Olanzapine compositions and methods of use

Abstract

The present disclosure provides pharmaceutical compositions for subcutaneous administration comprising olanzapine, an organic solvent, a tri-block copolymer, and a di-block copolymer, and methods of using such compositions to treat psychiatric diseases and disorders.

Description

Technical Field

[0001] This disclosure relates to pharmaceutical compositions for subcutaneous administration comprising olanzapine, an organic solvent, a triblock copolymer, and a diblock copolymer, and methods of using such compositions to treat mental illnesses and conditions that respond to olanzapine. Background Technology

[0002] Schizophrenia is a severely debilitating mental illness characterized by positive symptoms (such as delusions, hallucinations, and severe behavioral disturbances) and negative symptoms (such as emotional flattening, aphasia, and avoidance) (New York State Office of Mental Health, 2019; Stefan et al., 2002).

[0003] The global lifetime risk of developing this condition is approximately 1% across different geographical, cultural, and socioeconomic regions. Because the disease follows a chronic course and involves long-term, persistent damage in most patients, long-term treatment with antipsychotic medication is usually required.

[0004] Non-adherence and high discontinuation rates are particularly problematic in patients with schizophrenia. Premature discontinuation of antipsychotic medication is common; in the Clinical Antipsychotic Intervention Efficacy Trial (CATIE), 74% of patients discontinued medication within 18 months due to poor tolerability or inadequate efficacy, patient choice (i.e., non-compliance / withdrawal), or investigator-related reasons (Lieberman et al., 2005). Even among those who do not explicitly discontinue medication, non-adherence to long-term oral medication regimens remains one of the most significant treatment problems in schizophrenia and related conditions (Kane et al., 2013). Consequently, many of these patients do not experience the full benefits of antipsychotic medication and frequently relapse or worsen, requiring readmission (Carbon and Correll, 2014) and often experiencing psychotic emergencies (Rainer, 2008).

[0005] Therefore, the availability of long-acting injectable (LAI) antipsychotics may improve 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 trials, cohort studies, and mirror studies to significantly reduce relapse and rehospitalization compared to oral antipsychotics, and to significantly improve many clinically relevant outcomes.

[0006] Olanzapine is a well-characterized and commonly used atypical antipsychotic prescription drug approved for the treatment of schizophrenia, available in oral and intramuscular (IM) formulations. Olanzapine is currently marketed in the United States as ZYPREXA tablets (2.5, 5, 7.5, 10, 15, and 20 mg); ZYPREXA INTRAMUSCULAR for rapid-acting injection (10 mg / mL); and as... Orally disintegrating tablets (5, 10, 15, and 20 mg) (ZYPREXA, ZYPREXA-HYDIS, ZYPREXA INTRAMUSCULAR US Prescription Information [USPI] 2021). ZYPREXA It is an extended-release suspension of olanzapine dihydroxynaphthylpropionate powder and solution, administered via deep intramuscular injection into the gluteal muscle every 2 weeks (150, 210, and 300 mg) or every 4 weeks (300 and 405 mg), depending on the target oral olanzapine dose (10, 15, or 20 mg / day). ZYPREXA (ZYPREXA (PI, 2021) is currently approved and marketed in the United States for the treatment of schizophrenia; however, it is only available through a limited distribution process. It is another olanzapine dihydroxynaphthyl acid product, which is similar to ZYPREXA. They have the same composition.

[0007] ZYPREXA Administration must be performed in a registered medical facility with readily available emergency response services. After each treatment, healthcare professionals must monitor the patient continuously for at least 3 hours at the facility, ensuring the patient is conscious, disoriented, and free from any signs and symptoms of post-injection delirium / sedation syndrome (PDSS) (a possible consequence of the route of administration) before discharge. PDSS is characterized by severe sedation (which may include coma) and / or delirium following injection. In PDSS events, patients exhibit elevated plasma concentrations of olanzapine, suggesting that accidental partial intravascular injection or vascular injury during administration may induce accelerated salt dissolution, potentially contributing to the PDSS. See, for example, Heres S, Kraemer S, Bergstrom RF, and Detke HC, Pharmacokinetics of olanzapine long-acting injection: the clinical perspective, Int. Clin. Psychopharmacol. 2014.

[0008] All patients must remain vigilant for PDSS symptoms and be able to access emergency medical assistance at facilities capable of providing medical monitoring and resuscitation. This is due to the safe use of ZYPREXA. Extensive and inconvenient preventative measures are required, and this product is rarely used in routine clinical practice. Therefore, the available options for psychiatrists in the clinical management of schizophrenia are limited. Alternative treatment options are needed.

[0009] WO2012090070 describes pharmaceutical formulations comprising biodegradable PLA-PEG-PLA triblock and mPEG-PLA diblock polymers, which can be used to deliver a variety of active substances. Summary of the Invention

[0010] In some aspects, this disclosure provides a pharmaceutical composition for administration via subcutaneous injection, wherein the composition comprises:

[0011] 20% to 45% (w / w) of olanzapine;

[0012] 35% to 65% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0013] A diblock copolymer comprising polylactic acid and polyethylene glycol, wherein the number average molecular weight of the diblock copolymer is 6 to 15 kg / mol and comprises 70% to 90% (w / w) polylactic acid by weight; and

[0014] The triblock copolymer comprises polylactic acid and polyethylene glycol, the number average molecular weight of the triblock copolymer being 6 to 19 kg / mol and containing 80% to 90% (w / w) polylactic acid by weight;

[0015] The diblock copolymer and the triblock copolymer together account for 10% to 25% (w / w) of the composition by weight.

[0016] In other respects, this disclosure provides a pharmaceutical composition for administration by subcutaneous injection, wherein the composition comprises essentially the following:

[0017] 20% to 45% (w / w) of olanzapine;

[0018] 35% to 65% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0019] A diblock copolymer comprising polylactic acid and polyethylene glycol, wherein the number average molecular weight of the diblock copolymer is 6 to 15 kg / mol and comprises 70% to 90% (w / w) polylactic acid by weight; and

[0020] The triblock copolymer comprises polylactic acid and polyethylene glycol, the number average molecular weight of the triblock copolymer being 6 to 19 kg / mol and containing 80% to 90% (w / w) polylactic acid by weight;

[0021] The diblock copolymer and the triblock copolymer together comprise 10% to 25% (w / w) of the composition by weight.

[0022] In some aspects, this disclosure provides a pharmaceutical composition for administration by subcutaneous injection, wherein the composition comprises:

[0023] 20% to 45% (w / w) of olanzapine;

[0024] 35% to 65% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0025] A diblock copolymer comprising polylactic acid and polyethylene glycol, wherein the number average molecular weight of the diblock copolymer is 6 to 15 kg / mol and comprises 70% to 90% (w / w) polylactic acid by weight; and

[0026] The triblock copolymer comprises polylactic acid and polyethylene glycol, the number average molecular weight of the triblock copolymer being 6 to 19 kg / mol and containing 80% to 90% (w / w) polylactic acid by weight;

[0027] The diblock copolymer and the triblock copolymer together comprise 10% to 25% (w / w) of the composition by weight.

[0028] The above-described pharmaceutical composition can safely and effectively treat patients with schizophrenia, schizoaffective disorder, bipolar disorder, or depression with a convenient once-monthly administration regimen. The composition can be administered to patients, providing olanzapine plasma C... 最大 Less than 100 ng / mL. Unbound by theory, it is understandable that when olanzapine plasma C... 最大 At concentrations below 100 ng / mL, treatment is clinically effective and PDSS can be avoided. Therefore, the compositions of the present invention can be administered monthly with little or no monitoring or intervention by a healthcare professional during the intervention period.

[0029] The present invention also provides methods for preparing the compositions of the present invention, methods for administering olanzapine to a patient using the compositions of the present invention, and methods for treating a disease or condition using the compositions of the present invention, said disease or condition being schizophrenia, schizoaffective disorder, bipolar disorder, or depression.

[0030] This disclosure also provides a kit comprising:

[0031] Containers containing olanzapine in doses of 318 to 950 mg, optionally 550 to 950 mg, and optionally 450 to 800 mg; and

[0032] A container comprising a mixture of 0.73 to 2.5 g, optionally 1.3 to 2.5 g, optionally 0.9 to 2.1 g, wherein the mixture is a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer, wherein the organic solvent is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or a combination thereof, wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, wherein the number average molecular weight of the diblock copolymer is 6 to 15 kg / mol and comprises 70% to 90% (w / w) polylactic acid by weight, and the triblock copolymer comprises polylactic acid and polyethylene glycol, wherein the number average molecular weight of the triblock copolymer is 6 to 19 kg / mol and comprises 80% to 90% (w / w) polylactic acid by weight.

[0033] Methods for treating patients using the kit disclosed herein are also provided.

[0034] Methods for switching a patient from daily oral olanzapine treatment to treatment including monthly administration of the compositions disclosed herein are also provided, as well as methods for switching a patient from long-acting intramuscular olanzapine formulations to the compositions disclosed herein.

[0035] The use of the above-mentioned pharmaceutical composition in medicine is also provided.

[0036] The use of the above-described pharmaceutical composition in the above-described method is also provided. Attached Figure Description

[0037] Figure 1 The X-ray diffraction (XRD) pattern of olanzapine crystal form II is shown.

[0038] Figure 2 The graph shows the mean (±SD) olanzapine plasma concentration versus time after a single subcutaneous injection of different compositions at a dose of 405 mg or after two repeated intramuscular administrations of ZYPADHERA products at a dose of 300 mg every 2 weeks.

[0039] Example 2 further describes this study. SD = Standard deviation.

[0040] Figure 3The graphs showing mean (+ / - SD) olanzapine plasma concentrations versus time, plotted on linear (upper) and semi-logarithmic (lower) scales by administration date, represent a safety analysis set of studies described in Example 5 following oral olanzapine concentrations at steady-state and washout periods. SD = standard deviation.

[0041] Figure 4 The mean (±SD) plasma olanzapine concentration (ng / mL) in healthy subjects, based on linear (upper) and semi-log (lower) scales, is shown in the study described in Example 5. SD = standard deviation.

[0042] Figure 5 The mean (±SD) plasma olanzapine concentrations (ng / mL) in patients following a single subcutaneous dose of formulation 1, based on linear (upper) and semi-logarithmic (lower) scales, are shown in the study described in Example 5. SD = standard deviation.

[0043] Figure 6 The graph shows the mean (± standard deviation) olanzapine plasma concentrations versus time on a linear scaling basis, plotted by cohort and administration date: multi-dose patient cohort after formulation 1 (safety analysis set). The horizontal line represents a clinically relevant olanzapine plasma concentration of 10 ng / mL.

[0044] Figure 7 The graph shows the mean (± standard deviation) olanzapine plasma concentrations versus time on a semi-logarithmic scale, plotted by cohort and administration date: multi-dose patient cohort after formulation 1 (safety analysis set). The horizontal line represents a clinically relevant olanzapine plasma concentration of 10 ng / mL.

[0045] Figure 8 The figures show the median pharmacokinetic characteristics and pharmacokinetic variability (5th and 95th percentiles) of olanzapine concentrations observed in the study described in Example 4 (left panel) and formulation 1 (right panel). 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).

[0046] Figure 9A schematic diagram of the study described in Example 6 is shown. During the screening phase, patients who had not previously received oral olanzapine would receive two doses of oral olanzapine over two consecutive days (the second dose should be taken at least 24 hours before randomization) to assess patient tolerability (oral olanzapine 10 mg / day or higher [but not exceeding 20 mg / day], at the investigator's discretion). Patients who had received olanzapine within the past year would not need to receive two doses of oral treatment. The investigator would confirm prior use, tolerability, and duration of olanzapine treatment to ensure prior tolerability. To maintain blinding in Phase 1, all patients would be re-randomized between Phase 1 and Phase 2; patients previously assigned to the active treatment group would maintain their Phase 1 treatment group (the re-randomization of patients in the Formulation 1 group was only to maintain blinding in Phase 1 and was, in fact, a deterministic grouping, not a randomization), while patients previously assigned to the placebo group would be randomized to one of the active treatment groups in a 1:1:1 ratio. Treatment grouping on an individual patient basis would only be revealed in Phase 2 after the study procedures related to the assessment of the Phase 1 efficacy and safety endpoints were completed and reported. The unblinding of Phase 2 treatment allocations was conducted by the sponsor or representative during weeks 8 to 12 according to a pre-defined procedure in the relevant study plan, provided that all requirements specified in that procedure were met. Therefore, although the administration in week 8 was allocated to Phase 2, all parties were treated in a blinded manner, similar to the administration in Phase 1. q1m = once a month; R = randomization.

[0047] Figure 10 Formulation 1 and ZYPREXA were shown. Results of in vitro release in human plasma at 37°C. See Example 7. Detailed Implementation

[0048] 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 this specification is for describing particular embodiments only and is not intended to be limiting of this disclosure.

[0049] When a range of values ​​is provided, it should be understood that the upper limit, lower limit, and every intermediate value between the upper and lower limits of the range are covered in this disclosure.

[0050] As used herein, the term “about” refers to the value shown and any number within ±10% of the value shown. Thus, for example, the term “about 10%” refers to any value in the range of 9 to 11 (inclusive).

[0051] As used herein, unless the context clearly indicates otherwise, the articles “a” and “an” refer to more than one grammatical object of the article (e.g., at least one). For example, “a composition” refers to one composition or more than one composition.

[0052] The term "olanzapine" refers to a compound with the chemical name 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,4b][1,5]benzodiazepine and the following chemical structure:

[0053]

[0054] Pharmaceutically acceptable salts of olanzapine are also within the scope of this disclosure.

[0055] U.S. Patent Nos. 5,229,382 and 5,736,541 describe crystal forms I and II of olanzapine, respectively. U.S. Patent No. 7,323,459 describes crystal forms H, G, Y, X, K, S, Q, Z, and J of olanzapine. As a free base or salt, such as hydrochloric acid or dihydroxynaphthyl salt, olanzapine is the active pharmaceutical ingredient (API) of a medicine used to treat schizophrenia and other neuropsychiatric disorders and conditions.

[0056] "Pharmaceutical acceptable" means approved or permitted by a U.S. federal or state regulatory agency or by an appropriate agency in a country outside the United States, or listed in the United States Pharmacopeia or other recognized pharmacopoeia as suitable for use in animals (e.g., humans).

[0057] "Pharmaceutically acceptable salt" refers to a salt of the compounds disclosed herein that is pharmaceutically acceptable and possesses the pharmacological activity required by 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 reacting with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (e.g., acetic acid, dihydroxynaphthoic 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-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- (1) Acid addition salts formed by toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucohepenoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) Salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth ions or aluminum ions) or coordinated with organic bases (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc.).

