Formulation 1, 105 mg, upper arm] experienced an ALT increase, one patient in Cohort 5 [Formulation 1, 318 mg] experienced an injection site abscess, and one patient in Cohort 9 [multiple q1m Formulation 1, 566 mg dose] experienced injection site erythema). No grade 4 or grade 5 adverse events were reported during the study.

[0529] Protocol-defined adverse events of particular interest included ISR (only those defined as adverse events). ISR adverse events were observed in all treatment cohorts except Cohort 6 (Formulation 1, 531 mg). The most frequently reported injection site adverse events were injection site abscess events (5 patients across all cohorts), injection site erythema (4 patients across all cohorts), and injection site pruritus (3 patients across all cohorts). The majority of these injection site adverse events were grade 1 or grade 2 in severity, except for one event of grade 3 injection site abscess in Cohort 5 (Formulation 1, 318 mg) and one event of grade 3 injection site erythema in Cohort 9 (multiple q1m Formulation 1, 566 mg). Seven of these events were classified as purulent lesions: five injection site abscesses, one of which was reported to have preceding inflammation, and two injection site infections without a clear dose-response. One event of injection site infection (one patient in Cohort 4) was not considered an ISR because the cause of the infection was irritation / scratching by the patient and was not associated with administration of Formulation 1, and was therefore classified as an injection site irritation. None of these events were considered serious, and all recovered and resolved after treatment with systemic antibiotics.

[0530] Dissimilar distributions and rates of purulent lesions by injection site were observed; specifically, 3 of 11 arm injections in 3 / 11 (27.3%) healthy subjects and 3 of 129 abdominal injections in 3 / 71 (4.2%) patients. None of these events had an impact on the pharmacokinetics of Formulation 1.

[0531] As expected for this class of medication, an initial increase in mean prolactin levels was observed in both treatment periods (oral olanzapine and Formulation 1). However, no adverse events related to hyperprolactinemia were observed during the study.

[0532] Overall, injections were generally well tolerated, with NPRS scores for injection pain intensity (0 = no pain, 10 = worst pain) immediately after dosing of 10 in one patient in Cohort 6 (Formulation 1, 531 mg), 9 in one patient in Cohort 5 (Formulation 1, 318 mg single dose) and one patient in Cohort 4 (Formulation 1, 425 mg), and 8 in two patients in Cohort 6 and one patient in Cohort 5; all other patients had NPRS scores ≦7. After Day 8, minimal and sporadic injection site pain scores were recorded. Injection site reactions were generally Grade 1 or Grade 2 in severity and transient in nature.

[0533] Laboratory tests (including clinical chemistry, hematology, and urinalysis), vital signs, and physical examination findings did not reveal any clinically meaningful trends in mean changes from baseline or clinically significant findings in any of these assessments, except for sporadic increases in creatine kinase that did not appear to be dose-related in both treatment periods and a weight gain from baseline of ≥7% in 38% of patients randomized to the multiple-dose patient cohort. Slight worsening of ECG findings was observed across all treatment cohorts; however, these were generally not considered clinically significant. Only one patient in the single-dose patient cohort (Cohort 5; Formulation 1, 318 mg) experienced an adverse event of tachycardia.

[0534] No clinically meaningful changes in PANSS, ESRS, AIMS, BARS, or ESS scores were observed during the study, and in general, patients' CGI-S and C-SSRS ratings remained stable throughout the study. No confirmed or suspected PDSS events (protocol-defined adverse events for expedited reporting) occurred during the study.

[0535] (Safety summary of formulation 1) Safety data for Formulation 1 have been evaluated from 71 patients and 30 healthy subjects receiving doses ranging from 70 to 566 mg, as well as from 6 healthy subjects treated with Formulation 1 vehicle. The systematic safety profile emerging from these data was consistent with other formulations of olanzapine. The lack of clinically meaningful changes from baseline in psychiatric, neurological, and clinical symptom assessment scales in this study, which included clinically stable patients previously treated with oral olanzapine, supports the extended release of olanzapine after injection of Formulation 1, resulting in a pharmacodynamic and systemic safety profile comparable to that of oral olanzapine. The identified ISR AEs were mostly mild to moderate in severity and none were serious. These ISR AEs do not significantly alter the benefit-risk profile of Formulation 1.

[0536] Example 6 A multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, including an open-label, long-term safety phase, to evaluate the efficacy, safety, and tolerability of olanzapine as a subcutaneous extended-release injectable suspension (Formulation 1) for the treatment of adult patients with schizophrenia

[0537] (Table 6.1. Objectives and Endpoints) [Table 9]

[0538] (Overall design) Patients whose schizophrenia exacerbation began ≤8 weeks prior to screening and who would benefit from hospitalization or continued hospitalization in a psychiatric hospital for schizophrenia symptoms may be included. The study consists of two periods: Period 1 (double-blind, placebo-controlled efficacy and safety period) and Period 2 (open-label safety period). For each patient, Period 1 is 8 weeks long and Period 2 is a maximum of 48 weeks long. Screening will last a maximum of 8 days prior to randomization. In Period 1, patients will be randomized in a 1:1:1:1 ratio to one of three Formulation 1 treatment groups (318 mg once monthly [q1m], 425 mg q1m, or 531 mg q1m) or placebo group q1m. To maintain blinding in Period 1, all patients will be re-randomized between Periods 1 and 2; patients previously assigned to an active treatment group will retain their Period 1 treatment assignment in Period 2, and patients previously assigned to a placebo group will be randomized in a 1:1:1 ratio to one of the active treatment groups in Period 2. End-of-treatment and follow-up visits will be 4 and 8 weeks after the last dose of study drug, respectively.

[0539] Test intervention and type of intervention

[0540] The objective of this study was to evaluate the efficacy, safety, and tolerability of subcutaneous olanzapine sustained-release injectable suspension (i.e., Formulation 1) compared with placebo in patients with schizophrenia. The total study duration was up to 61 weeks, with a treatment period of up to 56 weeks.

[0541] Number of participants:

[0542] Approximately 985 patients will be screened, resulting in approximately 640 randomized patients.

[0543] The study will enroll patients diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Diagnosis will be confirmed using a structured assessment tool (Structured Clinical Interview for DSM-5, Clinical Trials Version [SCID-5-CT]).

[0544] Acute status is confirmed by a total PANSS score of 80 to 120 at screening and baseline (pre-randomization), a score of ≥4 on at least two of the following four PANSS positive subscale items: hallucinatory behavior, delusions, conceptual integration disorder, or suspiciousness / persecutory feelings, and a CGI-S score of ≥4 (moderate distress) at screening and baseline (pre-randomization).

[0545] Patient inclusion criteria

[0546] In this study, patients could be randomized only if they met all of the following criteria: a. Patients are male or female, of any ethnic origin, aged 18 to 65 years at the time of screening. b. The patient is able to provide signed informed consent. Patients will be asked to agree to share their information with vendors who will verify that they are not currently or recently participating in another clinical trial, unless prohibited by local requirements. In addition, patients will be asked to consent to audio recording of the PANSS assessment (which will be reviewed, if necessary, to monitor the quality of the ratings). c. The patient has a current confirmed diagnosis of schizophrenia according to DSM-5 for a period of >1 year. The diagnosis must be reconfirmed by SCID-5-CT. d. Patients have a PANSS total score of 80 to 120 at screening and baseline (before randomization) and a score of ≥ 4 on at least two of the following four PANSS positive subscale items: hallucinatory behavior, delusions, conceptual disorganization, or suspiciousness / persecutory feelings. e. The patient has had an exacerbation of schizophrenia <8 weeks prior to screening and would likely benefit from hospitalization or continued hospitalization in a psychiatric hospital for schizophrenic symptoms. f. Patient has a CGI-S score of ≧4 (moderate ill-health) at screening and baseline (pre-randomization). g. Patients receiving antipsychotic treatment (other than clozapine) within the past year must have been responsive based on the investigator's judgment (and discussion with family, caregivers, or healthcare professionals, if applicable). h. The patient has an identified person (called a caregiver) who agrees to provide information about the patient's location, condition, and overall status during the outpatient portion of the study during Phase 1. Site personnel must identify the caregiver at the screening visit and must consider the caregiver a trusted contact. The caregiver must have regular contact with the patient (defined as at least three face-to-face contacts per week), and it is expected that this frequency of contact will continue throughout the outpatient portion of Phase 1 (and is also recommended for the remainder of the study, including Phase 2 and the FU period). This regular contact with the patient is not mandatory during the inpatient period of Phase 1. The patient's caregiver will be asked to sign a Caregiver ICF. i. 18.0 to 40.0 kg / m at screening 2 Body Mass Index below. j. Women may be included only if they have a negative beta-human chorionic gonadotropin (β-HCG) test at screening and baseline (if a borderline result is obtained by urine analysis, a serum test should be performed with a negative result), or if they are infertile (documented hysterectomy, bilateral oophorectomy, or bilateral salpingectomy or congenital infertility) or postmenopausal. k. Females of childbearing potential must agree not to try to become pregnant and, unless they have only same-sex partners, must agree to use highly effective contraception before their first dose of IMP and to continue using such methods throughout the study and for 70 days after their final dose of IMP. Highly effective contraception includes: l. Combined estrogen and progestogen hormonal contraceptives (oral, intravaginal, transdermal) associated with inhibition of ovulation; these should be initiated at the screening visit before the first dose of IMP. m. Progestogen-only hormonal contraceptives (oral, injectable, implantable) associated with inhibition of ovulation; these should be initiated at the screening visit before the first dose of IMP. n. Intrauterine contraceptive devices and intrauterine hormone-releasing systems; these must be in place at least two months before screening. o. Bilateral tubal occlusion. p. A partner who has had a vasectomy, provided that such partner is the only sexual partner and has been medically evaluated for such surgery. q. Sexual abstinence is considered highly effective only if it is defined as abstinence from heterosexual intercourse for a specified period of time. The reliability of sexual abstinence needs to be evaluated in relation to the length of the clinical trial and the patient's preferred and usual lifestyle. r. If the patient is an adult male, he or she must be surgically sterile, or, if capable of childbearing, must have only same-sex partners, or must currently be using an approved method of birth control and agree to continue using that method for the duration of the study (and for 70 days after the final dose of IMP). Male patients who have sexual partners who are females of childbearing potential must use condoms, even if they are surgically sterile. In addition, male patients must not donate sperm during the study or for 70 days after the final dose of IMP. s. Patients are able to understand the nature of the study and comply with protocol requirements, including prescribed dosing regimens (oral and subcutaneous), abstaining from prohibited concomitant medications, and at least 4 weeks of hospitalization at the clinical site; are able to read and understand written language to independently complete patient-reported outcome measures; and are able to reliably rate the rating scales. t. Patients must be willing to comply with the study restrictions, remain at the study center for the required period of time for the duration of the study (including at least 4 weeks of hospitalization in the clinical facility), and be willing to return to the study center for further visits and for FU treatment and evaluation, if applicable, as specified in this protocol. u. Patient has a place of residence that has remained unchanged for approximately 3 months prior to screening, and no change of residence is planned during the course of study participation. v. The patient is in adequate health as determined by medical and psychiatric history, physical examination, electrocardiogram (ECG), serum chemistry, hematology, coagulation urine tests, and serology.