[0058] "Pharmaceutical acceptable excipient" refers to a non-toxic, biologically tolerable, and biologically suitable substance (e.g., an inert substance) that is added to a pharmacological composition or otherwise used as a carrier, transporter, or diluent to facilitate the administration of a drug and is compatible with it.

[0059] When the term "alkyl" is used alone or as part of a substituent, it refers to a straight-chain or branched saturated hydrocarbon group ("C1-C6") having 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc. When a range of carbon atoms is used herein, such as C1-C6, it includes all ranges and individual carbon atom numbers. For example, "C1-C3" includes C1-C3, C1-C2, C2-C3, C1, C2, and C3.

[0060] The term "patient" or "patient" is used throughout this specification to describe a person receiving treatment (including prophylactic treatment) with the compositions provided in this disclosure. As used herein, the term "patient" or "patient" also refers to a single human being, or, where the context permits, a group of humans. Thus, in some embodiments, a patient is an individual human being. In other embodiments, a patient is a group of humans.

[0061] As used herein, the terms “subject” or “test subject” refer to a person to whom the compositions of this disclosure are administered.

[0062] In one embodiment, “treatment” or “management” for any disease or condition refers to improving the disease or condition (e.g., preventing or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, “treatment” or “management” refers to improving at least one physical or psychological parameter that the subject may not be able to discern. In yet another embodiment, “treatment” or “management” refers to regulating the disease or condition, whether physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, “treatment” or “management” refers to delaying the onset of a disease or condition or its symptoms. In some embodiments, “treatment” or “management” includes maintenance treatment, i.e., treatment aimed at maintaining the improvement in a patient’s condition by reducing or eliminating adverse changes in the patient’s clinical symptoms or physical or psychological parameters.

[0063] The term “effective” used to describe treatment means a treatment that is effective (i.e., produces the expected results, including but not limited to achieving primary and / or secondary clinical endpoints).

[0064] "Post-injection delirium / sedation syndrome" or "PDSS" should be understood as those symptoms or combinations of symptoms and conditions as defined in "Detke, HC et al., BMC Psychiatry 2010, 10:43" (which is incorporated herein by reference), or as any person skilled in the art would understand the term. For example, delirium-related symptoms include disorientation, confusion, ataxia, and dysarthria. Sedation-related symptoms include somnolence, sedation, or other changes in level of consciousness.

[0065] Number-average molecular weight (Mn) is typically measured by gel permeation chromatography (GPC), usually using polystyrene standards. Polymers can also be characterized by weight-average molecular weight (Mw). This can also be measured by gel permeation chromatography (GPC), typically using polystyrene standards. The polydispersity index is defined as the ratio of Mw to Mn, and is typically greater than 1 and less than 2.

[0066] Alternatively, or as an alternative to defining polymers by number-average molecular weight, polymers can also be defined by their theoretical molecular weight. The term "theoretical molecular weight" refers to the molecular weight of a copolymer determined by calculating the sum of the molar amounts of the repeating units that make up the polymer. The theoretical molecular weight indicates the average length of the target polymer chain.

[0067] As used herein, the terms "once a month" or "q1m" or "once a month" mean once a month, and they are used interchangeably. In some implementations, "once a month" or "q1m" or "once a month" means 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 implementations, "once a month" or "q1m" or "once a month" means once every 28 days ± 3 days, such as 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. "Once a month" or "q1m" or "once a month" can be applied on any day of the month, such as the 1st day, the 2nd day, the 3rd day, etc. Subsequent administration of the formulation “once a month” or “q1m” or “once a month” should be performed one month later (e.g., after 28 days ± 5 days or 28 days ± 3 days).

[0068] In some aspects, this disclosure provides pharmaceutical compositions for administration by subcutaneous injection, wherein the compositions comprise: 20% to 45% (w / w) olanzapine; 35% to 65% (w / w) an organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP), or combinations thereof; a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6 to 15 kg / mol and comprising 70% to 90% (w / w) polylactic acid by weight; and a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 6 to 19 kg / mol and comprising 80% to 90% (w / w) polylactic acid by weight; wherein the diblock copolymer and the triblock copolymer together comprise 10% to 25% (w / w) of the composition by weight.

[0069] The pharmaceutical composition disclosed herein 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, arm, small part of the back, thigh, etc.

[0070] In some aspects, the compositions disclosed herein comprise 20% to 45% (w / w), optionally 22% to 34% (w / w), optionally 30% to 32% (w / w) of olanzapine, for example, 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% (w / w) of olanzapine by weight. Olanzapine at 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% (w / w).

[0071] In some aspects, the compositions disclosed herein comprise about 20% to about 45% (w / w) of olanzapine by weight, 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%, 43.5%, about 44.0%, about 44.5%, or about 45.0% (w / w) of olanzapine by weight.

[0072] In some embodiments, the compositions disclosed herein comprise 22% to 34% (w / w) of olanzapine by weight, 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% (w / w) of olanzapine by weight.

[0073] In other embodiments, the compositions disclosed herein comprise about 22% to about 34% (w / w) of olanzapine by weight, 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% (w / w) of olanzapine by weight.

[0074] In some embodiments, the compositions disclosed herein comprise 20% to 24% (w / w) of olanzapine by weight, such as 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23%, 23.5% or 24.0% (w / w) of olanzapine by weight.

[0075] In other embodiments, the compositions disclosed herein comprise about 20% to 24% (w / w) of olanzapine by weight, 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% (w / w) of olanzapine by weight.

[0076] In some embodiments, the compositions disclosed herein comprise 20.5% (w / w) olanzapine by weight.

[0077] In other embodiments, the compositions disclosed herein comprise about 20.5% (w / w) olanzapine by weight.

[0078] In some embodiments, the compositions disclosed herein comprise 22.0% (w / w) olanzapine by weight.

[0079] In other embodiments, the compositions disclosed herein comprise about 22.0% (w / w) olanzapine by weight.

[0080] In some embodiments, the compositions disclosed herein comprise 23.5% (w / w) olanzapine by weight.

[0081] In other embodiments, the compositions disclosed herein comprise about 23.5% (w / w) olanzapine by weight.

[0082] In some embodiments, the compositions disclosed herein comprise 30% to 32% (w / w) of olanzapine by weight, such as 30.0%, 30.5%, 31%, 31.5% or 32.0% (w / w) of olanzapine by weight.

[0083] In other embodiments, the compositions disclosed herein comprise about 30% to about 32% (w / w) of olanzapine by weight, such as about 30%, about 31%, or about 32% (w / w) of olanzapine by weight.

[0084] In some embodiments, the compositions disclosed herein comprise 26.5% (w / w) olanzapine by weight.

[0085] In other embodiments, the compositions disclosed herein comprise about 26.5% (w / w) olanzapine by weight.

[0086] In some embodiments, the compositions disclosed herein comprise 29.0% (w / w) olanzapine by weight.

[0087] In other embodiments, the compositions disclosed herein comprise about 29.0% (w / w) olanzapine by weight.

[0088] In some embodiments, the compositions disclosed herein comprise 30.5% (w / w) olanzapine by weight.

[0089] In other embodiments, the compositions disclosed herein comprise about 30.5% (w / w) olanzapine by weight.

[0090] In some embodiments, the compositions disclosed herein comprise 32.0% (w / w) olanzapine by weight.

[0091] In other embodiments, the compositions disclosed herein comprise about 32.0% (w / w) olanzapine by weight.

[0092] In some embodiments, the compositions disclosed herein comprise 33.5% (w / w) olanzapine by weight.

[0093] In other embodiments, the compositions disclosed herein comprise about 33.5% (w / w) olanzapine by weight.

[0094] In some embodiments, the compositions disclosed herein comprise 40% to 45% (w / w) olanzapine by weight, 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% (w / w) olanzapine by weight.

[0095] In other embodiments, the compositions disclosed herein comprise about 40% to about 45% (w / w) of olanzapine by weight, 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% (w / w) of olanzapine by weight.

[0096] In some embodiments, the compositions disclosed herein comprise 40.7% (w / w) olanzapine by weight.

[0097] In other embodiments, the compositions disclosed herein comprise about 40.7% (w / w) olanzapine by weight.

[0098] In some embodiments, the compositions disclosed herein comprise 42.0% (w / w) olanzapine by weight.

[0099] In other embodiments, the compositions disclosed herein comprise about 42.0% (w / w) olanzapine by weight.

[0100] In some embodiments, the compositions disclosed herein comprise 43.5% (w / w) olanzapine by weight.

[0101] In other embodiments, the compositions disclosed herein comprise about 43.5% (w / w) olanzapine by weight.

[0102] In some embodiments, each gram of the disclosed composition contains about 220 to about 340 mg of olanzapine, for example, 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 24... 5mg, approximately 246mg, approximately 247mg, 248mg, approximately 249mg, approximately 250mg, approximately 251mg, approximately 252mg, approximately 253mg, approximately 254mg, approximately 255mg, approximately 256mg, approximately 257mg, approximately 258mg, approximately 259mg, approximately 260mg, approximately 261mg, approximately 262mg, approximately 263mg, approximately 264mg, approximately 265mg, approximately 266mg, approximately 267mg, approximately 268mg, approximately 269mg, approximately 270mg, approximately 271mg, approximately 272mg, approximately 273mg, approximately 274mg, approximately 275mg, approximately 276mg, approximately 277 mg, approximately 278mg, approximately 279mg, approximately 280mg, approximately 281mg, approximately 282mg, approximately 283mg, approximately 284mg, approximately 285mg, approximately 286mg, approximately 287mg, approximately 288mg, approximately 289mg, approximately 290mg, approximately 291mg, approximately 292mg, approximately 293mg, approximately 294mg, approximately 295mg, approximately 296mg, approximately 297mg, approximately 298mg, approximately 299mg, approximately 300mg, approximately 301mg, approximately 302mg, approximately 303mg, approximately 304mg, approximately 305mg, approximately 306mg, approximately 307mg, approximately 308mg, approximately 30 Olanzapine in doses of 9 mg, approximately 310 mg, approximately 311 mg, approximately 312 mg, approximately 313 mg, approximately 314 mg, approximately 315 mg, approximately 316 mg, approximately 317 mg, 318 mg, approximately 319 mg, approximately 320 mg, approximately 321 mg, approximately 322 mg, approximately 323 mg, approximately 324 mg, approximately 325 mg, approximately 326 mg, approximately 327 mg, approximately 328 mg, approximately 329 mg, approximately 330 mg, approximately 331 mg, approximately 332 mg, approximately 333 mg, approximately 334 mg, approximately 335 mg, approximately 336 mg, approximately 337 mg, approximately 338 mg, approximately 339 mg, or approximately 340 mg.

[0103] In some embodiments, each gram of the composition disclosed herein contains 265 mg of olanzapine. In some embodiments, each gram of the composition disclosed herein contains about 265 mg of olanzapine.

[0104] In some embodiments, each gram of the composition disclosed herein contains 290 mg of olanzapine. In some embodiments, each gram of the composition disclosed herein contains about 290 mg of olanzapine.

[0105] In some embodiments, each gram of the composition disclosed herein contains 305 mg of olanzapine. In some embodiments, each gram of the composition disclosed herein contains about 305 mg of olanzapine.

[0106] In some embodiments, each gram of the composition disclosed herein contains 320 mg of olanzapine. In some embodiments, each gram of the composition disclosed herein contains about 320 mg of olanzapine.

[0107] In some embodiments, each gram of the composition disclosed herein contains 335 mg of olanzapine. In some embodiments, each gram of the composition disclosed herein contains about 335 mg of olanzapine.

[0108] In some aspects, the compositions disclosed herein comprise an organic solvent. Suitable organic solvents for use in the compositions disclosed herein include: benzyl alcohol, benzyl benzoate, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether (DEGMEE), dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, ethylene glycol monoethyl ether acetate, glycerol formaldehyde, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidone (NMP), pyrrolidone-2, tetraethylene glycol, triacetin, glyceryl tartrate, glyceryl tributate, glyceryl tripropionate, or triethylene glycol dimethyl ether (triethylene glycol dimethyl ether), or mixtures of the above solvents.

[0109] In some aspects, the compositions disclosed herein comprise 35% to 65% (w / w) of an organic solvent, optionally 50% to 55% (w / w), 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%, 47.5%, 48% (w / w) of an organic solvent, by weight. 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% (w / w) of organic solvents.

[0110] In some aspects, the compositions disclosed herein comprise about 35% to about 65% (w / w) of an 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% (w / w) of an organic solvent by weight.

[0111] In some respects, organic solvents include dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP), or combinations thereof.

[0112] In some embodiments, the organic solvent comprises dimethyl sulfoxide (DMSO). In some embodiments, the organic solvent is preferably dimethyl sulfoxide (DMSO).

[0113] In other embodiments, the organic solvent comprises N-methyl-2-pyrrolidone (NMP).

[0114] In other embodiments, the organic solvent is a mixture of dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP). In such embodiments, DMSO and NMP can be present in any proportion. In another embodiment, it is preferred that the weight proportion of DMSO is higher than that of NMP.

[0115] In some embodiments, the compositions disclosed herein contain 35% to 40% (w / w) of an organic solvent, 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% (w / w) of an organic solvent by weight.

[0116] In other embodiments, the compositions disclosed herein comprise about 35% to about 40% (w / w) of an organic solvent by weight, 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% (w / w) of an organic solvent by weight.

[0117] In some embodiments, the compositions disclosed herein contain 35% (w / w) of an organic solvent by weight.

[0118] In other embodiments, the compositions disclosed herein contain about 35% (w / w) of an organic solvent by weight.

[0119] In some embodiments, the compositions disclosed herein contain 37.1% (w / w) of an organic solvent by weight.

[0120] In other embodiments, the compositions disclosed herein contain about 37.1% (w / w) of an organic solvent by weight.

[0121] In some embodiments, the compositions disclosed herein contain 38% (w / w) of an organic solvent by weight.

[0122] In other embodiments, the compositions disclosed herein contain about 38% (w / w) of an organic solvent by weight.

[0123] In some embodiments, the compositions disclosed herein contain 50% to 55% (w / w) of an organic solvent, 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% (w / w) of an organic solvent by weight.

[0124] In other embodiments, the compositions disclosed herein contain about 50% to about 55% (w / w) of an organic solvent by weight, such as about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% (w / w) of an organic solvent by weight.

[0125] In some embodiments, the compositions disclosed herein contain 50% (w / w) of an organic solvent by weight.

[0126] In other embodiments, the compositions disclosed herein contain about 50% (w / w) of an organic solvent by weight.

[0127] In some embodiments, the compositions disclosed herein contain 52% (w / w) of an organic solvent by weight.

[0128] In other embodiments, the compositions disclosed herein contain about 52% (w / w) of an organic solvent by weight.

[0129] In some embodiments, the compositions disclosed herein contain 53.5% (w / w) of an organic solvent by weight.