[0547] Patient exclusion criteria

[0548] Patients will not be randomized into the study if they meet any of the following criteria: a. The patient currently has a clinically significant DSM-5 diagnosis other than schizophrenia (currently has a primary diagnosis other than schizophrenia or a comorbid diagnosis that is the primary cause of current symptoms and impairment). b. The patient has a known history of one of the following: (a) borderline personality disorder, antisocial personality disorder, or bipolar disorder; (b) traumatic brain injury, Alzheimer's disease, or another form of dementia causing ongoing cognitive impairment, or any chronic organic disease of the central nervous system; and (c) intellectual disability of a severity that may affect their ability to participate in this study. c. Patients experienced an improvement (decrease) in total PANSS score of ≥ 20% between screening and Day 1 (baseline [randomization] visit). d. The patient was hospitalized for >14 days (excluding social or administrative hospitalizations) in the current exacerbation episode prior to screening. e. The patient is at significant risk for violent behavior based on the patient's medical history or the investigator's judgment. f. Patient is at significant suicide risk based on patient history or C-SSRS and investigator judgment. Patients who have a positive C-SSRS response to suicidal ideation items 3, 4, or 5 and / or a positive suicidal behavior response in the past 6 months are ineligible. g. The patient meets criteria for a moderate to severe substance use disorder (based on DSM-5 criteria), including chronic alcohol or drug abuse (excluding those related to caffeine or nicotine) within the past six months. A positive urine drug test result is not exclusive if, in the investigator's judgment, the patient does not meet the criteria for a substance use disorder. Patient eligibility in the case of a positive result without a medical explanation will be determined by the investigator based on the patient's demographics, substance use history, and discussion between the investigator and family members, caregivers, or healthcare professionals, if applicable. h. The patient is currently using an LAI antipsychotic or is still under coverage for a specific LAI at the time of screening. i. Patients have been taking clozapine or undergoing electroconvulsive therapy within the last 12 months prior to screening. j. The patient is currently receiving daily oral olanzapine at a dose >20 mg / day. k. Patient has or has a history of known hypersensitivity to olanzapine or any of the excipients in Formulation 1 or to oral formulations of olanzapine. l. Patients have treatment-resistant schizophrenia as determined by the investigator based on medical and psychiatric history or have documented failure of two or more antipsychotic medications (each administered for at least 6 weeks at the maximum tolerated dose). Participants who respond to antipsychotic medications alone when combined with clozapine are considered treatment-resistant. m. The patient is experiencing significant sedation or delirium after antipsychotic treatment as determined by medical and psychiatric history and by the investigator, or suffers from delirium due to a medical condition. n. The patient has any medical or psychiatric condition that, in the opinion of the investigator, may jeopardize or impair the patient's ability to participate in the study. o. Patient has known risk factors for undiagnosed / unstable arrhythmias, congenital long QT, hypokalemia, hypomagnesemia, or autonomic failure (primarily with clinically significant orthostatic hypotension). p. The patient has any clinically significant uncontrolled medical condition (treated or untreated). q. Any disorder that may interfere with the absorption, metabolism, or elimination of olanzapine. r. The patient has a non-fasting glucose level of ≧200 mg / d at screening. s. The patient changed their diabetes treatment within 4 weeks prior to the first injection of IMP. t. The patient has a serum triglyceride level of ≥ 500 mg / dL. u. The patient has a low-density lipoprotein level of ≧190 mg / dL. v. The patient has a history of ketoacidosis or hyperosmolar coma. w. The patient has a known alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase level of ≥ 2 x the laboratory's upper limit of normal (ULN), and an aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase level of ≥ 2 x ULN, and a total bilirubin level of ≥ 1.5 x ULN. The isolation parameters for exclusion are: -ALT or AST > 5 × ULN ALT or AST >3 x ULN, plus either a total bilirubin level >2 x ULN or an international normalized ratio >1.5 (unless the elevation in the international normalized ratio is caused by anticoagulants) - ALT or AST >3 x ULN and the occurrence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%) x. The patient has a ≥1200 / mm 3 have a neutrophil count of y. Patients are ≤75 × 10 3 with platelet count in μL. z. The patient has a serum creatinine of >2.5 mg / dL. aa. Patients have positive serologic tests for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B surface antigen, and / or hepatitis C. If the serological test for hepatitis C is positive but the ribonucleic acid (RNA) test is negative, and the patient has no history of or symptoms of active liver disease, enrollment will be permitted based on clinical judgment. bb. The patient is a pregnant or lactating woman, or is planning to become pregnant during the study. cc. The patient has previously participated in this study (excluding rescreening). dd. The patient is using or consuming or has been using or consuming any medication prohibited under this protocol. ee. The patient has used an investigational new chemical entity or medical device in a clinical trial within 30 days or 5 half-lives (whichever is longer) prior to the first dose of Formulation 1, or, in the case of a biological investigational product, within 3 months or 5 half-lives (whichever is longer). ff. The patient has donated or received any blood, plasma, or platelet transfusion within 30 days prior to the study, or plans to donate during the study period or within 6 months after the last dose of IMP. gg. The patient has a pending court appearance where he or she may be detained.

[0549] Eligibility criteria for Phase 2

[0550] To participate in Phase 2, patients must meet the following eligibility criteria: 1. The patient has completed the first stage. 2. The patient is considered to be clinically stable as determined by the investigator. 3. Patients are outpatients (i.e., meet RDQ criteria and are discharged before Phase 2).

[0551] Patients who do not meet the RDQ criteria but who, in the opinion of the investigator, demonstrate sufficient clinical stabilization to enter Period 2 and who may benefit from continued participation in the study may continue as inpatients for an additional 8 weeks into Period 2. For such patients, the RDQ may be assessed periodically at the investigator's discretion; if the RDQ criteria are not met by the end of the additional 8-week inpatient period (Week 16), the patient will be discontinued from study treatment and will be asked to complete the ET and FU visits.

[0552] Treatment intervention group and period

[0553] The screening phase involves treatment with two daily doses of oral olanzapine to establish tolerability (for patients who have not previously received oral olanzapine treatment in the past year) before randomization to Phase 1. During Phase 1 (8 weeks), patients receive two monthly subcutaneous injections of Formulation 1 (318 mg, 425 mg, or 531 mg) or placebo. During Phase 2 (up to 48 weeks), all patients receive up to 12 monthly injections of Formulation 1.

[0554] Investigational drugs used in this study

[0555] An IMP is defined as a test IMP and its matched placebo IMP.

[0556] See Table 6.3 for a description of the test IMP (Formulation 1) and placebo IMP.

[0557] (Investigational drug) Formulation 1 in the examples is a pharmaceutical composition of the present disclosure comprising 30% to 32% (w / w) olanzapine; 52% to 54% (w / w) dimethyl sulfoxide; 12% to 14% (w / w) diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6.5 to 12.5 kg / mol, and comprising 75% to 84% polylactic acid by weight (w / w); and 3% to 3.5% (w / w) triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 13 kg / mol, and comprising 83% to 88% polylactic acid by weight (w / w); the diblock copolymer and the triblock copolymer together constitute 15% to 17.5% by weight (w / w) of the composition.

[0558] The pharmaceutical product is intended for reconstitution, and a vehicle containing excipients is used for reconstitution.

[0559] Formulation 1 requires reconstitution from two components: one vial containing olanzapine bulk powder and one PFS containing vehicle (two block copolymer excipients dissolved in an organic solvent containing dimethyl sulfoxide). Prior to administration, Formulation 1 is reconstituted in a vial by adding the vehicle from the PFS and mixing.

[0560] Formulation 1 is administered by subcutaneous injection into the abdomen at q1m intervals at doses equivalent to oral olanzapine 10, 15, or 20 mg / day according to the conversions in Table 6.2. Upon reconstitution, Formulation 1 contains 305 mg of olanzapine per gram of total formulation. Dose is selected by withdrawing the specific prescription volume into a dosing syringe.

[0561] Injections are given alternately to the right and left of the umbilicus, with subsequent monthly injections rotated in clockwise order between abdominal quadrants.

[0562] Medication group

[0563] Formulation 1 will be administered at three doses in this study: low (318 mg qlm), medium (425 mg qlm), and high (531 mg qlm).

[0564] Table 6.2: Conversion between Oral Olanzapine and Formulation 1 Doses [Table 10]

[0565] Placebo investigational drug

[0566] Formulation 1 placebo consists of two components: one empty vial and one PFS containing vehicle (two block copolymer excipients dissolved in DMSO). Prior to administration, the placebo product is prepared by adding the vehicle from the PFS to the vial and mixing. The volume of Formulation 1 placebo administered is 0.8 ml.