[0130] In other embodiments, the compositions disclosed herein contain about 53.5% (w / w) of an organic solvent by weight.

[0131] In some embodiments, the compositions disclosed herein contain 54% (w / w) of an organic solvent by weight.

[0132] In other embodiments, the compositions disclosed herein contain about 54% (w / w) of an organic solvent by weight.

[0133] In some embodiments, the compositions disclosed herein contain 55% (w / w) of an organic solvent by weight.

[0134] In other embodiments, the compositions disclosed herein contain about 55% (w / w) of an organic solvent by weight.

[0135] In some embodiments, the compositions disclosed herein comprise 58% to 62% (w / w) of an organic solvent, such as 58.0%, 58.5%, 59.0%, 59.5%, 60.0%, 60.5%, 61.0%, 61.5%, or 62.0% (w / w) of an organic solvent by weight.

[0136] In other embodiments, the compositions disclosed herein comprise about 58% to about 62% (w / w) of an organic solvent by weight, 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% (w / w) of an organic solvent by weight.

[0137] In some embodiments, the compositions disclosed herein contain 58.5% (w / w) of an organic solvent by weight.

[0138] In other embodiments, the compositions disclosed herein contain about 58.5% (w / w) of an organic solvent by weight.

[0139] In some embodiments, the compositions disclosed herein contain 60.0% (w / w) of an organic solvent by weight.

[0140] In other embodiments, the compositions disclosed herein contain about 60.0% (w / w) of an organic solvent by weight.

[0141] In some embodiments, the compositions disclosed herein contain 61.5% (w / w) of an organic solvent by weight.

[0142] In other embodiments, the compositions disclosed herein contain about 61.5% (w / w) of an organic solvent by weight.

[0143] In some respects, the compositions disclosed herein comprise diblock copolymers and triblock copolymers.

[0144] In some aspects, the diblock copolymers in the compositions disclosed herein comprise polylactic acid (PLA) and polyethylene glycol (PEG).

[0145] 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.

[0146] In some embodiments, one end of the polyethylene glycol (PEG) in the diblock copolymer is capped with a C1-C6 alkyl group (e.g., -CH3, -CH2CH3, etc.). In other words, the terminal hydroxyl group at one end of the polyethylene glycol (PEG) chain is capped with a C1-C6 alkyl group, and the terminal hydroxyl group at the other end of the PEG chain forms an ester bond with the polylactide (PLA) chain.

[0147] In some embodiments, one end of the polyethylene glycol (PEG) in the diblock copolymer is capped with -CH3. This capped PEG can be referred to as mPEG. In other words, the terminal hydroxyl group at one end of the PEG chain is capped with -CH3, and the terminal hydroxyl group at the other end of the PEG chain forms an ester bond with the polylactide (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.

[0148] In some respects, the diblock copolymers in the compositions disclosed herein have the following structures:

[0149]

[0150] 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 units (M(LA) = 72 g / mol) and the ethylene oxide units (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 theoretical molecular weight of the diblock copolymer in the compositions disclosed herein is 6 to 15 kg / mol. In one embodiment, the theoretical molecular weight of the diblock polymer is 8.0 to 12.5 kg / mol or 6.0 to 9.5 kg / mol.

[0151] In some respects, the diblock copolymers in the compositions disclosed herein have a number average molecular weight of 6 to 15 kg / mol and contain 70% to 90% (w / w) polylactic acid by weight.

[0152] In some aspects, the number-average molecular weight of the diblock copolymers in the compositions disclosed herein is 6 to 15 kg / mol, optionally 6.5 to 13.5 kg / mol, for example 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 0.4, 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 or 15.0 kg / mol.

[0153] In some aspects, the number-average molecular weight of the diblock copolymers in the compositions disclosed herein is about 6 to about 15 kg / mol, for example, 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 9.5, 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 1 0.5, approximately 10.6, approximately 10.7, approximately 10.8, approximately 10.9, approximately 11.0, approximately 11.1, approximately 11.2, approximately 11.3, approximately 11.4, approximately 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, or approximately 15.0 kg / mol.

[0154] In some embodiments, the number-average molecular weight of the diblock copolymer is 7.0 to 12.5 kg / mol. In other embodiments, the number-average molecular weight of the diblock copolymer is 7.0 to 11.0 kg / mol. In some embodiments, the number-average molecular weight of the diblock copolymer is about 10.0 kg / mol. In other embodiments, the number-average molecular weight of the diblock copolymer is about 9.0 kg / mol.

[0155] In some aspects, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the disclosed compositions is from 1.9 to 4.0, for example 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.

[0156] In some aspects, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the disclosed compositions is from about 1.9 to 3.5, optionally from about 1.9 to 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.

[0157] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the present disclosure composition is 2.4.

[0158] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the present disclosure composition is about 2.4.

[0159] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the present disclosure composition is 2.8.

[0160] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the present disclosure composition is about 2.8.

[0161] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the present disclosure composition is 3.2.

[0162] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the present disclosure composition is about 3.2.

[0163] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the present disclosure composition is 3.5.

[0164] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the diblock copolymer of the present disclosure composition is about 3.5.

[0165] In some aspects, the diblock copolymers in the compositions disclosed herein comprise 70% to 90%, optionally 75% to 84%, optionally 84% to 88% (w / w) of polylactic acid by weight, such as 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% (w / w) of polylactic acid by weight.

[0166] In some aspects, the diblock copolymers in the compositions disclosed herein comprise about 70% to about 90% (w / w) of polylactic acid, 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% (w / w) of polylactic acid by weight.

[0167] In some embodiments, the diblock copolymers in the compositions disclosed herein comprise 75% to 84% (w / w) polylactic acid by weight, such as 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, or 84% (w / w) polylactic acid by weight.

[0168] In other embodiments, the diblock copolymers in the compositions disclosed herein comprise about 75% to about 84% (w / w) of polylactic acid by weight, such as about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, or about 84% (w / w) of polylactic acid by weight.

[0169] In some embodiments, the diblock copolymer in the compositions disclosed herein comprises 76% (w / w) polylactic acid by weight.

[0170] In other embodiments, the diblock copolymer in the compositions disclosed herein comprises about 76% (w / w) polylactic acid by weight.

[0171] In some embodiments, the diblock copolymers in the compositions disclosed herein comprise 80% (w / w) polylactic acid by weight.

[0172] In other embodiments, the diblock copolymer in the compositions disclosed herein comprises about 80% (w / w) polylactic acid by weight.

[0173] In some embodiments, the diblock copolymer in the compositions disclosed herein comprises 82% (w / w) polylactic acid by weight.

[0174] In other embodiments, the diblock copolymer in the compositions disclosed herein comprises about 82% (w / w) polylactic acid by weight.

[0175] In some embodiments, the diblock copolymers in the compositions disclosed herein comprise 73% to 77% (w / w) polylactic acid by weight, such as 73%, 74%, 75%, 76% or 77% (w / w) polylactic acid by weight.

[0176] In other embodiments, the diblock copolymers in the compositions disclosed herein comprise about 73% to about 77% (w / w) of polylactic acid by weight, such as about 73%, about 74%, about 75%, about 76%, or about 77% (w / w) of polylactic acid by weight.

[0177] In some embodiments, the diblock copolymer in the compositions disclosed herein comprises 73% (w / w) polylactic acid by weight.

[0178] In other embodiments, the diblock copolymer in the compositions disclosed herein comprises about 73% (w / w) polylactic acid by weight.

[0179] In some embodiments, the diblock copolymer in the compositions disclosed herein comprises 75% (w / w) polylactic acid by weight.

[0180] In other embodiments, the diblock copolymer in the compositions disclosed herein comprises about 75% (w / w) polylactic acid by weight.

[0181] In some embodiments, the diblock copolymer in the compositions disclosed herein comprises 77% (w / w) polylactic acid by weight.

[0182] In other embodiments, the diblock copolymer in the compositions disclosed herein comprises about 77% (w / w) polylactic acid by weight.

[0183] In some embodiments, the diblock copolymers in the compositions disclosed herein comprise 84% to 88% (w / w) polylactic acid by weight, such as 84%, 85%, 86%, 87% or 88% (w / w) polylactic acid by weight.

[0184] In other embodiments, the diblock copolymers in the compositions disclosed herein comprise about 84% to 88% (w / w) of polylactic acid by weight, such as about 84%, about 85%, about 86%, about 87%, or about 88% (w / w) of polylactic acid by weight.

[0185] In some embodiments, the diblock copolymers in the compositions disclosed herein comprise 84% (w / w) polylactic acid by weight.

[0186] In some embodiments, the diblock copolymers in the compositions disclosed herein comprise about 84% (w / w) polylactic acid by weight.

[0187] In some embodiments, the diblock copolymer in the compositions disclosed herein comprises 86% (w / w) polylactic acid by weight.

[0188] In some embodiments, the diblock copolymers in the compositions disclosed herein comprise about 86% (w / w) polylactic acid by weight.

[0189] In some embodiments, the diblock copolymer in the compositions disclosed herein comprises 88% (w / w) polylactic acid by weight.

[0190] In some embodiments, the diblock copolymers in the compositions disclosed herein comprise about 88% (w / w) polylactic acid by weight.

[0191] In some respects, the weight ratio of the diblock copolymer to the triblock copolymer is 6:1 to 2:1, optionally about 4:1.

[0192] In some aspects, the compositions disclosed herein comprise 10% to 18% (w / w), optionally 10% to 15%, optionally 12% to 17% (w / w) of a diblock copolymer, such as 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17% or 18% (w / w) of a diblock copolymer by weight.

[0193] In some aspects, the compositions disclosed herein comprise about 10% to about 17% (w / w) of a diblock copolymer by weight, such as about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17% or about 18% (w / w) of a diblock copolymer by weight.

[0194] In some embodiments, the compositions disclosed herein comprise 17.8% (w / w) of a diblock copolymer by weight.

[0195] In other embodiments, the compositions disclosed herein comprise about 17.8% (w / w) of a diblock copolymer by weight.

[0196] In some aspects, the compositions disclosed herein comprise 10% to 15% (w / w) of a 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%, and 12.2% by weight. Diblock copolymers of 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%, and 15.0% (w / w).

[0197] In some aspects, the compositions disclosed herein comprise about 10% to about 15% (w / w) of a diblock copolymer, such as about 10%, about 11%, about 12%, about 13%, about 14% or about 15% (w / w) of a diblock copolymer by weight.

[0198] In some embodiments, the compositions disclosed herein comprise 12.2% (w / w) of a diblock copolymer by weight.

[0199] In other embodiments, the compositions disclosed herein comprise about 12.2% (w / w) of a diblock copolymer by weight.

[0200] In some embodiments, the compositions disclosed herein comprise 12.8% (w / w) of a diblock copolymer by weight.

[0201] In other embodiments, the compositions disclosed herein comprise about 12.8% (w / w) of a diblock copolymer by weight.

[0202] In some embodiments, the compositions disclosed herein comprise 13.2% (w / w) of a diblock copolymer by weight.

[0203] In other embodiments, the compositions disclosed herein comprise about 13.2% (w / w) of a diblock copolymer by weight.

[0204] In some embodiments, the compositions disclosed herein comprise 13.6% (w / w) of a diblock copolymer by weight.

[0205] In other embodiments, the compositions disclosed herein comprise about 13.6% (w / w) of a diblock copolymer by weight.

[0206] In some embodiments, the compositions disclosed herein comprise 14.0% (w / w) of a diblock copolymer by weight.

[0207] In other embodiments, the compositions disclosed herein comprise about 14.0% (w / w) of a diblock copolymer by weight.

[0208] In some embodiments, the compositions disclosed herein comprise 14.4% (w / w) of a diblock copolymer by weight.

[0209] In other embodiments, the compositions disclosed herein comprise about 14.4% (w / w) of a diblock copolymer by weight.

[0210] In some respects, the triblock copolymers in the compositions disclosed herein comprise polylactic acid (PLA) and polyethylene glycol (PEG).

[0211] 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.

[0212] In some embodiments, the triblock copolymer in the compositions of this disclosure is an ABA copolymer, wherein the A group is polylactic acid and the B group is polyethylene glycol (PEG). In these embodiments, the terminal hydroxyl group at either end of the polyethylene glycol (PEG) chain forms an ester bond with the polylactide (PLA) chain. Typically, the triblock copolymer can be obtained by ring-opening polymerization of D,L-lactide initiated by the terminal hydroxyl group of the PEG chain.

[0213] In some respects, the triblock copolymers in the compositions disclosed herein have the following structures:

[0214]

[0215] Where n is the number of ethylene oxide units in PEG, and m is the number of lactic acid units in each PLA group. 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 ethylene oxide unit (M(EO), 44 g / mol) and the number of repeating units in each block as follows: MW(PLA-PEG-PLA) = n*44 + 2*M*72 + 18. The theoretical molecular weight of the triblock copolymer in the compositions disclosed herein is 6 to 19 kg / mol. In one embodiment, the theoretical molecular weight of the triblock polymer is 6.5 to 9.0 kg / mol or 10.0 to 17.0 kg / mol.

[0216] In some respects, the triblock copolymers in the compositions disclosed herein have a number average molecular weight of 6 to 19 kg / mol and contain 80% to 90% (w / w) polylactic acid by weight.

[0217] In some aspects, the number-average molecular weight of the triblock copolymers in the compositions disclosed herein is 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, for example 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, 1 1.6, 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.

[0218] In some aspects, the number-average molecular weight of the triblock copolymer in the compositions disclosed herein is 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, for example 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 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, about 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 15.0, approximately 16.0, approximately 16.1, approximately 16.2, approximately 16.3, approximately 16.4, approximately 16.5, approximately 16.6, approximately 16.7, approximately 16.8, approximately 16.9, approximately 17.0, approximately 17.1, approximately 17.2, approximately 17.3, approximately 17.4, approximately 17.5, approximately 17.6, approximately 17.7, approximately 17.8, approximately 17.9, approximately 18.0, approximately 18.1, approximately 18.2, approximately 18.3, approximately 18.4, approximately 18.5, approximately 18.6, approximately 18.7, approximately 18.8, approximately 18.9, or approximately 19.0 kg / mol.

[0219] The number-average molecular weight of the triblock copolymer can be from about 6 to about 13 kg / mol, optionally from about 7 to about 12 kg / mol. The number-average molecular weight of the triblock polymer can be from 9 to 18 kg / mol, optionally from 10 to 17 kg / mol. The number-average molecular weight of the triblock copolymer can be about 9.5 kg / mol. The number-average molecular weight of the triblock copolymer can be about 14 kg / mol.

[0220] In some aspects, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the disclosed compositions is from 2.8 to 4.5, for example 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.

[0221] In some aspects, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure compositions is from about 2.8 to about 4.5, for example, 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.

[0222] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is 3.5 to 4.5, for example 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4 or 4.5.

[0223] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure is from about 3.5 to about 4.5, for example, 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.

[0224] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is 3.6.

[0225] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is about 3.6.

[0226] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is 3.8.

[0227] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is about 3.8.

[0228] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is 4.0.

[0229] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is about 4.0.

[0230] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is 4.2.

[0231] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is about 4.2.

[0232] In some embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is 4.4.

[0233] In other embodiments, the molar ratio of lactic acid to ethylene oxide in the triblock copolymer of the present disclosure composition is about 4.4.

[0234] In some aspects, the triblock copolymers in the compositions disclosed herein comprise 80% to 90% (w / w) of polylactic acid, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% (w / w) of polylactic acid by weight.

[0235] In some aspects, the triblock copolymers in the compositions disclosed herein comprise about 80% to about 90%, optionally 83% to 88%, optionally 85% to 88%, optionally about 88% (w / w) of polylactic acid by weight, 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% (w / w) of polylactic acid by weight.

[0236] In some embodiments, the triblock copolymers in the compositions disclosed herein comprise 83% to 88% (w / w) of polylactic acid by weight, such as 83%, 84%, 85%, 86%, 87%, or 88% (w / w) of polylactic acid by weight.

[0237] In other embodiments, the triblock copolymer in the compositions disclosed herein comprises about 83% to about 88% (w / w) of polylactic acid by weight, such as about 83%, about 84%, about 85%, about 86%, about 87%, or about 88% (w / w) of polylactic acid by weight.

[0238] In some embodiments, the triblock copolymers in the compositions disclosed herein comprise 85% to 88% (w / w) of polylactic acid by weight, such as 85%, 86%, 87% or 88% (w / w) of polylactic acid by weight.

[0239] In some embodiments, the triblock copolymers in the compositions disclosed herein comprise about 85% to about 88% (w / w) of polylactic acid by weight, such as about 85%, about 86%, about 87%, or about 88% (w / w) of polylactic acid by weight.

[0240] In some embodiments, the triblock copolymer in the compositions disclosed herein preferably comprises about 85% (w / w) polylactic acid by weight.

[0241] In some embodiments, the triblock copolymer in the compositions disclosed herein preferably comprises about 87% (w / w) polylactic acid by weight.

[0242] In some embodiments, the triblock copolymer in the compositions disclosed herein comprises 82% to 87% (w / w) polylactic acid by weight, such as 82%, 83%, 84%, 85%, 86%, or 87% (w / w) polylactic acid by weight. In some embodiments, the triblock copolymer in the compositions disclosed herein preferably comprises 85% (w / w) polylactic acid by weight.

[0243] In some embodiments, the triblock copolymer in the compositions disclosed herein comprises about 82% to about 87% (w / w) polylactic acid by weight, such as about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, or about 88% (w / w) polylactic acid by weight. In some embodiments, the triblock copolymer in the compositions disclosed herein preferably comprises about 85% (w / w) polylactic acid by weight.

[0244] In some aspects, the compositions disclosed herein comprise 3% to 5% by weight, optionally 3% to 4% (w / w) of a triblock copolymer, such as 3%, 4% or 5% (w / w) by weight of a triblock copolymer.

[0245] In some aspects, the compositions disclosed herein comprise about 3% to about 5% (w / w) of a triblock copolymer, such as about 3%, about 4%, or about 5% (w / w) of a triblock copolymer by weight.

[0246] In some aspects, the compositions disclosed herein comprise 3% to 4% (w / w) of a triblock copolymer, for example, 3% or 4% (w / w) of a triblock copolymer by weight.

[0247] In some aspects, the compositions disclosed herein comprise about 3% to about 4% (w / w) of a triblock copolymer, for example, about 3% or about 4% (w / w) of a triblock copolymer by weight.

[0248] In some embodiments, the compositions disclosed herein comprise 3.0% (w / w) of a triblock copolymer by weight.

[0249] In other embodiments, the compositions disclosed herein comprise about 3.0% (w / w) of a triblock copolymer by weight.

[0250] In some embodiments, the compositions disclosed herein comprise 3.2% (w / w) of a triblock copolymer by weight.

[0251] In other embodiments, the compositions disclosed herein comprise about 3.2% (w / w) of a triblock copolymer by weight.

[0252] In some embodiments, the compositions disclosed herein comprise 3.5% (w / w) of a triblock copolymer by weight.

[0253] In other embodiments, the compositions disclosed herein comprise about 3.5% (w / w) of a triblock copolymer by weight.

[0254] In some embodiments, the compositions disclosed herein comprise 3.6% (w / w) of a triblock copolymer by weight.

[0255] In other embodiments, the compositions disclosed herein comprise about 3.6% (w / w) of a triblock copolymer by weight.

[0256] In some embodiments, the compositions disclosed herein comprise 3.7% (w / w) of a triblock copolymer by weight.

[0257] In other embodiments, the compositions disclosed herein comprise about 3.7% (w / w) of a triblock copolymer by weight.

[0258] In some embodiments, the compositions disclosed herein comprise 4.5% (w / w) of a triblock copolymer by weight.

[0259] In other embodiments, the compositions disclosed herein comprise about 4.5% (w / w) of a triblock copolymer by weight.

[0260] In some aspects, the diblock copolymer and the triblock copolymer together comprise 10% to 25% by weight, optionally 10% to 20%, optionally 14% to 20% (w / w) of the composition, for example, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25% (w / w) of the composition by weight.

[0261] In some embodiments, the diblock copolymer and the triblock copolymer together comprise about 10% to about 25% by weight, optionally about 10% to about 20%, optionally about 14% to about 20% (w / w) of the composition, for example, 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% (w / w) of the composition by weight.

[0262] In some embodiments, the diblock copolymer and the triblock copolymer together comprise 12% (w / w) of the composition by weight in the compositions disclosed herein.

[0263] In other embodiments, the diblock copolymer and triblock copolymer together comprise about 12% (w / w) of the composition by weight in the compositions disclosed herein.

[0264] In some embodiments, the diblock copolymer and the triblock copolymer together comprise 14% (w / w) of the composition by weight in the compositions disclosed herein.

[0265] In other embodiments, the diblock copolymer and triblock copolymer together comprise about 14% (w / w) of the composition by weight in the compositions disclosed herein.

[0266] In some embodiments, the diblock copolymer and the triblock copolymer together comprise 16% (w / w) of the composition by weight in the compositions disclosed herein.

[0267] In other embodiments, the diblock copolymer and triblock copolymer together comprise about 16% (w / w) of the composition by weight in the compositions disclosed herein.

[0268] In some embodiments, the diblock copolymer and the triblock copolymer together comprise 18% (w / w) of the composition by weight in the compositions disclosed herein.

[0269] In other embodiments, the diblock copolymer and triblock copolymer together comprise about 18% (w / w) of the composition by weight in the compositions disclosed herein.

[0270] In some embodiments, the diblock copolymer and the triblock copolymer together comprise 20% (w / w) of the composition by weight in the compositions disclosed herein.

[0271] In other embodiments, the diblock copolymer and the triblock copolymer together comprise about 20% (w / w) of the composition by weight in the compositions disclosed herein.

[0272] In some embodiments, the diblock copolymer and the triblock copolymer together comprise 22% (w / w) of the composition by weight in the compositions disclosed herein.

[0273] In other embodiments, the diblock copolymer and triblock copolymer together comprise about 22% (w / w) of the composition by weight in the compositions disclosed herein.

[0274] In one embodiment, the composition comprises:

[0275] 20% to 45% (w / w) of olanzapine;

[0276] 35% to 65% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0277] 10% to 17% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, wherein the number average molecular weight of the diblock copolymer is 6 to 15 kg / mol and comprises 70% to 90% (w / w) polylactic acid by weight; and

[0278] 3% to 5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 6 to 19 kg / mol and comprising 80% to 90% (w / w) of polylactic acid by weight;

[0279] The diblock copolymer and triblock copolymer together account for 13% to 22% (w / w) of the composition by weight.

[0280] In one embodiment, the composition comprises:

[0281] 22% to 34% (w / w) of olanzapine;

[0282] 50% to 55% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0283] 10% to 15% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, wherein the number average molecular weight of the diblock copolymer is 6 to 15 kg / mol and comprises 70% to 90% (w / w) polylactic acid by weight; and

[0284] 3% to 4% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 6 to 19 kg / mol and comprising 80% to 90% (w / w) of polylactic acid by weight;

[0285] The diblock copolymer and triblock copolymer together account for 13% to 19% (w / w) of the composition by weight.

[0286] In one embodiment, the composition comprises:

[0287] 30% to 32% (w / w) of olanzapine;

[0288] 52% to 54% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0289] 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6 to 15 kg / mol and comprising 70% to 90% (w / w) polylactic acid by weight; and

[0290] 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, wherein the number average molecular weight of the triblock copolymer is 6 to 19 kg / mol and comprises 80% to 90% (w / w) polylactic acid by weight;

[0291] The diblock copolymer and the triblock copolymer together account for 15% to 17.5% (w / w) of the composition by weight.

[0292] In one embodiment, the composition comprises:

[0293] 20% to 45% (w / w) of olanzapine;

[0294] 35% to 65% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0295] 10% to 17% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 13.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and

[0296] 3% to 5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, wherein the number average molecular weight of the triblock copolymer is 6 to 13 kg / mol and comprises 83% to 88% (w / w) of polylactic acid by weight;

[0297] The diblock copolymer and triblock copolymer together account for 13% to 22% (w / w) of the composition by weight.

[0298] In one embodiment, the composition comprises:

[0299] 22% to 34% (w / w) of olanzapine;

[0300] 50% to 55% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0301] 10% to 15% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 12.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and

[0302] 3% to 4% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 6 to 13 kg / mol and comprising 83% to 88% (w / w) of polylactic acid by weight;

[0303] The diblock copolymer and triblock copolymer together account for 13% to 19% (w / w) of the composition by weight.

[0304] In one embodiment, the composition comprises:

[0305] 30% to 32% (w / w) of olanzapine;

[0306] 52% to 54% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0307] 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 12.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and

[0308] 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 6 to 13 kg / mol and comprising 83% to 88% (w / w) polylactic acid by weight;

[0309] The diblock copolymer and the triblock copolymer together account for 15% to 17.5% (w / w) of the composition by weight.

[0310] In one embodiment, the composition comprises:

[0311] 30% to 32% (w / w) of olanzapine;

[0312] 52% to 54% (w / w) of dimethyl sulfoxide;

[0313] 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 12.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and

[0314] 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 6 to 13 kg / mol and comprising 83% to 88% (w / w) polylactic acid by weight;

[0315] The diblock copolymer and the triblock copolymer together account for 15% to 17.5% (w / w) of the composition by weight.

[0316] In one embodiment, the composition comprises:

[0317] 20% to 45% (w / w) of olanzapine;

[0318] 35% to 65% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0319] 10% to 17% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 13.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and

[0320] 3% to 5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 9 to 18 kg / mol and comprising 83% to 88% (w / w) of polylactic acid by weight;

[0321] The diblock copolymer and triblock copolymer together account for 13% to 22% (w / w) of the composition by weight.

[0322] In one embodiment, the composition comprises:

[0323] 22% to 34% (w / w) of olanzapine;

[0324] 50% to 55% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0325] 10% to 15% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 12.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and

[0326] 3% to 4% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 9 to 18 kg / mol and comprising 83% to 88% (w / w) polylactic acid by weight;

[0327] The diblock copolymer and triblock copolymer together account for 13% to 19% (w / w) of the composition by weight.

[0328] In one embodiment, the composition comprises:

[0329] 30% to 32% (w / w) of olanzapine;

[0330] 52% to 54% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0331] 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 12.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and

[0332] 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 9 to 18 kg / mol and comprising 83% to 88% (w / w) of polylactic acid by weight;

[0333] The diblock copolymer and the triblock copolymer together account for 15% to 17.5% (w / w) of the composition by weight.

[0334] In one embodiment, the composition comprises:

[0335] 20% to 40% (w / w) olanzapine;

[0336] 40% to 65% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0337] 10% to 17% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 7.0 to 12.5 kg / mol and comprising 78% to 81% (w / w) polylactic acid by weight; and

[0338] 3% to 5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 7.0 to 12.0 kg / mol and comprising 85% to 88% (w / w) polylactic acid by weight;

[0339] The diblock copolymer and triblock copolymer together account for 13% to 22% (w / w) of the composition by weight.

[0340] In one embodiment, the composition comprises:

[0341] 22% to 34% (w / w) of olanzapine;

[0342] 50% to 55% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0343] 10% to 15% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 7.0 to 12.5 kg / mol and comprising 78% to 81% (w / w) polylactic acid by weight; and

[0344] 3% to 4% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 7.0 to 12.0 kg / mol and comprising 85% to 88% (w / w) of polylactic acid by weight;

[0345] The diblock copolymer and triblock copolymer together account for 13% to 19% (w / w) of the composition by weight.

[0346] In one embodiment, the composition comprises:

[0347] 30% to 32% (w / w) of olanzapine;

[0348] 52% to 54% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0349] 12% to 14% (w / w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 7.0 to 12.5 kg / mol and comprising 78% to 81% (w / w) polylactic acid by weight; and

[0350] 3% to 3.5% (w / w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 7.0 to 12.0 kg / mol and comprising 85% to 88% (w / w) of polylactic acid by weight;

[0351] The diblock copolymer and the triblock copolymer together account for 15% to 17.5% (w / w) of the composition by weight.

[0352] In some aspects, this disclosure relates to a kit comprising: a container containing 318 to 950 mg, optionally 550 to 950 mg, or optionally 450 to 800 mg of olanzapine; and a container containing 0.73 to 2.5 g, optionally 1.3 to 2.5 g, or optionally 0.9 to 2.1 g of a mixture, said mixture being a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer, said organic solvent being dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or combinations thereof, said diblock copolymer comprising polylactic acid and polyethylene glycol, said diblock copolymer having a number average molecular weight of 6.5 to 15 kg / mol and containing 70% to 90% (w / w) polylactic acid by weight, said triblock copolymer comprising polylactic acid and polyethylene glycol, said triblock copolymer having a number average molecular weight of 7 to 15 kg / mol and containing 80% to 90% (w / w) polylactic acid by weight.

[0353] In some respects, the kit disclosed herein includes a container containing olanzapine.

[0354] In some aspects, the kits disclosed herein include containers containing olanzapine in the following weights: 318 to 950 mg, optionally 550 to 950 mg, optionally 450 to 800 mg, for example 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, 4... 90mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 531mg, 535mg, 540mg , 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600 mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 637mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 695mg, 700mg, 705mg, 710mg 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 743mg, 745mg, 750mg, 755mg, 760mg, 765mg, 77 0mg, 775mg, 780mg, 785mg, 790mg, 795mg, 800mg, 805mg, 810mg, 815mg, 820mg, 825mg, 830mg Olanzapine in doses of 835mg, 840mg, 845mg, 850mg, 855mg, 860mg, 865mg, 870mg, 875mg, 880mg, 885mg, 890mg, 895mg, 900mg, 905mg, 910mg, 915mg, 920mg, 925mg, 930mg, 935mg, 940mg, 945mg, or 950mg.