[0567] Other components

[0568] Kits for IMP and placebo IMP contain: Two 16-gauge needles: one for adding the vehicle to the reconstitution vial and one for withdrawing the reconstituted drug product into the dosing syringe One 3mL Luer Lock disposable syringe with Luer Lock tip One 21-gauge, 16 mm (i.e., 5 / 8 inch) hypodermic safety needle for subcutaneous administration equipped with a needle protector

[0569] Table 6.3: Investigational drugs used in this study [Table 11] IMP = investigational new drug; INN = international nonproprietary name; q1m = monthly; sc = subcutaneous.

[0570] Acceptable concomitant medications

[0571] emergency medication

[0572] Acceptable rescue medications shall include zolpidem, zopiclone, zaleplon, or diphenhydramine for insomnia; benztropine, trihexyphenidyl, or diphenhydramine for Parkinson's disease-like symptoms; and propranolol and benzodiazepines for akathisia.

[0573] In addition, the use of lorazepam (up to 6 mg / day or the locally tolerated maximum daily dose [the lower of the two]) is permitted as needed for indications other than akathisia (anxiety) during the screening phase and in Period 1. Use in this context must be limited to no more than 72 consecutive hours, and lorazepam should not be taken within 8 hours prior to assessment with the rating scale.

[0574] During Phase 2, the use of lorazepam (according to the locally approved dose) will be permitted for indications other than akathisia (anxiety). Antihistamines and anticholinergics will be permitted for agitation and insomnia during the study.

[0575] Antidepressants and mood stabilizers

[0576] (Screening and Phase 1:) Patients who have been treated with antidepressants and / or mood stabilizers for at least 3 months prior to screening and who have had no change in dose for at least 4 weeks prior to screening (except for indications that exclude the patient from participation in the study, such as schizoaffective disorder) may continue their treatment during Screening Phase / Phase 1. Dose changes or initiation of new treatment with such medications during Screening Phase / Phase 1 will not be permitted.

[0577] (2nd period:) During Phase 2, patients who have been receiving mood stabilizers and antidepressants for at least 3 months prior to screening prior to study entry, who have had no change in dose for at least 4 weeks prior to screening, and who continued their treatment during Phase 1, will be allowed to continue their treatment. New administration of mood stabilizers will not be permitted; dose adjustments of mood stabilizers may be permitted on a case-by-case basis after discussion with the MM.

[0578] Antidepressant dose adjustments will be permitted during Period 2 at the investigator's clinical judgment. Patients not previously receiving antidepressants will be permitted to initiate treatment with select antidepressants (including selective serotonin reuptake inhibitors [other than fluvoxamine], serotonin and norepinephrine reuptake inhibitors, and trazodone) during Period 2, based on the investigator's clinical judgment. Investigators are encouraged to consult with MM or the sponsor before initiating new antidepressant treatment. Use of other antidepressants (such as tricyclic and tetracyclic antidepressants and bupropion) will be prohibited.

[0579] Screening (up to 8 days prior to randomization into Period 1):

[0580] Patients will undergo screening procedures and assessments for up to 8 days before randomization into Period 1. Patients provide informed consent at the screening visit and before any study-related procedures are performed. Patients will be asked to agree to share their information with a vendor who will confirm that they are not currently or recently participating in another clinical trial unless prohibited by local requirements. In addition, patients will be asked to consent to audio recording of the PANSS assessment (which will be reviewed, if necessary, to monitor the quality of the scores). Patients willing to participate in optional pharmacogenetic and biomarker sampling and optional audio recording exploratory assessments will sign a separate Informed Consent Form (ICF) for this purpose.

[0581] Patients who began experiencing an exacerbation ≤8 weeks prior to screening (exacerbation should be confirmed by the investigator based on patient history and / or medical history) and who would benefit from hospitalization or continued hospitalization in a psychiatric hospital for schizophrenic symptoms may be included in the study.

[0582] Patients' comprehensive Positive and Negative Symptom Scale (PANSS) scores should be ≥80 and ≤120 at screening, with scores of ≥4 on at least two of the following four PANSS positive subscales: hallucinatory behavior, delusions, conceptual disorganization, or suspiciousness / persecutory feelings.

[0583] Patients must have an identified person (called a caregiver) who agrees to provide information about the patient's location, condition, and overall status during the outpatient portion of the study during Phase 1. Site personnel must identify the caregiver at the screening visit and consider the caregiver a trusted contact. The caregiver must have regular contact with the patient (defined as at least three face-to-face contacts per week), and it is expected that this frequency of contact will continue throughout the outpatient portion of Phase 1 (and is also recommended for the remainder of the study, including Phase 2 and the FU period). The patient's caregiver will be asked to sign a Caregiver ICF at screening.

[0584] Patients who are not already hospitalized will be admitted for the duration of the screening phase (see details related to length of hospital stay and discharge criteria in the "Phase 1" section below).

[0585] Patients will be tapered off their existing oral antipsychotic medication at a rate at the discretion of the investigator. The tapering process should be completed prior to randomization.

[0586] Patients entering this study who have not previously received oral olanzapine will receive two oral doses of olanzapine on two consecutive days during the screening phase (the second dose should be administered at least 24 hours prior to randomization) to assess patient tolerability (at least 10 mg / day of oral olanzapine [but not more than 20 mg / day] as determined by the investigator). The PANSS and Clinical Global Impression-Severity Scale (CGI-S) will be completed prior to oral olanzapine administration.

[0587] Patients who have received olanzapine within the last year are not required to receive these two oral doses. The investigator will review previous use, tolerability, and duration of olanzapine treatment to confirm previous tolerability.

[0588] If a patient meets all study inclusion criteria and none of the study exclusion criteria, but the results of the screening blood sample drawn during the 8-day screening period are not available by screening day 8, the screening period may be extended by 2 days (to screening day 10) to allow for receipt of results confirming the patient's eligibility. If the results are not available by screening day 10, the patient will be considered a screen failure and will be considered for rescreening.

[0589] 1st Term (8 weeks):

[0590] Period 1 is an 8-week double-blind, placebo-controlled efficacy and safety period (acute treatment phase).

[0591] Randomized patients will have a PANSS total score of 80 or greater and 120 or less at baseline (before randomization) and a score of ≥ 4 on at least two of the following four PANSS positive subscale items: hallucinatory behavior, delusions, conceptual integration disorder, or suspiciousness / persecutory feelings.

[0592] Patients who demonstrate a decline in total PANSS score of ≥ 20% between the screening visit and the baseline (randomization) visit are ineligible for randomization into the study.

[0593] Randomized patients will receive treatment with subcutaneous injections of Formulation 1 (low [318 mg q1m], medium [425 mg q1m], or high dose [531 mg q1m]) or placebo at Visit 2 (Week 0) and Visit 7 (Week 4).

[0594] At Visits 2 and 7, the PANSS, Columbia-Suicide Severity Rating Scale (C-SSRS), CGI-S, and Clinical Global Impression-Improvement (CGI-I; Visit 7 [Week 4] only) rating scales will be completed before administration of the study medication (IMP); all other rating scales and questionnaires will be completed either before or after IMP administration. All assessments administered after IMP administration will be completed on the day of IMP administration.

[0595] Prior to screening, patients are either outpatients or inpatients. All patients are hospitalized upon study entry (screening) and remain hospitalized during the screening phase and for the first 4 weeks after randomization (until the second IMP dose). After the second injection, patients may be discharged if all discharge criteria have been met and, in the opinion of the investigator, discharge is appropriate.

[0596] During the entire first period (including inpatient and outpatient settings), a ±3-day window will be allowed before or after the scheduled visit date for medication visits; a ±2-day window will be allowed for all other visits (every effort will be made to keep assessments to their scheduled dates during the inpatient period). Visit dates will be calculated from the date of the last IMP administration. In exceptional cases, at the investigator's discretion and with the permission of the medical monitor (MM) or sponsor, medication visits will occur (and be recorded accordingly) up to 5 days before the scheduled visit date.

[0597] Second trimester (up to 48 weeks):

[0598] After completing the first period (8 weeks), eligible patients will continue to the second period, the safety period (long-term safety phase; up to 48 weeks), during which they will receive monthly subcutaneous injections of Formulation 1.

[0599] Visit 11 (Week 8) is the final visit of Period 1 and the first visit of Period 2. To maintain blinding in Period 1, all patients will be re-randomized between Periods 1 and 2; patients previously assigned to an active treatment group will retain their Period 1 treatment assignment (the re-randomization of patients in the Formulation 1 group is done solely to maintain blinding in Period 1 and is effectively a deterministic assignment, not a randomization), and patients previously assigned to the placebo group will be randomized in a 1:1:1 ratio to one of the active treatment groups. Treatment with Formulation 1 at this visit will be assigned to Period 2 and will be conducted according to the re-randomized treatment assignment. Rating scales and questionnaires, as well as other assessments, will be completed only once. Disclosure of Period 2 treatment assignment will occur for each patient only after the completion and reporting of appropriate study procedures related to the evaluation of efficacy and safety endpoints in Period 1. Disclosure of Period 2 treatment assignment will occur between Weeks 8 and 12 by the sponsor or its representative according to predefined procedures in the relevant study plan. However, provided that all requirements specified in this procedure are met, the week 8 dose will be assigned to Period 2, but will be blinded by all parties in the same way as the period 1 dose.

[0600] The study will continue on an outpatient basis (or on an inpatient basis for patients who remain hospitalized for up to an additional 8 weeks), with telephone contact (or other comparable form of remote communication) occurring weekly between monthly clinic visits. If, in the investigator's judgment, the patient is likely to deteriorate or pose a danger to themselves or others, the patient will be referred for an unscheduled visit, if necessary, and / or hospitalized, and the patient will be treated at the investigator's discretion. If treatment with unauthorized medications, such as antipsychotics other than Formulation 1, is required, the patient will be asked to discontinue study treatment and complete the ET and FU visits.

[0601] The PANSS, C-SSRS, CGI-S, and CGI-I scales will be completed prior to IMP administration; all other scales and questionnaires may be completed either before or after IMP administration (except Visit 11 [Week 8], where all assessments must be completed before IMP administration). All assessments administered after IMP administration will be completed on the day of IMP administration.

[0602] During the entire period of Period 2 (including telephone visits), a window of ±3 days before or after the scheduled visit date will be allowed for medication visits; for patients who are inpatients at the beginning of Period 2, every effort will be made to keep assessments to the scheduled dates during the hospitalization period. Visit dates will be calculated from the date of the last IMP administration. In exceptional cases, at the investigator's discretion and with the permission of the MM or sponsor, medication visits may occur (and be recorded accordingly) up to 5 days before the scheduled visit date.

[0603] Patients who begin Phase 2 will receive treatment for up to 48 weeks. An end-of-treatment (EOT) visit will be completed 4 weeks after the patient's last injection.

[0604] Dose adjustment:

[0605] During Period 2, the investigator may, based on clinical judgment, make a dose adjustment of Formulation 1 (to one of the doses proposed in the protocol) starting at Visit 12 (Week 12). Dose adjustments will be documented on the CRF.

[0606] Procedures for potential post-injection delirium / sedation syndrome

[0607] During Periods 1 and 2, after IMP administration, patients will remain in the clinic for at least 3 hours for observation. If a possible PDSS event occurs, vital signs and blood samples for plasma drug concentrations and (for patients who consent to biomarker collection) biomarkers should be collected promptly after the possible PDSS event is suspected. If a suspected PDSS event is reported, toxicology blood tests should be collected from the patient promptly after the suspected PDSS. Additional pharmacokinetic samples will be collected at 3, 6, 12, and 24 hours after the onset of the event and 24 hours after resolution, or when feasible. Additional biomarker samples should be collected 24 hours after the onset of the event and 24 hours after resolution, or when feasible. Vital signs should be measured at the same time points as the additional pharmacokinetic samples are collected.

[0608] The total duration of patient participation in the study included up to 8 days of screening during which oral olanzapine was administered on 2 consecutive days (to establish tolerability), 8 weeks of treatment with Formulation 1 or placebo (Phase 1 [acute treatment phase]), up to 48 weeks of treatment with Formulation 1 (Phase 2 [long-term safety phase]), and 4 weeks of FU.

[0609] The end of the study will be defined as the last visit of the last patient.

[0610] A schematic diagram of this study is shown in FIG.

[0611] Efficacy assessment

[0612] The primary efficacy endpoint of the study was the change in PANSS total score from baseline to week 8.

[0613] The key secondary efficacy endpoint was the change in Clinical Global Impression-Illness Severity Scale (CGI-S) score from baseline to week 8.

[0614] The key secondary efficacy endpoint was the change from baseline to week 8 in the Personal and Social Performance Scale (PSP).

[0615] Additional secondary efficacy and safety endpoints to be measured include: · Change in total PANSS score from baseline to weeks 1, 2, and 4; Change from baseline in Clinical Global Impression-Improvement (CGI-I) scale scores Change from baseline in Patient Global Impression-Improvement (PGI-I) scale scores Change from baseline in the Quality of Life Scale (SQLS) score in patients with schizophrenia Number of participants who reported using at least one concomitant medication Number of participants who discontinue the trial The number of participants who discontinue the trial due to adverse events Change from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score Change from baseline in mean Simpson-Angus Scale (SAS) score Change from baseline in the Barnes Akathisia Rating Scale (BARS) total score Number of participants with any suicidal thoughts or behaviors according to the Columbia-Suicide Severity Rating Scale (C-SSRS) Change from baseline in the Calgary Depression Scale for Schizophrenia (CDSS)

[0616] Other assessments may include the Structured Clinical Interview for DSM-5, Clinical Trial Version (SCID-5-CT) or the 3-stage EuroQol 5-item questionnaire.

[0617] For a description of the Positive and Negative Syndrome Scale (PANSS), see paragraph 0418 above. Audio recordings of PANSS assessments may be made (which should be reviewed, as necessary, to monitor the quality of the ratings).

[0618] The PANSS will be administered by the investigator / trained assessor at screening and all time points specified in Tables 6.4 and 6.5.

[0619] (Table 6.4-1st period) [Table 12]

[0620] (Table 6.5 2nd period) [Table 13]

[0621] See paragraph

[0420] above for a description of the Clinical Global Impression-Improvement (CGI-I) scale. The CGI-I will be administered by the investigator / trained assessor at the time points specified in Tables 6.4 and 6.5. The CGI-I during Periods 1 and 2 will be compared with the CGI-S score at the baseline visit (Visit 2 of Period 1).

[0622] The Clinical Global Impression-Severity of Illness (CGI-S) rating scale is described in paragraph

[0422] above. The investigator / trained assessor will complete the CGI-S at the time points specified in Tables 6.4 and 6.5.

[0623] The Patient Global Impression-Improvement (PGI-I) rating scale is described in paragraph

[0424] above (see time points specified in Tables 6.4 and 6.5).

[0624] The Personal and Social Performance (PSP) scale is a physician-rated instrument administered to patients at the times specified in Tables 6.4 and 6.5 and further explained in paragraph

[0426] .

[0625] (Other evaluations) Structured Clinical Interview for DSM-5, Clinical Trial Version (SCID-5-CT)

[0626] The SCID-5-CT is a semi-structured questionnaire that provides guidance for making a DSM-5 diagnosis and is administered at screening by a clinician or trained mental health professional familiar with DSM-5 classification and diagnostic criteria.

[0627] The SCID-5-CT can be used to ensure that major DSM-5 diagnoses are systematically assessed and that all study patients have symptoms that meet DSM-5 criteria for inclusion and exclusion, and to characterize the study population in terms of current and previous psychiatric diagnoses.

[0628] Quality of Life Assessment Scale

[0629] The quality of life assessment scales used in this study include the following two scales:

[0630] The Schizophrenia Quality of Life Scale (SQLS), 4th revision (see paragraph

[0428] ), will be administered at the times specified in Tables 6.4 and 6.5 and will be used to capture quality of life.

[0631] The 3-stage EuroQol 5-item questionnaire (EQ-5D-3L; see paragraph

[0430] ) was administered at the time points specified in Tables 6.4 and 6.5 and is a standardized questionnaire assessing global health status.

[0632] Safety evaluation

[0633] In this study, safety will be assessed by qualified investigators by evaluating reported adverse events (including serious adverse events, extrapyramidal symptoms, injection pain, and other ISRs [local tolerability]), vital signs (blood pressure, pulse and orthostatic changes, and temperature), weight, clinical tests, ECG, use of concomitant medications, time to all-cause discontinuation, all-cause discontinuation rates and discontinuation rates due to adverse events (tolerability), and rating scales (including AIMS, BARS, SAS, C-SSRS, and CDSS).

[0634] Post-injection delirium / sedation syndrome monitoring

[0635] Patients receiving Formulation 1 (per the time points in Tables 6.4 and 6.5) should remain under clinical observation for at least 3 hours after administration and be monitored for symptoms of a potential PDSS event.

[0636] If a possible PDSS event is suspected, the MM and sponsor should be contacted immediately. Vital signs and blood samples for plasma drug concentrations and biomarkers (for patients who consent to biomarker collection) should be collected promptly after a possible PDSS event is suspected. If a suspected PDSS event is reported, toxicology blood tests should be collected from the patient promptly after the PDSS event is suspected.

[0637] Additional pharmacokinetic samples will be collected at 3, 6, 12, and 24 hours after the onset of the event and 24 hours after resolution, or when feasible. Additional biomarker samples should be collected 24 hours after the onset of the event and 24 hours after resolution, or when feasible. Vital signs should be measured at the same time points as additional pharmacokinetic samples are collected.

[0638] Any potential PDSS event requires assessment by the investigator according to the following criteria:

[0639] If a possible PDSS event occurs, the IDMC will review the event to determine whether it meets all five criteria in the following definition for the clinical diagnosis of PDSS: 1. One or both of the conditions set out in (a) and (b): a. At least one sign or symptom attributable to at least three of the following symptom clusters consistent with olanzapine overdose, with at least one of the symptoms being at least moderate in severity: - Seizures -Sedation / somnolence -Delirium / confusion / disorientation / other cognitive impairment -Dysarthria / other speech disorders -Ataxia / other movement disorders -Extrapyramidal symptoms -Agitation / irritability / anxiety / restlessness -Dizziness / weakness / general fatigue b. If the patient: Any one of the following signs and symptoms: inability to awaken, loss of consciousness, stupor, or coma 2. The condition occurs within 24 hours of administration of Formulation 1. 3. The condition cannot be explained by a significant dose increase (i.e., overdose) of Formulation 1 or the initiation of additional oral olanzapine (or other forms of olanzapine) or other sedatives. 4. Underlying medical conditions, including concurrent substance use or abuse, have been ruled out. 5. Olanzapine plasma levels >100 ng / mL ≤3 hours after injection.