[0355] In some aspects, the kit disclosed herein includes a container containing olanzapine in the following weights: about 318 to about 950 mg, optionally about 550 to 950 mg, optionally 450 mg to 800 mg, 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 435 mg, etc. g, approximately 440mg, approximately 445mg, approximately 450mg, approximately 455mg, approximately 460mg, approximately 465mg, approximately 470mg, approximately 475mg, approximately 480mg, approximately 485mg, approximately 490mg, approximately 495mg, approximately 500mg, approximately 505mg, approximately 510mg, approximately 515mg, approximately 520mg, approximately 525mg, approximately 530mg, approximately 531mg, approximately 535mg, approximately 540mg, approximately 545mg, approximately 550mg, approximately 555mg, approximately 560mg, approximately 565mg, approximately 570mg, approximately 575mg, approximately 580mg, approximately 585mg, approximately 590mg, approximately 595mg, approximately 600mg, approximately 605mg Approximately 610mg, approximately 615mg, approximately 620mg, approximately 625mg, approximately 630mg, approximately 635mg, approximately 637mg, approximately 640mg, approximately 645mg, approximately 650mg, approximately 655mg, approximately 660mg, approximately 665mg, approximately 670mg, approximately 675mg, approximately 680mg, approximately 685mg, approximately 690mg, approximately 695mg, approximately 700mg, approximately 705mg, approximately 710mg, approximately 715mg, approximately 720mg, approximately 725mg, approximately 730mg, approximately 735mg, approximately 740mg, approximately 743mg, approximately 745mg, approximately 750mg, approximately 755mg, approximately 760mg, approximately 765mg, approximately 770mg, approximately Olanzapine in doses of 775mg, approximately 780mg, approximately 785mg, approximately 790mg, approximately 795mg, approximately 800mg, approximately 805mg, approximately 810mg, approximately 815mg, approximately 820mg, approximately 825mg, approximately 830mg, approximately 835mg, approximately 840mg, approximately 845mg, approximately 850mg, approximately 855mg, approximately 860mg, approximately 865mg, approximately 870mg, approximately 875mg, approximately 880mg, approximately 885mg, approximately 890mg, approximately 900mg, approximately 905mg, approximately 910mg, approximately 915mg, approximately 920mg, approximately 925mg, approximately 930mg, approximately 935mg, approximately 940mg, approximately 945mg, or approximately 950mg.

[0356] In some embodiments, the kit disclosed herein includes a container containing 318 mg of olanzapine.

[0357] In other embodiments, the kit disclosed herein includes a container containing approximately 318 mg of olanzapine.

[0358] In some embodiments, the kit disclosed herein includes a container containing 575 mg of olanzapine.

[0359] In other embodiments, the kit disclosed herein includes a container containing approximately 575 mg of olanzapine.

[0360] In some embodiments, the kit disclosed herein includes a container containing 600 mg of olanzapine.

[0361] In other embodiments, the kit disclosed herein includes a container containing approximately 600 mg of olanzapine.

[0362] In some embodiments, the kit disclosed herein includes a container containing 710 mg of olanzapine.

[0363] In other embodiments, the kit disclosed herein includes a container containing approximately 710 mg of olanzapine.

[0364] In some embodiments, the kit disclosed herein includes a container containing 815 mg of olanzapine.

[0365] In other embodiments, the kit disclosed herein includes a container containing approximately 815 mg of olanzapine.

[0366] In some embodiments, the kit disclosed herein includes a container containing 885 mg of olanzapine.

[0367] In other embodiments, the kit disclosed herein includes a container containing approximately 885 mg of olanzapine.

[0368] In some respects, the kit disclosed herein includes a container containing a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer.

[0369] In some aspects, the kit disclosed herein includes a container containing a mixture of 0.73 to 2.5 g, optionally 1.3 to 2.5 g, optionally 0.9 to 2.1 g, said mixture being a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer, for example, a container containing a mixture of 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 g, said mixture being a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer.

[0370] In some aspects, the kit disclosed herein includes a container containing a mixture of about 0.73 to about 2.5 g, optionally about 1.3 to about 2.5 g, said mixture being a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer, for example, a container containing a mixture of 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 g, said mixture being a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer.

[0371] In some aspects, the kit disclosed herein includes a container containing 0.73 to 2.5 g of a mixture, said mixture being a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer, said organic solvent being dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or a combination thereof, said diblock copolymer comprising polylactic acid and polyethylene glycol, said diblock copolymer having a number average molecular weight of 6.5 to 15 kg / mol and containing 70% to 90% (w / w) polylactic acid by weight, said triblock copolymer comprising polylactic acid and polyethylene glycol, said triblock copolymer having a number average molecular weight of 7 to 15 kg / mol and containing 80% to 90% (w / w) polylactic acid by weight.

[0372] In some embodiments, the container containing the mixture of organic solvent, diblock copolymer and triblock copolymer contains about 0.73 g of the mixture.

[0373] In some embodiments, the container containing the mixture of organic solvent, diblock copolymer and triblock copolymer contains about 1.4 g of the mixture.

[0374] In some embodiments, the container containing the mixture of organic solvent, diblock copolymer and triblock copolymer contains about 1.5 g of the mixture.

[0375] In some embodiments, the container containing the mixture of organic solvent, diblock copolymer and triblock copolymer contains about 1.7 g of the mixture.

[0376] In some embodiments, the container containing the mixture of organic solvent, diblock copolymer and triblock copolymer contains about 2.0 g of the mixture.

[0377] In some embodiments of the kit disclosed herein, the particle size distribution of olanzapine in the kit is 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 about 0.44 g / mL, or any combination thereof. Olanzapine having these characteristics is described in U.S. Provisional Application No. 63 / 301,202, filed January 20, 2022.

[0378] As used herein, the term “D(90)” indicates that 90% (by volume) of the particles have a diameter less than or equal to the value shown. For example, D(90) or d(90) of 25 μm indicates that 90% (by volume) of the particles have a diameter less than or equal to 25 μm. As used herein, the term “D(3,2)” refers to the mean surface moment (Sottellal mean diameter, SMD), which may be relevant in cases where surface area is important (e.g., dissolution), reflecting the amount of fine particles in the sample. Particle size is typically determined by laser diffraction, optionally using a Mastersizer device from Malvern Instruments.

[0379] As used herein, “tap density” (TD) refers to the ability of a powder sample to pack together under vibration and provides a standard for measuring the cohesiveness of a powder, which may be related to its flowability and filling properties. Tap density can be determined by methods known to those skilled in the art. For example, bulk density / tap density can be determined according to European Pharmacopoeia 2.9.34. Method 1 (https: / / www.drugfuture.com / Pharmacopoeia / EP7 / DATA / 20934E.PDF; PDF downloaded November 14, 2021). Specifically, bulk density and tap density can be determined using an ERWEKA SV M 122 tap density tester equipped with a 100 mL glass cylinder. Approximately 30 g of powder is poured into a 100 mL graduated cylinder through a funnel. Bulk density is calculated by dividing the amount of powder (g) by the measured volume (mL). The tap density is then determined as follows:

[0380] Step (i): Tap the sample 10 times and read the volume V. 10 ;

[0381] Step (ii): Tap the sample 500 times (10+490) and read the volume V. 500 ;

[0382] Step (iii): Tap the sample 1250 times (500 + 750), and read the volume V. 1250 ;

[0383] Step (iv): Tap the sample 2500 times (1250+1250), and read the volume V.2500 ;

[0384] Step (v): If V 500 and V 1250 If the difference exceeds 2 mL, repeat the tapping: that is, tap the sample 1250 times and repeat until the difference is less than 2 mL.

[0385] Bulk density = weight of sample before impact / volume of sample.

[0386] Tap density = weight after tapping / volume.

[0387] calculate:

[0388] Bulk density = m(mg) / V0(mL)

[0389] Tap density = m(mg) / V 2500 (mL)

[0390] See also Example 1 below.

[0391] In some embodiments of the kit disclosed herein, the particle size distribution of olanzapine is characterized by a D(90) of 20 μm to 37 μm, for example, 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.

[0392] In other embodiments of the kit disclosed herein, the particle size distribution of olanzapine is characterized by D(90) being about 20 μm to about 37 μm, for example 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.

[0393] In some embodiments of the kit disclosed herein, the particle size distribution of olanzapine is characterized by D(90) being 24 μm to 35 μm, for example 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.

[0394] In other embodiments of the kit disclosed herein, the particle size distribution of olanzapine is characterized by D(90) being about 24 μm to about 35 μm, for example 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.

[0395] In some embodiments of the kit disclosed herein, the particle size distribution of olanzapine is characterized by D(3,2) being 5.5 μm to 7.5 μm, for example 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.

[0396] In other embodiments of the kit disclosed herein, the particle size distribution of olanzapine is characterized by D(3,2) being from about 5.5 μm to about 7.5 μm, for example, 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.

[0397] In some embodiments of the kit disclosed herein, the particle size distribution of olanzapine is characterized by a D(3,2) of 5.8 μm to 7.0 μm, for example, 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.

[0398] In other embodiments of the kit disclosed herein, the particle size distribution of olanzapine is characterized by D(3,2) being from about 5.8 μm to about 7.0 μm, for example, 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.

[0399] In some embodiments of the kit disclosed herein, the tap density of olanzapine is from 0.35 g / mL to 0.44 g / mL, for example 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.

[0400] In some embodiments of the kit disclosed herein, the tap density of olanzapine is from about 0.35 g / mL to about 0.44 g / mL, for example, about 0.35 g / mL, about 0.36 g / mL, about 0.39 g / mL, about 0.34 g / mL, about 0.40 g / mL, about 0.41 g / mL, about 0.42 g / mL, about 0.47 g / mL, or about 0.44 g / mL.

[0401] In some embodiments of the kit disclosed herein, the particle size distribution of olanzapine is 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.

[0402] In other embodiments of the kit disclosed herein, the particle size distribution of olanzapine is 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.

[0403] In some embodiments of the kit disclosed herein, the particle size distribution of olanzapine is 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.

[0404] In other embodiments of the kit disclosed herein, the particle size distribution of olanzapine is 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 a tap density of about 0.35 g / mL to about 0.44 g / mL.

[0405] In some embodiments of the kits disclosed herein, olanzapine comprises polymorph II.

[0406] As used herein, olanzapine crystal form II is the polymorph described in U.S. Patent No. 5,736,541. The XRPD spectrum of the crystal form II polymorph is essentially as follows: Figure 1 As shown. The main characteristic peaks of olanzapine crystal form II are defined as the peaks at approximately 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.

[0407] In some embodiments of the kit disclosed herein, the container containing olanzapine is a vial.

[0408] In some embodiments of the kit disclosed herein, the container containing olanzapine is a glass vial.

[0409] In some embodiments of the kit disclosed herein, the container containing olanzapine is a 10 mL glass vial.

[0410] In some embodiments of the kit disclosed herein, the container containing olanzapine is a sterile glass vial.

[0411] In some embodiments of the kit disclosed herein, the container containing olanzapine is a 10 mL sterile glass vial.

[0412] In some embodiments of the kit disclosed herein, the container comprising a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer is a syringe.

[0413] In some embodiments of the kit disclosed herein, the container comprising the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.0 to 2.5 mL syringe.

[0414] In some embodiments of the kit disclosed herein, the container comprising the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.25 mL syringe.

[0415] In some embodiments of the kit disclosed herein, the container comprising a mixture of organic solvent, diblock copolymer, and triblock copolymer is a sterile syringe.

[0416] In some embodiments of the kit disclosed herein, the container comprising the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.0 to 2.5 mL sterile syringe.

[0417] In some embodiments of the kit disclosed herein, the container comprising the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.25 mL sterile syringe.

[0418] In some embodiments of the kit disclosed herein, the container comprising a mixture of organic solvent, diblock copolymer, and triblock copolymer is a pre-filled syringe.

[0419] In some embodiments of the kit disclosed herein, the container comprising the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.0 to 2.5 mL pre-filled syringe.

[0420] In some embodiments of the kit disclosed herein, the container comprising the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.25 mL pre-filled syringe.

[0421] In some embodiments of the kit disclosed herein, the container comprising a mixture of organic solvent, diblock copolymer, and triblock copolymer is a pre-filled sterile syringe.

[0422] In some embodiments of the kit disclosed herein, the container comprising the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.0 to 2.5 mL pre-filled sterile syringe.

[0423] In some embodiments of the kit disclosed herein, the container comprising the mixture of organic solvent, diblock copolymer, and triblock copolymer is a 2.25 mL pre-filled sterile syringe.

[0424] In some embodiments, the kit disclosed herein also includes a needle. The needle is mountable to a syringe, allowing subcutaneous injection of the disclosed composition. In some embodiments, the needle is a 21-gauge needle. These embodiments are superior to other formulations known in the art, such as ZYPREXA, which requires a larger pore size 16-gauge needle. Smaller 21-gauge needles typically reduce injection site pain and patient anxiety.

[0425] In some embodiments, the needle length is 5 / 8 inch. These embodiments are superior to other formulations known in the art, such as ZYPREXA which utilizes a 1.5-inch needle. Shorter needles typically reduce injection site pain and patient anxiety.

[0426] In some respects, the kits disclosed herein are used for preparing the pharmaceutical compositions disclosed herein.

[0427] In some embodiments, the pharmaceutical compositions of this disclosure are prepared from a kit by the following steps: 1) filling a pre-filled syringe (organic solvent, diblock copolymer, and triblock copolymer) into a vial containing olanzapine; 2) mixing the contents of the vial to form the pharmaceutical composition. The composition can then be administered to a patient by removing all or part of the composition from the vial using a syringe and then subcutaneously injecting the composition into the patient.

[0428] In some aspects, this disclosure relates to a method for preparing the pharmaceutical composition of the present disclosure, wherein the method comprises adding a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer to solid olanzapine.

[0429] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is 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 about 0.44 g / mL, or any combination thereof.

[0430] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is characterized by D(90) being 20 μm to 37 μm, for example 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.

[0431] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is characterized by D(90) being about 20 μm to about 37 μm, for example 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.

[0432] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is characterized by D(90) being 24 μm to 35 μm, for example 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.

[0433] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is characterized by D(90) being about 24 μm to about 35 μm, for example 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.

[0434] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is characterized by a D(3,2) of 5.5 μm to 7.5 μm, for example, 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.

[0435] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is characterized by D(3,2) being from about 5.5 μm to about 7.5 μm, for example, 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.