[0640] Example 7 In vitro release in human plasma

[0641] Commercially available human plasma was placed in a tightly capped Erlenmeyer flask on an orbital shaker water bath. The temperature was maintained at 37°C, and rotation was set at 100 RPM throughout the study. Formulation 1 and Zyprexa Relprevv® were reconstituted according to the manufacturer's instructions and injected directly into human plasma. At specific time points over 72 hours, aliquots of sample solution were withdrawn from the Erlenmeyer flask and immediately filtered through a 0.45 μm syringe filter. The sampled volume of plasma was replaced with an equal volume of fresh plasma, thermostated at 37°C, to maintain a constant total plasma volume in the flask. Olanzapine was quantified from the collected in vitro release samples by LC-MS / MS equipped with an ESI ion source. This study demonstrates that the risk of PDSS with Formulation 1 technology is minimized. See Figure 10. The present invention will now be further described with reference to the following items: 1. 20%-45% (w / w) olanzapine; 35% to 65% (w / w) organic solvent, including dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; A diblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and a triblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); 1. A pharmaceutical composition for administration by subcutaneous injection comprising: The composition, wherein the diblock copolymer and the triblock copolymer together comprise 10% to 25% of the composition by weight (w / w). 2. The pharmaceutical composition according to item 1, comprising 20% ​​to 24% olanzapine by weight (w / w). 3. The pharmaceutical composition according to item 2, comprising 20.5% olanzapine by weight (w / w). 4. The pharmaceutical composition according to item 2, comprising 22% olanzapine by weight (w / w). 5. The pharmaceutical composition according to item 2, comprising 23.5% olanzapine by weight (w / w). 6. The pharmaceutical composition according to item 1, comprising 22% to 34% olanzapine by weight (w / w). 7. The pharmaceutical composition according to item 6, comprising 30% to 32% olanzapine by weight (w / w). 8. The pharmaceutical composition according to item 6, comprising 26.5% olanzapine by weight (w / w). 9. The pharmaceutical composition according to item 6, comprising 29.0% olanzapine by weight (w / w). 10. The pharmaceutical composition according to item 6 or 7, comprising 30.5% olanzapine by weight (w / w). 11. The pharmaceutical composition according to item 6 or 7, comprising 32.0% olanzapine by weight (w / w). 12. The pharmaceutical composition according to item 6, comprising 33.5% olanzapine by weight (w / w). 13. The pharmaceutical composition according to item 1, comprising 40% to 45% olanzapine by weight (w / w). 14. The pharmaceutical composition according to item 13, comprising 40.7% olanzapine by weight (w / w). 15. The pharmaceutical composition according to item 13, comprising 42.0% olanzapine by weight (w / w). 16. The pharmaceutical composition according to item 13, comprising 43.5% olanzapine by weight (w / w). 17. The pharmaceutical composition according to any one of items 1 to 16, wherein the organic solvent is dimethyl sulfoxide (DMSO). 18. The pharmaceutical composition according to any one of items 1 to 16, wherein the organic solvent is N-methyl-2-pyrrolidinone (NMP). 19. The pharmaceutical composition according to any one of items 1 to 16, wherein the organic solvent is a mixture of dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidinone (NMP). 20. The pharmaceutical composition according to any one of items 1 to 19, comprising 35% to 40% by weight (w / w) of said organic solvent. 21. The pharmaceutical composition according to item 20, comprising 35% by weight (w / w) of said organic solvent. 22. The pharmaceutical composition according to item 20, comprising 37.1% by weight (w / w) of the organic solvent. 23. The pharmaceutical composition according to item 20, comprising 38% by weight (w / w) of the organic solvent. 24. The pharmaceutical composition according to any one of items 1 to 19, comprising 50% to 55% by weight (w / w) of the organic solvent. 25. The pharmaceutical composition according to item 24, comprising 50% by weight (w / w) of the organic solvent. 26. The pharmaceutical composition according to item 24, comprising 52% by weight (w / w) of the organic solvent. 27. The pharmaceutical composition according to item 24, comprising 53.5% by weight (w / w) of the organic solvent. 28. The pharmaceutical composition according to item 24, comprising 54% by weight (w / w) of the organic solvent. 29. The pharmaceutical composition according to item 24, comprising 55% by weight (w / w) of the organic solvent. 30. The pharmaceutical composition according to any one of items 1 to 19, comprising 58% to 62% by weight (w / w) of said organic solvent. 31. The pharmaceutical composition according to item 30, comprising 58.5% by weight (w / w) of the organic solvent. 32. The pharmaceutical composition according to item 30, comprising 60% by weight (w / w) of the organic solvent. 33. The pharmaceutical composition according to item 30, comprising 61.5% by weight (w / w) of the organic solvent. 34. The pharmaceutical composition according to any one of items 1 to 33, wherein the diblock copolymer comprises 75% to 84% polylactic acid by weight (w / w). 35. The pharmaceutical composition according to item 34, wherein the diblock copolymer comprises 76% polylactic acid by weight (w / w). 36. The pharmaceutical composition according to item 34, wherein the diblock copolymer comprises 80% polylactic acid by weight (w / w). 37. The pharmaceutical composition according to item 34, wherein the diblock copolymer comprises 82% polylactic acid by weight (w / w). 38. The pharmaceutical composition according to any one of items 1 to 37, wherein the diblock copolymer comprises 73% to 77% polylactic acid by weight (w / w). 39. The pharmaceutical composition according to item 38, wherein the diblock copolymer comprises 73% polylactic acid by weight (w / w). 40. The pharmaceutical composition according to item 38, wherein the diblock copolymer comprises 75% polylactic acid by weight (w / w). 41. The pharmaceutical composition according to item 38, wherein the diblock copolymer comprises 77% polylactic acid by weight (w / w). 42. The pharmaceutical composition according to any one of items 1 to 33, wherein the diblock copolymer comprises 84% ​​to 88% polylactic acid by weight (w / w). 43. The pharmaceutical composition according to item 42, wherein the diblock copolymer comprises 84% ​​polylactic acid by weight (w / w). 44. The pharmaceutical composition according to item 42, wherein the diblock copolymer comprises 86% polylactic acid by weight (w / w). 45. The pharmaceutical composition according to item 42, wherein the diblock copolymer comprises 88% polylactic acid by weight (w / w). 46. ​​The pharmaceutical composition according to any one of items 1 to 45, wherein the diblock copolymer has a number average molecular weight of 6.5 to 13.5 kg / mol, optionally 7.0 to 13.5 kg / mol. 47. The pharmaceutical composition according to any one of items 1 to 46, wherein the diblock copolymer has a number average molecular weight of about 9 kg / mol. 48. The pharmaceutical composition according to any one of items 1 to 47, wherein the diblock copolymer has a number average molecular weight of about 10 kg / mol. 49. The pharmaceutical composition according to any one of items 1 to 47, wherein the diblock copolymer has a number average molecular weight of about 11 kg / mol. 50. The pharmaceutical composition of any one of items 1 to 49, wherein the weight ratio of the diblock copolymer to the triblock copolymer is from 6:1 to 2:1, optionally about 4:1. 51. The pharmaceutical composition according to any one of items 1 to 50, comprising 10% to 17% by weight (w / w) of the diblock copolymer. 52. The pharmaceutical composition according to any one of items 51, comprising 10% to 15% by weight (w / w) of the diblock copolymer. 53. The pharmaceutical composition according to item 51, comprising 12.2% by weight (w / w) of the diblock copolymer. 54. The pharmaceutical composition according to item 51, comprising 12.8% by weight (w / w) of the diblock copolymer. 55. The pharmaceutical composition according to item 51, comprising 13.2% by weight (w / w) of the diblock copolymer. 56. The pharmaceutical composition according to item 51, comprising 13.6% by weight (w / w) of the diblock copolymer. 57. The pharmaceutical composition according to item 51, comprising 14.0% by weight (w / w) of the diblock copolymer. 58. The pharmaceutical composition according to item 51, comprising 14.4% by weight (w / w) of the diblock copolymer. 59. The pharmaceutical composition according to any one of items 1 to 58, wherein the triblock copolymer comprises 85% to 88% polylactic acid by weight (w / w). 60. The pharmaceutical composition according to item 59, wherein the triblock copolymer comprises 87% polylactic acid by weight (w / w). 61. The pharmaceutical composition according to item 59, wherein the triblock copolymer comprises 85% polylactic acid by weight (w / w). 62. The pharmaceutical composition according to any one of items 1 to 61, wherein the triblock copolymer has a number average molecular weight of 6.0 to 13.0 kg / mol, optionally 7.0 to 12.0 kg / mol. 63. The pharmaceutical composition according to any one of items 1 to 62, wherein the triblock copolymer has a number average molecular weight of about 9.5 kg / mol. 64. The pharmaceutical composition according to any one of items 1 to 62, wherein the triblock copolymer has a number average molecular weight of about 14 kg / mol. 65. The pharmaceutical composition according to any one of items 1 to 64, comprising 3% to 5% by weight (w / w) of the triblock copolymer. 66. The pharmaceutical composition according to any one of items 1 to 65, wherein the composition comprises 3% to 4% by weight (w / w) of the triblock copolymer. 67. The pharmaceutical composition according to any one of items 1 to 66, comprising 3.0% by weight (w / w) of the triblock copolymer. 68. The pharmaceutical composition according to any one of items 1 to 66, comprising 3.2% by weight (w / w) of the triblock copolymer. 69. The pharmaceutical composition according to any one of items 1 to 66, comprising 3.5% by weight (w / w) of the triblock copolymer. 70. The pharmaceutical composition according to any one of items 1 to 66, comprising 3.6% by weight (w / w) of the triblock copolymer. 71. The pharmaceutical composition according to any one of items 1 to 66, comprising 3.7% by weight (w / w) of the triblock copolymer. 72. The pharmaceutical composition according to any one of items 1 to 65, comprising 4.5% by weight (w / w) of the triblock copolymer. 73. The pharmaceutical composition according to any one of items 1 to 72, wherein the diblock copolymer and the triblock copolymer together constitute 10 to 20%, optionally 14 to 20%, by weight (w / w) of the composition. 74. The pharmaceutical composition according to item 73, wherein the diblock copolymer and the triblock copolymer together constitute 12% of the composition by weight (w / w). 75. The pharmaceutical composition according to item 73, wherein the diblock copolymer and the triblock copolymer together constitute 14% of the composition by weight (w / w). 76. The pharmaceutical composition according to item 73, wherein the diblock copolymer and the triblock copolymer together constitute 16% of the composition by weight (w / w). 77. The pharmaceutical composition according to item 73, wherein the diblock copolymer and the triblock copolymer together constitute 18% of the composition by weight (w / w). 78. The pharmaceutical composition according to item 73, wherein the diblock copolymer and the triblock copolymer together constitute 20% of the composition by weight (w / w). 79. The pharmaceutical composition according to any one of items 1 to 72, wherein the diblock copolymer and the triblock copolymer together constitute 22% of the composition by weight (w / w). 80. The pharmaceutical composition of any one of items 1 to 79, wherein the composition contains about 220 mg to about 340 mg of olanzapine per gram of composition. 81. The pharmaceutical composition according to any one of items 1 to 80, containing about 265 mg of olanzapine per gram of the composition. 82. The pharmaceutical composition according to any one of items 1 to 80, containing about 290 mg of olanzapine per gram of the composition. 83. The pharmaceutical composition according to any one of items 1 to 80, containing about 305 mg of olanzapine per gram of the composition. 84. The pharmaceutical composition according to any one of items 1 to 80, containing about 320 mg of olanzapine per gram of the composition. 85. The pharmaceutical composition of any one of items 1 to 80, containing approximately 335 mg of olanzapine per gram of composition. 86. A container containing about 318 mg to about 950 mg of olanzapine; and a container containing about 0.73 to about 2.5 grams of a mixture of an organic solvent, which is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), or a combination thereof, a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w), and a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w); A kit comprising: 87. The kit according to item 86, wherein the container containing olanzapine contains approximately 318 mg of olanzapine. 88. The kit according to item 86, wherein the container containing olanzapine contains approximately 575 mg of olanzapine. 89. The kit according to item 86, wherein the container containing olanzapine contains approximately 600 mg of olanzapine. 90. The kit according to item 86, wherein the container containing olanzapine contains approximately 710 mg of olanzapine. 91. The kit according to item 86, wherein the container containing olanzapine contains approximately 815 mg of olanzapine. 92. The kit according to item 86, wherein the container containing olanzapine contains approximately 885 mg of olanzapine. 93. The kit of any one of items 86 to 92, wherein the container containing the mixture of the organic solvent, diblock copolymer, and triblock copolymer contains about 0.73 grams of the mixture. 94. The kit according to any one of items 86 to 92, wherein the container containing the mixture of the organic solvent, the diblock copolymer, and the triblock copolymer contains about 1.5 grams of the mixture. 95. The kit of any one of items 86 to 92, wherein the container containing the mixture of the organic solvent, diblock copolymer, and triblock copolymer contains about 1.7 grams of the mixture. 96. The kit according to any one of items 86 to 92, wherein the container containing the mixture of the organic solvent, the diblock copolymer, and the triblock copolymer contains about 2.0 grams of the mixture. 97. The kit of any one of items 86 to 96, wherein the container containing olanzapine is a glass vial. 98. The kit according to any one of items 86 to 97, wherein the container containing the mixture of the organic solvent, the diblock copolymer comprising polylactic acid and polyethylene glycol, and the triblock copolymer comprising polylactic acid and polyethylene glycol is a syringe. 99. The kit of item 98, further comprising a needle, the needle being attachable to the syringe. 100. The kit of item 99, wherein the needle is a 21 gauge needle. 101. The kit of item 99 or 100, wherein the needle is 5 / 8 inch long. 102. A kit according to any one of items 86 to 101 for use in preparing a composition according to any one of items 1 to 84. 103. A method for preparing the composition according to any one of items 1 to 85, comprising adding a mixture of the organic solvent, the diblock copolymer comprising polylactic acid and polyethylene glycol, and the triblock copolymer comprising polylactic acid and polyethylene glycol to solid olanzapine. 104. The method of item 103, wherein the mixture of the organic solvent, the diblock copolymer comprising polylactic acid and polyethylene glycol, and the triblock copolymer comprising polylactic acid and polyethylene glycol is added to the solid olanzapine in the vial by syringe. 105. The kit of any one of items 86 to 102 or the method of item 103 or 104, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, or a tap density of about 0.35 g / ml to 0.44 g / ml, or any combination thereof. 106. The kit or method according to item 105, wherein the olanzapine has a particle size distribution characterized by a D(90) of 20 μm to about 37 μm. 107. The kit or method according to item 106, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 24 μm to about 35 μm. 108. The kit or method according to item 106, wherein the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm. 109. The kit or method according to item 106, wherein the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.8 μm to about 7.0 μm. 110. The kit or method according to any one of items 105 to 109, wherein the olanzapine has a tap density of about 0.35 g / ml to about 0.44 g / ml. 111. The kit or method according to item 105, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm and a D(3,2) of about 5.5 μm to about 7.5 μm. 112. The kit or method according to item 105, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml. 113. The kit or method according to item 105, wherein the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm and a tap density of about 0.35 g / ml to about 0.44 g / ml. 114. The kit or method according to item 105, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm and a D(3,2) of about 5.5 μm to about 7.5 μm, and has a tap density of about 0.35 g / ml to about 0.44 g / ml. 115. The kit or method according to any one of items 86 to 114, wherein the olanzapine is polymorphic form II. 116. A method for administering olanzapine to a patient, comprising subcutaneously injecting the patient with a composition described in any one of items 1 to 85. 117. A method for treating a disease or disorder, which is schizophrenia, schizoaffective disorder, bipolar disorder, or depressive state, in a patient in need thereof, comprising subcutaneously administering to the patient a composition according to any one of items 1 to 85. 118. The method of item 117, wherein the disease or disorder is schizophrenia. 119. The method of item 117, wherein the disease or disorder is schizoaffective disorder. 120. The method of item 117, wherein the disease or disorder is bipolar disorder. 121. The method of item 117, wherein the disease or disorder is a depressive state. 122. The method of any one of items 116-121, wherein the patient has a PANSS total score of 80 to 120 at baseline (prior to randomization), together with a score of ≧4 on at least two of the following four PANSS positive subscale items: hallucinatory behavior, delusions, conceptual integration disorder, or suspiciousness / persecutory feelings. 123. The method of any one of items 116 to 122, wherein the subcutaneously administered composition contains 300 mg to 600 mg of olanzapine. 124. The method of item 123, wherein the subcutaneously administered composition contains 300 to 350 mg, optionally 310 to 320 mg, of olanzapine. 125. The method of item 124, wherein the subcutaneously administered composition contains approximately 318 mg of olanzapine. 126. The method of item 123, wherein the subcutaneously administered composition contains 400 to 450 mg, optionally 415 to 435 mg, of olanzapine. 127. The method of item 126, wherein the subcutaneously administered composition contains about 425 mg of olanzapine. 128. The method of item 123, wherein the subcutaneously administered composition contains 500 to 550 mg, optionally 520 to 540 mg, of olanzapine. 129. The method of item 128, wherein the subcutaneously administered composition contains approximately 531 mg of olanzapine. 130. The method of any one of items 116 to 129, wherein the subcutaneously administered composition has a volume of about 0.5 to 1.8 mL. 131. The method of any one of items 116 to 130, wherein the subcutaneously administered composition has a volume of about 0.9 to 1.5 mL. 132. The method of item 131, wherein the composition has a volume of about 0.9 mL. 133. The method of item 131, wherein the composition has a volume of about 1.2 mL. 134. The method of item 131, wherein the composition has a volume of about 1.5 mL. 135. The method of any one of items 116 to 134, wherein the composition is administered once a month. 136. The method of any one of items 116 to 135, wherein the composition is administered once every 28±5 days. 137. The method of any one of items 116 to 136, wherein the composition is administered once every 28±3 days. 138. The method of any one of items 116 to 137, wherein the composition is administered once every 28 days. 139. AUC after a single subcutaneous administration of the composition ∞ AUC of oral olanzapine calculated over a 28-day period tau 139. The method of any one of items 116 to 138, wherein the dose-normalized ratio to is between 0.97 and 1.29. 140. AUC after a single subcutaneous administration of the composition ∞ AUC of oral olanzapine calculated over a 28-day period tau 139. The method of any one of items 116 to 139, wherein the dose-normalized ratio to is about 1.1. 141. Administration of the composition to the patient by subcutaneous injection results in an olanzapine plasma C max141. The method of any one of items 116 to 140, resulting in the patient having 142. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 100 ng / mL after the first subcutaneous injection. max 142. The method of any one of items 116 to 141, resulting in the patient having 143. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 100 ng / mL after the second subcutaneous injection. max 143. The method of any one of items 116 to 142, resulting in the patient having 144. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 90 ng / mL after the first subcutaneous injection. max 144. The method of any one of items 116 to 143, resulting in the patient having 145. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 90 ng / mL after a second subcutaneous injection. max 145. The method of any one of items 116 to 144, resulting in the patient having 146. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 80 ng / mL after the first subcutaneous injection. max 146. The method of any one of items 116 to 145, resulting in the patient having 147. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 80 ng / mL after the second subcutaneous injection. max 147. The method of any one of items 115 to 146, resulting in the patient having 148. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 70 ng / mL after the first subcutaneous injection. max 148. The method of any one of items 116 to 147, resulting in the patient having 149. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 70 ng / mL after the second subcutaneous injection. max149. The method of any one of items 116 to 148, resulting in the patient having 150. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 60 ng / mL after the first subcutaneous injection. max 149. The method of any one of items 116 to 149, resulting in the patient having 151. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 60 ng / mL after the second subcutaneous injection. max 151. The method of any one of items 116 to 150, resulting in the patient having 152. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 50 ng / mL after the first subcutaneous injection. max 152. The method of any one of items 116 to 151, resulting in the patient having 153. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 50 ng / mL after the second subcutaneous injection. max 153. The method of any one of items 116 to 152, resulting in the patient having 154. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 40 ng / mL after the first subcutaneous injection. max 154. The method of any one of items 116 to 153, resulting in the patient having 155. Administration of the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 40 ng / mL after the second subcutaneous injection. max 155. The method of any one of items 116 to 154, resulting in the patient having 156. The method of any one of items 116 to 155, wherein administering the composition to a patient by subcutaneous injection results in the patient having an olanzapine plasma concentration of at least 10 ng / mL for at least 21 of 30 days following the subcutaneous injection. 157. The method of any one of items 116 to 156, wherein administering the composition to a patient by subcutaneous injection results in the patient having an olanzapine plasma concentration of at least 20 ng / mL for at least 21 of 30 days following the subcutaneous injection. 158. The method of any one of items 116 to 157, wherein administering the composition to a patient by subcutaneous injection results in the patient having an olanzapine plasma concentration of at least 10 ng / mL for at least 30 days after the subcutaneous injection. 159. The method of any one of items 116 to 158, wherein administering the composition to a patient by subcutaneous injection results in the patient having an olanzapine plasma concentration of at least 20 ng / mL for at least 30 days after the subcutaneous injection. 160. A method of treating a patient with olanzapine, comprising: a) providing a kit according to any one of items 86 to 102 or 105 to 115; b) withdrawing the mixture of organic solvent, diblock copolymer, and triblock copolymer from the container in the kit containing the mixture; c) adding the mixture of b) to the container containing olanzapine in the kit and then mixing to form a subcutaneous olanzapine pharmaceutical composition; and d) subcutaneously administering the subcutaneous olanzapine pharmaceutical composition to the patient in need of olanzapine treatment; Including, The method, wherein the treatment is effective for about one month. 161. The method of any one of items 116 to 160, wherein the treatment results in the patient having a lower score on the Positive and Negative Syndrome Scale (PANSS) than the patient had before receiving the treatment. 162. The method of any one of items 116 to 161, wherein the treatment results in the patient having a lower score on the Clinical Global Impression-Improvement (CGI-I) scale than the patient had before receiving the treatment. 163. The method of any one of items 116 to 162, wherein the treatment results in the patient having a lower score on the Clinical Global Impression-Severity (CGI-S) scale than the patient had before receiving the treatment. 164. The method of any one of items 116 to 163, wherein the treatment results in the patient having a lower score on the Patient Global Impression-Improvement (PGI-I) than the patient had before receiving the treatment. 165. The method of any one of items 116 to 164, wherein the treatment results in the patient having a higher score on the Personal and Social Performance Scale (PSP) than the patient had before receiving the treatment. 166. The method of any one of items 116 to 165, wherein the treatment results in the patient having a lower score on the Schizophrenia Quality of Life Scale (SQLS), Fourth Revision, than the patient had before receiving the treatment. 167. The method of any one of items 116 to 166, wherein the treatment results in the patient having a lower score on the 3-stage EuroQol 5-item questionnaire (EQ-5D-3L) than the patient had before receiving the treatment. 168. The method of any one of items 116 to 167, wherein the treatment results in the patient having a D2 receptor occupancy of 60 to 80%, optionally 65 to 80%, optionally 65 to 70%, as determined by positron emission tomography (PET). 169. A method for switching a patient from daily oral olanzapine therapy to a therapy comprising monthly administration of the composition of any one of items 1 to 85, comprising: i) administering a final dose of the daily oral olanzapine therapy orally, where the final dose is administered orally, after which no further oral olanzapine therapy is administered; and on the following day, subcutaneously administering to the patient the composition of any one of items 1 to 85; thereby switching the subject from daily oral olanzapine therapy to a therapy comprising administration of the composition of any one of items 1 to 84. 170. A method for switching a patient from a long-acting intramuscular injectable olanzapine formulation to the composition of any one of items 1 to 85 without the need for additional oral olanzapine therapy, comprising administering a final dose of the long-acting intramuscular injectable olanzapine formulation; and, at the time of the next dose, optionally one month after the previous dose if the previous dose was administered once a month, or optionally two weeks after the previous dose if the previous dose was administered once every two weeks, subcutaneously administering the composition of any one of items 1 to 85; wherein the method is performed without administering additional oral olanzapine therapy to the patient. 171. A pharmaceutical composition as defined in any one of items 1 to 85 for use in medicine. 172. A pharmaceutical composition as defined in any one of items 1 to 85 for use in a method as defined in any one of items 116 to 170. 173. A method of treating an olanzapine-naive patient, comprising administering to the patient an oral daily dose of 10 mg to 20 mg of olanzapine for two consecutive days to assess the patient's tolerance of olanzapine, and if the patient tolerates the oral olanzapine, subcutaneously administering the pharmaceutical composition of any one of items 1 to 86.