[0436] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is characterized by a D(3,2) of 5.8 μm to 7.0 μm, for example, 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.

[0437] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is characterized by D(3,2) being from about 5.8 μm to about 7.0 μm, for example, 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.

[0438] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the tap density of olanzapine is from 0.35 g / mL to 0.44 g / mL, for example 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.

[0439] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the tap density of olanzapine is from about 0.35 g / mL to about 0.44 g / mL, for example, 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.

[0440] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is 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.

[0441] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is 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.

[0442] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is 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.

[0443] In some embodiments of the method for preparing the pharmaceutical composition disclosed herein, the particle size distribution of olanzapine is 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 a tap density of about 0.35 g / mL to about 0.44 g / mL.

[0444] In some embodiments of the method for preparing the pharmaceutical composition of this disclosure, olanzapine comprises polymorph II.

[0445] In some embodiments of the method for preparing the pharmaceutical compositions disclosed herein, a mixture of an organic solvent, a diblock copolymer comprising polylactic acid and polyethylene glycol, and a triblock copolymer comprising polylactic acid and polyethylene glycol is added to a vial of solid olanzapine via a syringe.

[0446] In some aspects, this disclosure relates to a method of administering olanzapine to a patient, wherein the method comprises: subcutaneously injecting the disclosed pharmaceutical composition into the patient.

[0447] In some aspects, this disclosure relates to methods for treating a disease or condition in a patient in need, said disease or condition being schizophrenia, schizoaffective disorder, bipolar disorder, or depression, wherein said method comprises: subcutaneously injecting the pharmaceutical composition of the present disclosure into the patient.

[0448] In one specific implementation, tolerance is established by oral olanzapine treatment prior to initiating subcutaneous injection therapy.

[0449] In some aspects, the disclosed method includes subcutaneous injection of the disclosed pharmaceutical composition into a patient. In such aspects, the subcutaneous injection can be performed at any suitable site on the patient's body. In some embodiments, the subcutaneous injection is performed in the patient's abdomen. In other embodiments, the subcutaneous injection is performed in the patient's upper arm. In other embodiments, the subcutaneous injection is performed in the patient's thigh. In other embodiments, the subcutaneous injection is performed in the patient's back.

[0450] In some implementations, the disease or condition is schizophrenia.

[0451] In some implementations, the disease or condition is schizoaffective disorder.

[0452] In some implementations, the disease or condition is bipolar disorder.

[0453] In some implementations, the disease or condition is depression.

[0454] In some embodiments of the treatment methods disclosed herein, prior to subcutaneous application of the composition of this disclosure (e.g., at the start of treatment for a single patient, or at baseline (before randomization) of a patient population), the patient has a total PANSS score of 80 to 120 (inclusive) and scores ≥4 on at least two of the following four items of the PANSS positive subscale: hallucinatory behavior, delusions, conceptual confusion, or suspicion / persecution.

[0455] In some aspects of the disclosed treatment methods, the subcutaneously administered drug composition comprises 300 to 600 mg of olanzapine, such as 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, 4... Olanzapine in doses of 35mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, or 600mg.

[0456] In some embodiments of the disclosed treatment method, the subcutaneously administered pharmaceutical composition comprises 300 to 350 mg, optionally 310 to 320 mg, of olanzapine, such as 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, etc. Olanzapine in doses of 321mg, 322mg, 323mg, 324mg, 325mg, 326mg, 327mg, 328mg, 329mg, 330mg, 331mg, 332mg, 333mg, 334mg, 335mg, 336mg, 337mg, 338mg, 339mg, 340mg, 341mg, 342mg, 343mg, 344mg, 345mg, 346mg, 347mg, 348mg, 349mg, or 350mg.

[0457] In some embodiments, the subcutaneously administered pharmaceutical composition comprises about 318 mg of olanzapine. In some embodiments, the subcutaneously administered pharmaceutical composition comprises about 323 mg of olanzapine. In some embodiments, the subcutaneously administered pharmaceutical composition comprises about 328 mg of olanzapine.

[0458] In some embodiments of the disclosed treatment method, the subcutaneously administered pharmaceutical composition comprises 400 to 450 mg, optionally 415 to 435 mg, of olanzapine, such as 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, 415 mg, 419 mg, etc. Olanzapine in doses of 420mg, 421mg, 422mg, 423mg, 424mg, 425mg, 426mg, 427mg, 428mg, 429mg, 430mg, 431mg, 432mg, 433mg, 434mg, 435mg, 436mg, 437mg, 438mg, 439mg, 440mg, 441mg, 442mg, 443mg, 444mg, 445mg, 446mg, 447mg, 448mg, 449mg, or 450mg.

[0459] In some embodiments, the subcutaneously administered pharmaceutical composition comprises about 425 mg of olanzapine. In some embodiments, the subcutaneously administered pharmaceutical composition comprises about 430 mg of olanzapine. In some embodiments, the subcutaneously administered pharmaceutical composition comprises about 435 mg of olanzapine.

[0460] In some embodiments of the disclosed treatment method, the subcutaneously administered pharmaceutical composition comprises 500 to 550 mg, optionally 520 to 540 mg, of olanzapine, such as 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, 521 mg, etc. Olanzapine in doses of 522mg, 523mg, 524mg, 525mg, 526mg, 527mg, 528mg, 529mg, 530mg, 531mg, 532mg, 533mg, 533mg, 534mg, 535mg, 536mg, 537mg, 538mg, 539mg, 540mg, 541mg, 542mg, 543mg, 544mg, 545mg, 546mg, 547mg, 548mg, 549mg, or 550mg.

[0461] In some embodiments, the subcutaneously administered pharmaceutical composition comprises 531 mg of olanzapine. In some embodiments, the subcutaneously administered pharmaceutical composition comprises about 536 mg of olanzapine. In some embodiments, the subcutaneously administered pharmaceutical composition comprises about 541 mg of olanzapine.

[0462] In some aspects of the disclosed treatment methods, the subcutaneously administered composition comprises about 300 to about 600 mg of olanzapine, such as 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, about 435 mg, etc. olanzapine in doses of approximately 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.

[0463] In some embodiments of the disclosed treatment method, the subcutaneously administered composition comprises about 318 mg of olanzapine.

[0464] In some embodiments of the disclosed treatment method, the subcutaneously administered composition comprises about 425 mg of olanzapine.

[0465] In some embodiments of the disclosed treatment method, the subcutaneously administered composition comprises about 531 mg of olanzapine.

[0466] In some aspects of the disclosed treatment methods, the volume of the subcutaneously administered pharmaceutical composition is from 0.5 mL to 2.0 mL, for example 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.

[0467] In some aspects of the disclosed treatment methods, the volume of the subcutaneously administered pharmaceutical composition is from about 0.5 mL to about 2.0 mL, for example, 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.

[0468] In some aspects of the disclosed treatment methods, the volume of the subcutaneously administered pharmaceutical composition is from 0.5 mL to 1.8 mL, for example 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.

[0469] In some aspects of the disclosed treatment methods, the volume of the subcutaneously administered pharmaceutical composition is from about 0.5 mL to about 1.8 mL, for example, 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.

[0470] In some embodiments of the disclosed treatment methods, the volume of the subcutaneously administered pharmaceutical composition is from 0.9 mL to 1.5 mL.

[0471] In some embodiments of the disclosed treatment method, the volume of the subcutaneously administered pharmaceutical composition is 0.9 mL.

[0472] In some embodiments of the disclosed treatment method, the volume of the subcutaneously administered pharmaceutical composition is about 0.9 mL.

[0473] In some embodiments of the disclosed treatment method, the volume of the subcutaneously administered pharmaceutical composition is 1.2 mL.

[0474] In some embodiments of the disclosed treatment methods, the volume of the subcutaneously administered pharmaceutical composition is about 1.2 mL.

[0475] In some embodiments of the disclosed treatment method, the volume of the subcutaneously administered pharmaceutical composition is 1.5 mL.

[0476] In some embodiments of the disclosed treatment method, the volume of the subcutaneously administered pharmaceutical composition is about 1.5 mL.

[0477] In some aspects of the disclosed treatment methods, AUC ∞(Following a single subcutaneous dose of the drug composition) and the AUC of oral olanzapine tau The dose normalization ratio (calculated over 28 days) ranged from 0.97 to 1.29.

[0478] In some implementations of the disclosed treatment methods, AUC ∞ (Following a single subcutaneous dose of the drug composition) and the AUC of oral olanzapine tau The dose normalization ratio (calculated over 28 days) is approximately 1.1.

[0479] In some aspects of the disclosed treatment methods, administration of the drug composition to patients via subcutaneous injection results in patients having olanzapine plasma C1 levels within 11 to 14 days after administration. 最大 .

[0480] As used in this article, the term "C" 最大 "Refers to the maximum plasma concentration of olanzapine."

[0481] Unintentionally bound by theory, it is believed that after subcutaneous injection of the disclosed pharmaceutical composition, the organic solvent diffuses and the block copolymer (which is insoluble in aqueous media) precipitates, thereby forming a reservoir encapsulating olanzapine. Through drug diffusion and / or gradual reservoir degradation, olanzapine is slowly released from the reservoir, achieving and maintaining therapeutic levels of the drug over a certain period of time. In some embodiments, this period is 28 days ± 5 days, for example 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In some embodiments, this period is 30 days or about 30 days. In some embodiments, this period is 60 days or about 60 days.

[0482] In the method of this disclosure, the pharmaceutical composition of this disclosure is administered subcutaneously once a month. Therefore, a treatment regimen using the composition of this disclosure comprises a series of monthly subcutaneous injections. Each monthly subcutaneous injection has associated pharmacokinetic parameters, such as the maximum plasma concentration of olanzapine (C0.05). 最大 ),t 最大 AUC, etc.

[0483] In some aspects of the disclosed treatment method, patients reach a steady state where the pharmacokinetic parameters of olanzapine do not change significantly with consecutive monthly subcutaneous injections. In some embodiments, steady state is reached between the first and second monthly subcutaneous injections. In other embodiments, steady state is reached between the second and third monthly subcutaneous injections.

[0484] In some embodiments of the disclosed treatment method, the patient reaches a steady state C. 最大 This resulted in olanzapine C being administered via continuous monthly subcutaneous injections. 最大No significant changes were observed. In some embodiments, steady state was reached after the second monthly subcutaneous injection. In other embodiments, steady state was reached after the third monthly subcutaneous injection.

[0485] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in the patient's olanzapine plasma C... 最大 Less than 100 ng / mL.

[0486] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in olanzapine plasma C2 levels after the first subcutaneous injection. 最大 Less than 100 ng / mL.

[0487] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after a second subcutaneous injection. 最大 Less than 100 ng / mL.

[0488] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after the third subcutaneous injection. 最大 Less than 100 ng / mL.

[0489] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in the patient's olanzapine plasma C... 最大 Less than 90 ng / mL.

[0490] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in olanzapine plasma C2 levels after the first subcutaneous injection. 最大 Less than 90 ng / mL.

[0491] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after a second subcutaneous injection. 最大 Less than 90 ng / mL.

[0492] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after the third subcutaneous injection. 最大 Less than 90 ng / mL.

[0493] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in the patient's olanzapine plasma C... 最大 Less than 80 ng / mL.

[0494] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in olanzapine plasma C2 levels after the first subcutaneous injection. 最大 Less than 80 ng / mL.

[0495] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after a second subcutaneous injection. 最大 Less than 80 ng / mL.

[0496] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after the third subcutaneous injection. 最大 Less than 80 ng / mL.

[0497] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in the patient's olanzapine plasma C... 最大 Less than 70 ng / mL.

[0498] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in olanzapine plasma C2 levels after the first subcutaneous injection. 最大 Less than 70 ng / mL.

[0499] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after a second subcutaneous injection. 最大 Less than 70 ng / mL.

[0500] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after the third subcutaneous injection. 最大 Less than 70 ng / mL.

[0501] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in the patient's olanzapine plasma C... 最大 Less than 60 ng / mL.

[0502] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in olanzapine plasma C2 levels after the first subcutaneous injection. 最大 Less than 60 ng / mL.

[0503] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after a second subcutaneous injection. 最大 Less than 60 ng / mL.

[0504] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after the third subcutaneous injection. 最大 Less than 60 ng / mL.

[0505] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in the patient's olanzapine plasma C... 最大 Less than 50 ng / mL.

[0506] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in olanzapine plasma C2 levels after the first subcutaneous injection. 最大 Less than 50 ng / mL.

[0507] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after a second subcutaneous injection. 最大 Less than 50 ng / mL.

[0508] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after the third subcutaneous injection. 最大 Less than 50 ng / mL.

[0509] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in the patient's olanzapine plasma C... 最大 Less than 40 ng / mL.

[0510] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection results in a decrease in olanzapine plasma C2 levels after the first subcutaneous injection. 最大 Less than 40 ng / mL.

[0511] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after a second subcutaneous injection. 最大 Less than 40 ng / mL.

[0512] In some aspects of the disclosed treatment methods, administration of the drug composition to the patient via subcutaneous injection resulted in a decrease in olanzapine plasma C2 levels after the third subcutaneous injection. 最大 Less than 40 ng / mL.

[0513] In some aspects of the disclosed treatment methods, administration of the drug composition to a patient via subcutaneous injection results in a plasma concentration of at least 10 ng / mL of olanzapine for at least 21 days out of a 30-day period following the injection. In these aspects, the 21 days for an olanzapine plasma concentration of at least 10 ng / mL are not necessarily the first 21 days of the 30-day period following the injection, nor are they necessarily a consecutive 21-day timeframe.

[0514] In some aspects of the disclosed treatment methods, administration of the drug composition to a patient via subcutaneous injection results in a plasma concentration of at least 20 ng / mL of olanzapine for at least 21 days within a 30-day period following the injection. In these aspects, the 21 days for an olanzapine plasma concentration of at least 20 ng / mL are not necessarily the first 21 days of the 30-day period following the injection, nor are they necessarily a consecutive 21-day timeframe.

[0515] In some aspects of the disclosed treatment methods, administration of the drug composition to a patient via subcutaneous injection results in a plasma concentration of at least 10 ng / mL of olanzapine for at least 30 days within 30 days following the injection.

[0516] In some aspects of the disclosed treatment methods, administration of the drug composition to a patient via subcutaneous injection results in a plasma concentration of at least 20 ng / mL of olanzapine for at least 30 days within 30 days following the injection.

[0517] In some aspects, this disclosure relates to a method of treating a patient with olanzapine, the method comprising: a) providing a kit of this disclosure; b) removing the mixture from a container in the kit containing a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer; c) adding the mixture from b) to a 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 a patient requiring olanzapine treatment; wherein the treatment effectively treats the patient for approximately one month.