Claims

1. 20% to 45% (w / w) olanzapine; 35% to 65% (w / w) of an organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidinone (NMP), or a combination thereof; A diblock copolymer comprising polylactic acid and polyethylene glycol, having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w); and a triblock copolymer comprising polylactic acid and polyethylene glycol and having a number average molecular weight of 6 to 19 kg / mol and comprising 80% to 90% polylactic acid by weight (w / w); 1. A pharmaceutical composition for administration by subcutaneous injection comprising: The pharmaceutical composition, wherein the diblock copolymer and the triblock copolymer together comprise 10% to 25% of the composition by weight (w / w).

2. 10. The pharmaceutical composition of claim 1, comprising 20% ​​to 24% olanzapine by weight (w / w).

3. 10. The pharmaceutical composition of claim 1, comprising 22% to 34% olanzapine by weight (w / w).

4. 4. The pharmaceutical composition of claim 3, comprising 30% to 32% olanzapine by weight (w / w).

5. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the organic solvent is dimethyl sulfoxide (DMSO).

6. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the organic solvent is N-methyl-2-pyrrolidinone (NMP).

7. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the organic solvent is a mixture of dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidinone (NMP).

8. 8. The pharmaceutical composition according to any one of claims 1 to 7, comprising 35% to 40% by weight (w / w) of said organic solvent.

9. 8. The pharmaceutical composition according to any one of claims 1 to 7, comprising 50% to 55% by weight (w / w) of said organic solvent.

10. 8. The pharmaceutical composition according to any one of claims 1 to 7, comprising 58% to 62% by weight (w / w) of said organic solvent.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the diblock copolymer comprises 75% to 84% polylactic acid by weight (w / w).

12. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the diblock copolymer comprises 73% to 77% polylactic acid by weight (w / w).

13. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the diblock copolymer comprises 84% ​​to 88% polylactic acid by weight (w / w).

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the diblock copolymer has a number average molecular weight of 6.5 to 13.5 kg / mol, optionally 7.0 to 13.5 kg / mol.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the weight ratio of said diblock copolymer to said triblock copolymer is from 6:1 to 2:1, optionally about 4:

1.

16. 16. The pharmaceutical composition of any one of claims 1 to 15, comprising 10% to 17% by weight (w / w) of said diblock copolymer.

17. 17. The pharmaceutical composition of claim 16, comprising 10% to 15% by weight (w / w) of the diblock copolymer.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein the triblock copolymer comprises 85% to 88% polylactic acid by weight (w / w).

19. 19. The pharmaceutical composition of any one of claims 1 to 18, wherein the triblock copolymer has a number average molecular weight of 6.0 to 13.0 kg / mol, optionally 7.0 to 12.0 kg / mol.

20. 20. The pharmaceutical composition of any one of claims 1 to 19, comprising 3% to 5% by weight (w / w) of said triblock copolymer.

21. 21. The pharmaceutical composition of any one of claims 1 to 20, comprising 3% to 4% by weight (w / w) of said triblock copolymer.

22. 22. The pharmaceutical composition of any one of claims 1 to 21, wherein the diblock copolymer and the triblock copolymer together comprise 10-20% by weight (w / w) of the composition, optionally 14-20% by weight (w / w) of the composition.

23. 23. The pharmaceutical composition of any one of claims 1 to 22, comprising about 220 mg to about 340 mg of olanzapine per gram of composition.

24. a first container containing about 318 mg to about 950 mg of olanzapine; and The kit comprises a second container containing about 0.73 to about 2.5 grams of a mixture of an organic solvent, which is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), or a combination thereof, and a diblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 15 kg / mol, and comprising 70% to 90% polylactic acid by weight (w / w), and a triblock copolymer comprising polylactic acid and polyethylene glycol, and having a number average molecular weight of 6 to 19 kg / mol, and comprising 80% to 90% polylactic acid by weight (w / w).

25. 25. The kit of claim 24, wherein the first container containing the olanzapine is a glass vial.

26. 26. The kit of claim 24 or 25, wherein the second container containing the mixture of the organic solvent, the diblock copolymer comprising polylactic acid and polyethylene glycol, and the triblock copolymer comprising polylactic acid and polyethylene glycol is a syringe.

27. 27. The kit of claim 26, further comprising a needle, the needle being attachable to the syringe.

28. 28. The kit of claim 27, wherein the needle is a 21 gauge needle.

29. 29. The kit of claim 27 or 28, wherein the needle is 5 / 8 inch long.

30. A kit according to any one of claims 24 to 29 for use in the preparation of a composition according to any one of claims 1 to 23.

31. 24. A method for preparing the composition of any one of claims 1 to 23, comprising adding a mixture of the organic solvent, the diblock copolymer comprising polylactic acid and polyethylene glycol, and the triblock copolymer comprising polylactic acid and polyethylene glycol to solid olanzapine.

32. 32. The method of claim 31, wherein the mixture of the organic solvent, the diblock copolymer comprising polylactic acid and polyethylene glycol, and the triblock copolymer comprising polylactic acid and polyethylene glycol is added to the solid olanzapine in the vial by syringe.

33. 33. The kit of any one of claims 24 to 30 or the method of claim 31 or 32, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, or a tap density of about 0.35 g / ml to 0.44 g / ml, or any combination thereof.

34. 34. The kit or method of claim 33, wherein the olanzapine has a particle size distribution characterized by a D(90) of 20 μm to about 37 μm.

35. 35. The kit or method of claim 34, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 24 μm to about 35 μm.

36. 34. The kit or method of claim 33, wherein the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm.

37. 34. The kit or method of claim 33, wherein the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.8 μm to about 7.0 μm.

38. 38. The kit or method of any one of claims 33 to 37, wherein the olanzapine has a tap density of about 0.35 g / ml to about 0.44 g / ml.

39. 34. The kit or method of claim 33, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm and a D(3,2) of about 5.5 μm to about 7.5 μm.

40. 34. The kit or method of claim 33, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

41. 34. The kit or method of claim 33, wherein the olanzapine has a particle size distribution characterized by a D(3,2) of about 5.5 μm to about 7.5 μm, and a tap density of about 0.35 g / ml to about 0.44 g / ml.

42. 34. The kit or method of claim 33, wherein the olanzapine has a particle size distribution characterized by a D(90) of about 20 μm to about 37 μm and a D(3,2) of about 5.5 μm to about 7.5 μm, and has a tap density of about 0.35 g / ml to about 0.44 g / ml.

43. 43. The kit or method of any one of claims 24 to 42, wherein the olanzapine is in polymorphic Form II.

44. 24. A method of administering olanzapine to a patient, comprising subcutaneously injecting the composition of any one of claims 1 to 23 into said patient.

45. 24. A method of treating a disease or disorder which is schizophrenia, schizoaffective disorder, bipolar disorder, or depression in a patient in need thereof, comprising subcutaneously administering to said patient a composition of any one of claims 1 to 23.

46. 46. ​​The method of claim 45, wherein the disease or disorder is schizophrenia.

47. 46. ​​The method of claim 45, wherein the disease or disorder is schizoaffective disorder.

48. 46. ​​The method of claim 45, wherein the disease or disorder is bipolar disorder.

49. 46. ​​The method of claim 45, wherein the disease or disorder is depression.

50. 50. The method of any one of claims 44-49, wherein the patient has a PANSS total score of 80 to 120 at baseline (prior to randomization), together with a score of ≧4 on at least two of the following four PANSS positive subscale items: hallucinatory behavior, delusions, impaired conceptual integration, or suspiciousness / feelings of persecution.

51. 51. The method of any one of claims 44-50, wherein the subcutaneously administered composition comprises 300 mg to 600 mg of olanzapine.

52. 52. The method of claim 51, wherein the subcutaneously administered composition comprises 300-350 mg, optionally 310-320 mg, of olanzapine.

53. 52. The method of claim 51, wherein the subcutaneously administered composition comprises 400 to 450 mg, optionally 415 to 435 mg, of olanzapine.

54. 52. The method of claim 51, wherein the subcutaneously administered composition comprises 500 to 550 mg, optionally 520 to 540 mg, of olanzapine.

55. 55. The method of any one of claims 44-54, wherein the subcutaneously administered composition has a volume of about 0.5 to 1.8 mL.

56. 56. The method of any one of claims 44-55, wherein the subcutaneously administered composition has a volume of about 0.9 to 1.5 mL.

57. 57. The method of any one of claims 44-56, wherein the composition is administered once a month.

58. 58. The method of any one of claims 44-57, wherein the composition is administered once every 28±5 days.

59. 59. The method of any one of claims 44 to 58, wherein the composition is administered once every 28±3 days.

60. 60. The method of any one of claims 44-59, wherein the composition is administered once every 28 days.

61. AUC after a single subcutaneous administration of the composition ∞ AUC of oral olanzapine calculated over a 28-day period tau 61. The method of any one of claims 44-60, wherein the dose-normalized ratio to is between 0.97 and 1.

29.

62. AUC after a single subcutaneous administration of the composition ∞ AUC of oral olanzapine calculated over a 28-day period tau 62. The method of any one of claims 44-61, wherein the dose-normalized ratio to is about 1.

1.

63. administering the composition to the patient by subcutaneous injection results in an olanzapine plasma C max 63. The method of any one of claims 44 to 62, resulting in said patient having

64. Administering the composition to a patient by subcutaneous injection provides an olanzapine plasma C of less than 100 ng / mL after a first subcutaneous injection. max 64. The method of any one of claims 44 to 63, wherein said method results in said patient having

65. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 100 ng / mL after a second subcutaneous injection. max 65. The method of any one of claims 44 to 64, wherein said method results in said patient having

66. Administering the composition to a patient by subcutaneous injection provides an olanzapine plasma C of less than 90 ng / mL after a first subcutaneous injection. max 66. The method of any one of claims 44 to 65, resulting in said patient having

67. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 90 ng / mL after a second subcutaneous injection. max 67. The method of any one of claims 44 to 66, resulting in said patient having

68. Administering the composition to a patient by subcutaneous injection provides an olanzapine plasma C of less than 80 ng / mL after a first subcutaneous injection. max 68. The method of any one of claims 44 to 67, resulting in said patient having

69. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 80 ng / mL after a second subcutaneous injection. max 69. The method of any one of claims 44 to 68, resulting in said patient having

70. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 70 ng / mL after a first subcutaneous injection. max 70. The method of any one of claims 44 to 69, resulting in said patient having

71. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 70 ng / mL after a second subcutaneous injection. max 71. The method of any one of claims 44 to 70, wherein said method results in said patient having

72. Administering the composition to a patient by subcutaneous injection provides an olanzapine plasma C of less than 60 ng / mL after a first subcutaneous injection. max 72. The method of any one of claims 44 to 71, resulting in said patient having

73. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 60 ng / mL after a second subcutaneous injection. max 73. The method of any one of claims 44 to 72, resulting in said patient having

74. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 50 ng / mL after a first subcutaneous injection. max 74. The method of any one of claims 44 to 73, wherein said method results in said patient having

75. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 50 ng / mL after a second subcutaneous injection. max 75. The method of any one of claims 44 to 74, wherein said method results in said patient having

76. Administering the composition to a patient by subcutaneous injection provides an olanzapine plasma C of less than 40 ng / mL after a first subcutaneous injection. max 76. The method of any one of claims 44 to 75, resulting in said patient having

77. Administering the composition to a patient by subcutaneous injection results in an olanzapine plasma C of less than 40 ng / mL after a second subcutaneous injection. max 77. The method of any one of claims 44 to 76, resulting in said patient having

78. 78. The method of any one of claims 44-77, wherein administering the composition to a patient by subcutaneous injection results in the patient having a plasma level of olanzapine of at least 10 ng / mL for at least 21 out of 30 days following said subcutaneous injection.

79. 79. The method of any one of claims 44-78, wherein administering the composition to a patient by subcutaneous injection results in the patient having a plasma level of olanzapine of at least 20 ng / mL for at least 21 of a 30 day period following the subcutaneous injection.

80. 80. The method of any one of claims 44-79, wherein administering the composition to a patient by subcutaneous injection results in the patient having a plasma level of olanzapine of at least 10 ng / mL for at least 30 days following the subcutaneous injection.

81. 81. The method of any one of claims 44-80, wherein administering the composition to a patient by subcutaneous injection results in the patient having a plasma level of olanzapine of at least 20 ng / mL for at least 30 days following said subcutaneous injection.

82. 1. A method of treating a patient with olanzapine, comprising: a) providing a kit according to any one of claims 24 to 30 or 33 to 43; b) withdrawing the mixture of organic solvent, diblock copolymer, and triblock copolymer from the second container in the kit containing the mixture; c) adding the mixture of b) to the first container in the kit containing the olanzapine, and then mixing to form a subcutaneous olanzapine pharmaceutical composition; and d) subcutaneously administering the subcutaneous olanzapine pharmaceutical composition to the patient in need of olanzapine treatment; Including, The method, wherein the treatment is effective for about one month.

83. 83. The method of any one of claims 44-82, wherein said treatment results in said patient having a lower score on the Positive and Negative Syndrome Scale (PANSS) than said patient had before receiving said treatment.

84. 84. The method of any one of claims 44-83, wherein said treatment results in the patient having a lower score on the Clinical Global Impression-Improvement (CGI-I) scale than the patient had before receiving said treatment.

85. 85. The method of any one of claims 44-84, wherein said treatment results in the patient having a lower score on the Clinical Global Impression-Severity (CGI-S) scale than the patient had before receiving said treatment.

86. 86. The method of any one of claims 44-85, wherein said treatment results in the patient having a lower score on a Patient Global Impression-Improvement (PGI-I) than the patient had before receiving said treatment.

87. 87. The method of any one of claims 44-86, wherein treatment results in the patient having a higher score on a Personal and Social Performance Scale (PSP) than the patient had before receiving said treatment.

88. 88. The method of any one of claims 44-87, wherein said treatment results in the patient having a lower score on the Schizophrenia Quality of Life Scale (SQLS), Fourth Revision, than the patient had before receiving said treatment.

89. 89. The method of any one of claims 44-88, wherein said treatment results in said patient having a lower score on the 3-stage EuroQol 5-item questionnaire (EQ-5D-3L) than said patient had before receiving said treatment.

90. The treatment results in a D of 60-80%, optionally 65-80%, optionally 65-70%, as determined by positron emission tomography (PET). 2 90. The method of any one of claims 44 to 89, resulting in said patient having receptor occupancy.

91. 24. A method of switching a patient from daily oral olanzapine therapy to a therapy comprising once-monthly administration of a composition according to any one of claims 1 to 23, administering to the patient a final dose of the daily oral olanzapine therapy orally, after which no further oral olanzapine therapy is administered to the patient; and the next day, subcutaneously administering to said patient a composition according to any one of claims 1 to 23; thereby switching the patient from daily oral olanzapine therapy to a therapy comprising administration of a composition according to any one of claims 1 to 23. The method comprising:

92. 24. A method of switching a patient from a long-acting intramuscular injectable olanzapine formulation to a composition according to any one of claims 1 to 23 without the need for additional oral olanzapine therapy, comprising: administering to said patient a final dose of said long-acting intramuscular olanzapine formulation; and at the next dose, optionally one month after the previous dose if the previous dose was a monthly dose, or optionally two weeks after the previous dose if the previous dose was a biweekly dose, subcutaneously administering to the patient a composition according to any one of claims 1 to 23; The method is performed without administering additional oral olanzapine therapy to the patient.

93. A pharmaceutical composition as defined in any one of claims 1 to 23 for use in medicine.

94. A pharmaceutical composition as defined in any one of claims 1 to 23 for use in a method as defined in any one of claims 44 to 92.

95. 1. A method of treating an olanzapine-naive patient, comprising: administering to the patient an oral daily dose of 10 mg to 20 mg of olanzapine for two consecutive days; assessing whether the patient tolerates the daily oral dose of olanzapine; and Subcutaneous administration of the pharmaceutical composition of any one of claims 1 to 23 to said patient who has been assessed as being able to tolerate said daily dose of oral olanzapine. The method comprising:

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