[0518] In some aspects of the disclosed treatment method, administration of the pharmaceutical composition to a patient via subcutaneous injection results in the patient scoring lower on the Positive and Negative Syndrome Scale (PANSS) than the patient scored before receiving the subcutaneous injection of the composition. In some aspects, the disclosed treatment method is superior to placebo in reducing the total PANSS score, for example, by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 points relative to placebo, preferably at least 6 points, more preferably at least 8 points, and most preferably at least 10 points.

[0519] The PANSS is a 30-item scale used to assess positive and negative symptoms of schizophrenia (Kay SR, Fiszbein A, and 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 relationships between these symptoms, and the overall psychopathological state. Each item is rated on a 7-point scale, from 1 (none) to 7 (extreme). The positive symptom scale includes 7 items with a maximum score of 49; the negative symptom scale includes 7 items with a maximum score of 49; and the general psychopathology scale includes 16 items with a maximum score of 112.

[0520] In some aspects of the disclosed treatment methods, administration of the drug composition to patients via subcutaneous injection resulted in patients scoring lower on the Clinical Global Impression-I (CGI-I) scale than they had before receiving the subcutaneous injection of the composition.

[0521] The CGI-I scale allows for a comprehensive assessment of the overall improvement in a patient's symptoms. The CGI-I scale uses a 7-point scale to rate the degree of improvement in patient symptoms, ranging from 1 (significant improvement) to 7 (significant deterioration). See Guy, W., ECDE U Manual of Psychopharmacology Assessment (Revised), Rockville (Maryland): U.S. Department of Health, Education and Welfare; Public Health Service; Administration of Alcohol, Substance Abuse and Mental Health; Institute of Psychopharmacology, National Institute of Mental Health, 1976b; 218-222.

[0522] In some aspects of the disclosed treatment methods, administration of the drug composition to patients via subcutaneous injection resulted in a lower Clinical Global Impression-Disease Severity Scale (CGI-S) score than the score before receiving the subcutaneous injection of the composition.

[0523] CGI-S allows raters to assess a patient's current disease severity on a scale of 1 to 7, where 1 = normal / no disease, 2 = borderline mental illness, 3 = mild illness, 4 = moderate illness, 5 = significant illness, 6 = severe illness, and 7 = very severe illness. See Guy, W., ECDE U Manual of Psychopharmacology Assessment (Revised), Rockville (Maryland): U.S. Department of Health, Education and Welfare; Public Health Service; Administration of Alcohol, Substance Abuse and Mental Health; Institute of Psychopharmacology, National Institute of Mental Health, 1976b; 218-222.

[0524] In some aspects of the disclosed treatment methods, administration of the drug composition to a patient via subcutaneous injection resulted in a lower Patient Overall Impression-I (PGI-I) score than the patient's score before receiving the subcutaneous injection of the composition.

[0525] The PGI-I scale is a single-item patient self-assessment tool used to measure improvement in a patient's condition; patients rate their perceived changes in their condition in response to treatment. Patients are asked to select a response option on a scale of 1 to 7, where 1 = significantly improved, 2 = somewhat improved, 3 = slightly improved, 4 = no change, 5 = slightly worsened, 6 = significantly worsened, and 7 = significantly worsened. See Steinert T, Eisele F. G, Albani C, Flammer E, Borbé R.[PGI-I (patient's global impression) as an outcome and quality indicator ofpsychiatric in-patient treatment:results and concordance with doctor's assessments].Psychiatr Prax 2010;37(7):343-9.

[0526] In some aspects of the disclosed treatment methods, administration of the drug composition to patients via subcutaneous injection resulted in patients scoring higher on the Personal and Social Functioning Scale (PSP) than they had before receiving the subcutaneous injection of the composition.

[0527] The PSP is a clinician assessment tool used to measure the personal and social functioning of patients with schizophrenia. See Morosini PL, Magliano L, Brambilla L, Ugolini S, and 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, April 2000; 101(4):323-9. The PSP is a single-item rating scale with a maximum score of 100 points, divided into 10 equally spaced intervals. The score is based on an assessment of the patient's functioning in four categories: 1) socially beneficial activities, including work and study; 2) personal and social relationships; 3) self-care; and 4) disruptive and aggressive behaviors. Higher scores indicate better personal and social functioning, with scores of 91 to 100 indicating adequate and good functioning, while scores below 30 indicate poor functioning requiring enhanced supervision.

[0528] In some aspects of the disclosed treatment methods, administration of the drug composition to patients via subcutaneous injection resulted in patients scoring lower on the Schizophrenia Quality of Life Scale (SQLS) Revision 4 than they had before receiving the subcutaneous injection of the composition.

[0529] The Schizophrenia Quality of Life Scale Revision 4 (Martin CR and Allan R, Factorstructure of the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4), Psychol Health Med 2007; 12(2):126-34) is a 33-item scale that produces scores on three subscales: 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 a lower quality of life.

[0530] In some aspects of the disclosed treatment methods, administration of the drug composition to patients via subcutaneous injection resulted in a decrease in patients' Level 3 EuroQol five-dimensional questionnaire (EQ-5D-3L) scores.

[0531] The EuroQol 5D-3L Level 3 questionnaire is a standardized questionnaire for assessing overall health status. The EQ-5D-3L consists of two parts. In Part 1, patients rate their health status in five domains (mobility, self-care, daily activities, pain / discomfort, and anxiety / depression) on a scale of 1 to 3, where 1 = no problem, 2 = some problem, and 3 = serious problem. In Part 2, patients rate their health status on a visual analog scale on a scale of 0 to 100; a score of 0 represents the worst imaginable health status, and a score of 100 represents the best imaginable health status. See EuroQol Group, EuroQol—a new facility for the measurement of health-related quality of life, Health Policy 1990, 16:199-208; Rabin R and de Charro F, EQ-5D: a measure of health status from the EuroQol Group, Ann Med 2001, 33(5):337-43.

[0532] In some aspects of the disclosed treatment methods, administration of the drug composition results in a D2 receptor occupancy rate of 60% to 80%, optionally 65% ​​to 80%, optionally 65% ​​to 70%, as measured by positron emission tomography (PET).

[0533] Dopamine D2 receptor occupancy (D2RO) levels are considered one of the driving factors for the clinical efficacy and safety response of antipsychotic drugs. The currently accepted hypothesis is that D2RO receptor occupancy in the striatum should be 60% to 80% to achieve optimal antipsychotic efficacy and minimal side effects; a lower threshold is clinically necessary, while exceeding a higher threshold increases the risk of side effects, particularly extrapyramidal symptoms (EPS). The relationship between olanzapine concentration and striatal D2RO receptor occupancy is described by the Emax model as follows:

[0534]

[0535] Wherein, D2RO is the dopamine D2 receptor occupancy, Cp is the olanzapine plasma concentration, and Kd is the apparent equilibrium dissociation constant, which is the plasma concentration of the active fraction when 50% D2 receptor occupancy is observed. ROmax is the maximum achievable receptor occupancy. For most antipsychotic drugs, the ROmax value in the model is fixed at 100%. The estimated value of the Kd parameter is 11 ng / mL (Mamo D et al., D2 receptor occupancy of olanzapine pamoate depot using positron emission tomography: an open-label study in patients with schizophrenia, Neuropsychopharmacology, January 2008, 33(2):298-304).

[0536] In some aspects, this disclosure relates to a method of switching a patient from daily oral olanzapine treatment to the pharmaceutical composition of this disclosure, wherein the method comprises: i) administering the last dose of daily oral olanzapine treatment orally, without further administration of oral olanzapine treatment; administering the pharmaceutical composition of this disclosure subcutaneously to the patient the following day; thereby switching the subject from daily oral olanzapine treatment to a long-acting injectable olanzapine formulation.

[0537] In some aspects, this disclosure relates to a method of switching a patient from daily oral olanzapine treatment to the pharmaceutical composition of this disclosure, wherein the method comprises: i) administering the last dose of daily oral olanzapine treatment orally, without further administration of oral olanzapine treatment; and then, 2 to 7 days after the last oral dose, administering the pharmaceutical composition of this disclosure subcutaneously to the patient; thereby switching the subject from daily oral olanzapine treatment to a long-acting injectable olanzapine formulation.

[0538] In other respects, this disclosure relates to a method for switching a patient from a long-acting intramuscular olanzapine formulation to the pharmaceutical composition of this disclosure without supplemental oral olanzapine treatment, wherein the method comprises: administering a final dose of the long-acting intramuscular olanzapine formulation; and at the next administration: optionally, if the previous dose was a monthly dose, administering the pharmaceutical composition of this disclosure subcutaneously one month after the previous dose, or optionally, if the previous dose was a bi-weekly dose, administering the pharmaceutical composition of this disclosure subcutaneously two weeks after the previous dose; wherein the method is performed without administering supplemental oral olanzapine treatment to the patient.

[0539] A method for switching a patient from a long-acting intramuscular olanzapine formulation to the pharmaceutical composition disclosed herein is also provided, the method comprising:

[0540] a) Administration of the final dose of a long-acting intramuscular olanzapine formulation; and

[0541] b) At the next administration, administer the pharmaceutical composition of this disclosure to the patient, wherein:

[0542] The final dose of the long-acting intramuscular olanzapine formulation contains 150 mg of olanzapine, and the pharmaceutical composition disclosed herein contains 318 mg of olanzapine; or

[0543] The final dose of the long-acting intramuscular olanzapine formulation contains 300 mg of olanzapine, and the pharmaceutical composition disclosed herein contains 318 mg of olanzapine; or

[0544] The final dose of the long-acting intramuscular olanzapine formulation comprises 210 mg of olanzapine, and the pharmaceutical composition disclosed herein comprises 425 mg of olanzapine; or

[0545] The final dose of the long-acting intramuscular olanzapine formulation comprises 405 mg of olanzapine, and the pharmaceutical composition disclosed herein comprises 425 mg of olanzapine; or

[0546] The final dose of the long-acting intramuscular olanzapine formulation contains 405 mg of olanzapine, and the pharmaceutical composition disclosed herein contains 531 mg of olanzapine.

[0547] In the implementation of the above method, after conversion, there were no clinically significant changes in mental, neurological, and clinical symptoms compared to baseline, and the subjects remained clinically stable.

[0548] In this context, the phrase "next administration" refers to the administration event in which the next dose of long-acting intramuscular olanzapine will be administered if the long-acting intramuscular olanzapine formulation has not been interrupted. In some embodiments, the long-acting intramuscular olanzapine formulation is ZYPREXA. In some embodiments, the long-acting intramuscular olanzapine formulation is administered at a monthly dose. In other embodiments, the long-acting intramuscular olanzapine formulation is administered at a bi-weekly dose.

[0549] In some respects, this disclosure relates to the treatment of olanzapine-naïve patients. The method for treating patients includes administering 10 mg to 20 mg of olanzapine orally daily for two consecutive days to assess the patient's tolerance to olanzapine, and if the patient tolerates oral olanzapine, administering a subcutaneous injection of the pharmaceutical composition disclosed herein. As used herein, "olanzapine-naïve patient" refers to a patient who has not previously received olanzapine.

[0550] The treatment methods disclosed in this article provide safe and effective treatment for schizophrenia, schizoaffective disorder, bipolar disorder, or depression. The efficacy of the disclosed methods can be verified using the clinical tools described herein (e.g., PANSS, CGI-S, etc.). The safety of the disclosed methods can be verified by one or more of the following: no serious adverse events, no extrapyramidal symptoms, no injection pain or other injection site reactions (local tolerance), vital signs (blood pressure, pulse, and postural changes, and body temperature), weight, laboratory tests, electrocardiogram, concomitant medications, all-cause discontinuation time, all-cause discontinuation rate, and discontinuation rate due to adverse events (tolerance), and the following rating scales: Abnormal Involuntary Movement Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale, Columbia Suicide Severity Rating Scale, and Calgary Schizophrenia-Depression Rating Scale.

[0551] In some implementations, the subject's weight gain is less than 10%, optionally less than 9%, optionally less than 8%, optionally less than 7%, optionally less than 6%, and optionally less than 5% relative to their initial weight at the start of treatment. The subject's weight is typically measured throughout the entire duration of treatment. Weight may be measured over a period of 8, 48, or 56 weeks.

[0552] The safety of the disclosed method ensures that, in some embodiments of the disclosed method, monitoring of the patient's PDSS is not required. In these embodiments, the pharmacist is not required to monitor the patient's PDSS.

[0553] Example

[0554] List of abbreviations

[0555]

[0556]

[0557]

[0558]

[0559] For reference, the pharmacokinetics and dosage ratios of IM olanzapine are provided:

[0560] Intramuscular Olanzapine Pharmacokinetics

[0561] The immediate-release intramuscular injection (ZYPREXAIN TRAMUSCULAR) results in rapid absorption, with peak plasma concentrations occurring within 15 to 45 minutes. Pharmacokinetic studies in healthy volunteers showed that a 5 mg dose of intramuscular olanzapine for injection produced, on average, the maximum plasma concentration was approximately five times that produced by an equivalent dose of oral olanzapine. The AUC achieved after intramuscular administration was similar to that achieved after oral administration of the same dose. The half-life observed after intramuscular administration was similar to that after oral administration. The pharmacokinetic profile was linear within the clinically applicable range. Metabolism after intramuscular administration was qualitatively similar to that after oral administration.

[0562] Sustained-release (slowly dissolving) intramuscular injection (ZYPREXA) [Olanzapine dihydroxynaphthyl] causes systemic olanzapine plasma concentrations to remain elevated for weeks to months. ZYPREXA The basic pharmacokinetic properties of olanzapine are similar to those of daily oral olanzapine. ZYPREXA The only fundamental pharmacokinetic difference between oral and intravenous olanzapine administration is the change in slow release and rate-controlled absorption. ZYPREXA is injected every 2 or 4 weeks. It can provide olanzapine plasma concentrations similar to daily oral olanzapine doses. ZYPREXA is administered in doses of 150 mg to 405 mg every 2 or 4 weeks. Steady-state plasma concentrations were within the range known to be associated with daily oral doses of 5 to 20 mg olanzapine. Compared to the oral half-life of approximately 30 hours, intramuscular Zyprexa... The effective half-life of olanzapine after administration is approximately 30 days. (ZYPREXA injection) Subsequently, exposure to olanzapine may persist for several months. The long-term persistence of systemic olanzapine 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 and trough immediately before the next injection. The fluctuations in olanzapine plasma concentrations between peaks and troughs are comparable to those of once-daily oral administration.

[0563] Dosage ratio and oral dose correspondence

[0564] ZYPREXA The following administration regimens are available: 150 mg / 2 weeks, 300 mg / 4 weeks, 210 mg / 2 weeks, 405 mg / 4 weeks, or 300 mg / 2 weeks. Higher doses will proportionally increase systemic exposure. ZYPREXA The olanzapine exposure levels correspond to the oral olanzapine dose and dosing regimen, as detailed in the table below, “Recommended doses based on oral ZYPREXA doses”.

[0565]

[0566] Source: ZYPREXA USPI 2018

[0567] Example 1: Materials

[0568] The copolymer was synthesized according to the method described in US 6350812 (incorporated herein by reference), with slight modifications. Typically, the desired amount of PEG (providing a triblock copolymer) or methoxy-PEG (providing a diblock polymer) was heated at 65°C and vacuum dried in a reactor vessel for 2 hours. D,L-lactide (corresponding to the target 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 at 140°C and rapidly degassed under vacuum. The reaction was carried out at 140°C for four days at a constant nitrogen flow rate (0.2 bar). The reaction was cooled to room temperature, its contents were dissolved in acetone, and then precipitated with ethanol. The resulting product was then dried under reduced pressure. Alternatively, the copolymer can be purchased from Corbion.

[0569] pass 1 The residual lactide content and LA / EO molar ratio of the obtained product were characterized by 1H NMR. A Brucker Advance 300MHz spectrometer was used for further analysis. 1 1H NMR spectral analysis. For all 1 ¹H NMR spectra were obtained by integrating and analyzing the characteristic peaks of PLA and PEG using TopSpin software. Chemical shifts were referenced to the solvent value of CDCl₃, δ = 7.26 ppm.

[0570] The obtained products were further characterized by gel permeation chromatography (GPC) to determine their molecular weight distribution. GPC was performed using an LC system equipped with a refractive index detector. This instrument was equipped with a series of Waters styrene columns (selected from HR4, HR3, HR2, and HR1) and maintained at a constant temperature. The sample was run at a constant flow rate in BHT-stable THF. The molecular weight distribution (Mn, Mw, and polydispersity index) was determined by routine calibration using polystyrene calibration standards.

[0571] Olanzapine polymorph II was used. Characterization included X-ray diffraction (XRD), particle size distribution, and packing density / tap density.

[0572] Typical XRD patterns obtained are as follows Figure 1As shown. The main characteristic peaks of olanzapine crystal form II are defined as the peaks at approximately 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.

[0573] For the purposes of this paper, the particle size distribution (PSD) was determined as volume percentages, namely D(90) and D(3,2), and was measured by laser diffraction using a Malvern Mastersizer 2000 equipped with a Hydro 2000S dispersion unit.

[0574] Measurements were performed in a saturated aqueous dispersion medium (refractive index = 1.22 (general purpose)). The sample was added as a concentrated suspension with stirring until a 10% to 20% opacity was achieved. The results were obtained over 10 measurement cycles with a recycle time (after acoustic processing) of 30 seconds. The following parameters were used:

[0575] • Distributed unit: Hydro 2000S

[0576] • Measurement range: 0.02-2000μm

[0577] • Analysis models: General purpose, ordinary, and Mie models

[0578] Sensitivity: Normal

[0579] • Particle shape: Irregular

[0580] • Sample refractive index: 1.709

[0581] • Absorbance: 0.01

[0582] • Dispersant: Olanzapine saturated aqueous dispersion medium

[0583] • Refractive index of the dispersive medium: 1.330

[0584] • Shading rate: 10% to 20%

[0585] Pump / mixer speed: 2500 rpm

[0586] • Liquid level sensor threshold: 64%

[0587] • Sample measurement time: 10 seconds

[0588] • Background measurement time: 10 seconds

[0589] • Repeated measurements (per aliquot): 10

[0590] • Internal ultrasound: 30 seconds at 90% power

[0591] • Recirculation time (after ultrasonic treatment): 30 seconds

[0592] • Number of measurements (equal sample divisions): 1

[0593] Sample preparation: The sample was prepared as a concentrated suspension. Using a spatula, approximately 50 to 100 mg of olanzapine sample was added to a small glass beaker, along with a few drops of saturated aqueous dispersion medium. A paste was obtained by gentle mixing. An additional 1 mL of saturated aqueous dispersion medium was then added to obtain a homogeneous, concentrated suspension.

[0594] Bulk density / tap density was determined according to European Pharmacopoeia 2.9.34. Method 1 (https: / / www.drugfuture.com / Pharmacopoeia / EP7 / DATA / 20934E.PDF; PDF downloaded on November 14, 2021).

[0595] Bulk density and tapped density were determined using an ERWEKA SVM122 tapped density tester equipped with a 100 mL glass cylinder. Approximately 30 g of powder was carefully poured into a 100 mL graduated cylinder with a funnel. Bulk density was calculated by dividing the amount of powder (g) by the measured volume (mL). Tapped density was then determined as follows:

[0596] Tap 10x - Read volume (=V) 10 )

[0597] 500 taps x (10 + 490) - read volume ( = V) 500 )

[0598] 1250 taps x (500 + 750) - read volume (= V) 1250 )

[0599] 2500 taps x (1250 + 1250) - read volume (= V) 2500 )

[0600] If V 500 and V 1250 If the difference is greater than 2 mL, repeat the tapping: that is, tap 1250x again and repeat until the difference is less than 2 mL.

[0601] Bulk density = weight of sample before impact / volume of sample.

[0602] Tap density = weight after tapping / volume.

[0603] calculate:

[0604] Bulk density = m(mg) / V0(mL)

[0605] Tap density = m(mg) / V2500 (mL)

[0606] Example 2

[0607] Pharmacokinetic studies were conducted on untreated young female dogs weighing approximately 8 kg, and test items were selected. Six animals were assigned to each treatment group and were numbered and identified before the start of the study.

[0608] Animals in the control group (Group 1) received repeated intramuscular administration of ZYPADHERA (compared to ZYPREXA sold in the United States) into the femoral muscle every 2 weeks. (Same), for 2 months. Reconstitute the reference product according to the instructions described in the SPC (Product Features Overview) to achieve an olanzapine concentration of 150 mg / mL. Administer 300 mg of olanzapine (2 mL) to each animal per injection using a 19G 1″ 1 / 2 needle.

[0609] Animals in groups 2 through 5 received a single subcutaneous injection of the corresponding test item. The olanzapine dose was fixed at 405 mg, with adjustments made according to the composition of the test item. The test item was reconstituted immediately before administration and injected using a 21G1″ needle. It was reported that injection of the test item in group 3 was more difficult compared to the other groups and therefore not optimal.

[0610] Table 2.1 provides an overview of the PK study design.

[0611] Table 2.1

[0612]

[0613] N / A: Not applicable

[0614] f(PLA): The fraction of polylactic acid (wt%) in the polymer.

[0615] The diblock copolymer consists of polylactic acid (PLA) and polyethylene glycol (PEG), with a number average molecular weight of 6.5 to 15 kg / mol, containing 70% to 90% (w / w) PLA by weight. The triblock copolymer consists of PLA and PEG, with a number average molecular weight of 6 to 15 kg / mol, containing 80% to 90% (w / w) PLA by weight. In these experiments, the diblock copolymer was kept constant, and two triblock copolymers with different number average molecular weights were tested.

[0616] The first day of treatment was designated as day 0 (D0), and blood samples were collected as follows:

[0617] Group 1: Before each injection and at 1 hour, 3 hours, 6 hours, 12 hours, 24 hours (D1), 48 hours (D2), 72 hours (D3), 144 hours (D6), 216 hours (D9), and 288 hours (D12) after each intramuscular administration;

[0618] Groups 2 through 5: Before each injection and at 1, 3, 6, 12, 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 hours (D48), 1224 hours (D51), 1296 hours (D54), 1368 hours (D57), and 1440 hours (D60) after subcutaneous application. After centrifugation, the plasma was collected into test tubes containing K2-EDTA and stored at -80°C until analysis by LC MS / MS.

[0619] Research results are as follows Figure 2 As shown in Table 2.2.

[0620] Table 2.2

[0621]

[0622] (1) For T 最大 The median value in the report (minimum - maximum value) (2)；(3)；(4) Mean ± SD

[0623] (3) For subcutaneous application of C 30D For intramuscular administration of C 谷值 **AUC 0-28D

[0624] like Figure 2 As shown, the average PK curves confirmed the ability of the four tested compositions to release olanzapine over the target time period of one month. For all subcutaneous formulations tested, plasma concentrations remained quantifiable after one month and were close to those obtained after intramuscular injection. 谷值 Numerical values. Furthermore, during this 1-month period, the mean plasma levels of olanzapine obtained after subcutaneous injection were generally within the range of the mean plasma levels in the control group (two administrations). For nearly 3 weeks post-injection, the mean plasma levels for different test items remained near stable exposure levels, followed by a slow decline. C after subcutaneous administration of different formulations 最大 The value was lower than the C of the reference drug ZypAdhera. 最大 .

[0625] Example 3

[0626] Effects of heating or rubbing the injection site on the pharmacokinetic (PK) of formulation 1 in male SD-IGS rats

[0627] This study aimed to evaluate the effects of external factors such as heating and friction at the injection site on the PK curve during the first 24 hours after olanzapine administration in male SD-IGS rats under clinically similar conditions following a single subcutaneous injection of formulation 1.

[0628] Test item D represents formulation 1, which is a pharmaceutical composition disclosed herein comprising: 30% to 32% (w / w) olanzapine; 52% to 54% (w / w) dimethyl sulfoxide; 12% to 14% (w / w) a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 12.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and 3% to 3.5% (w / w) a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 6 to 13 kg / mol and comprising 83% to 88% (w / w) polylactic acid by weight; wherein the diblock copolymer and the triblock copolymer together comprise 15% to 17.5% (w / w) of the composition by weight.

[0629] The study included three groups, with six animals in each group. The study design is shown in Table 3.1.

[0630] Table 3.1: Research-Experimental Design

[0631]

[0632] SC = Subcutaneous

[0633] All groups were administered 70 μL of formulation 1 subcutaneously, with a target dose of 80 mg / kg, which is the maximum tolerated dose of formulation 1 in SD-IGS rats.

[0634] Blood samples were collected from the tail vein of all animals using a continuous collection protocol with the following time points: before administration, 10 minutes after administration (for groups 1 and 2 only), 30 minutes, 1 hour, 2 hours, 4 hours, 4.5 hours, 5.5 hours, 12 hours, 24 hours, 48 ​​hours, and 72 hours.

[0635] In all animal samples, olanzapine was present in all plasma samples from 10 minutes to 24 hours after administration.

[0636] Low variability in exposure parameters was observed in all groups (14% to 35%). Olanzapine plasma concentrations increased immediately in all groups, reaching C60 levels within 10 minutes of administration. 最大It then dropped to a plateau concentration, which remained there for 72 hours. In most of the animals studied, C... 最大 It occurs before the intervention, therefore C 最大 Any changes were independent of the intervention. In some animals, a modest increase in olanzapine plasma concentrations was observed after the intervention, but the effect on exposure was not significant.

[0637] Small peaks in olanzapine plasma concentrations were observed in some animals, none of which were associated with the intervention, followed by elimination similar to that in other individuals within the group, indicating that no dose dumping occurred.

[0638] All groups had the same exposure, which was determined by similar AUC. 0-72h The value indicates.

[0639] In summary, extreme manipulation of the injection site of Formulation 1, whether by heating or friction, at 0.5 or 4 hours post-injection did not affect the pharmacokinetic (PK) or local tolerance at the injection site in rats. This supports the conclusion that dose dumping of Formulation 1 is unlikely to occur in humans. Dose dumping is a phenomenon of premature and excessive drug release. This significantly increases the drug concentration in plasma, leading to side effects and potential drug-induced toxicity.

[0640] Example 4

[0641] Following promising PK results obtained in the studies described in Examples 2 and 3, further studies were conducted in humans using Formulation 1.

[0642] Pharmaceuticals are used for reconstitution. Carriers containing excipients are used for reconstitution.

[0643] The Phase I clinical trial drug includes the following components:

[0644] • A single-use vial containing olanzapine powder, or an empty vial (for placebo administration).

[0645] • A single-use PFS containing a carrier (diluent)

[0646] • Two 16-gauge needles are used for reconstitution; one is used to add the carrier to the vial, and the other is used to reconstitute the drug (formulation 1) and then draw it into the administration syringe.

[0647] • A Luer-lock disposable syringe with a Luer-lock tip

[0648] • A 21-gauge, 16mm subcutaneous injection safety needle with a needle protection device, used for subcutaneous injection.

[0649] Olanzapine, used as a sustained-release injectable suspension (Formulation 1) and carrier, should be stored at 2°C to 8°C. Under the specified storage conditions, the API (olanzapine) is a yellow powder, and the carrier is a frozen, opaque solid. Both components need to be acclimated to room temperature before reconstitution, under which conditions the drug is a yellow powder and the carrier is a clear, colorless solution. Reconstitution of the drug (i.e., the active pharmaceutical ingredient powder containing the carrier) yields a yellow, opaque suspension.

[0650] Example 5

[0651] This study was an open-label, SAD and MAD study designed to evaluate the safety, tolerability, and pharmacokinetic (PK) of formulation 1 in healthy subjects and patients diagnosed with schizophrenia or schizoaffective disorder. Healthy subjects received a subtherapeutic dose of formulation 1 up to 105 mg, and patients received a therapeutic dose up to 566 mg. Patients were clinically stable and not currently receiving antipsychotic treatment other than oral olanzapine. Eligible subjects and patients were assigned to one of eight active cohorts or a loading cohort, as detailed in Table 5.1 below.

[0652] Table 5.1: Treatment Groups in the Study

[0653]

[0654] N / A = Not applicable; sc = Subcutaneous; q1m = Once a month.

[0655] All cohorts included safety, tolerability, and enhanced PK sampling assessments.

[0656] In addition to the starting dose of 70 mg, the study followed an adaptive design: the decision to use escalating doses of formulation 1 was based on the review of PK and safety data from previous lower doses of formulation 1.

[0657] Research Results

[0658] The administration methods for all subjects and patients in all cohorts are shown in Table 5.1; none of the stop rules in the protocol were met.

[0659] Population statistics

[0660] 127 healthy subjects and patients met the enrollment criteria and were deemed eligible to enter Phase 1 of the study (oral olanzapine treatment phase).

[0661] During Phase 1 of the study, a total of 36 healthy subjects and 91 patients were enrolled (54 patients were randomized to receive a single dose of formulation 1, and 37 patients were randomized to participate in multiple doses of formulation 1).

[0662] During Phase 2, a total of 30 healthy subjects and 71 patients received at least one dose of Formulation 1 and were included in each enrolled dataset used for safety and pharmacokinetic analyses. In Phase 2 of the study, an additional 6 healthy subjects were randomly assigned to the load therapy group.

[0663] Pharmacokinetics

[0664] During the study, a washout period was established between the last oral dose of olanzapine and formulation 1, reducing the administration time from 7 days to 2 days for the single-dose cohort (4 and 5) and the multi-dose cohort (8 and 9). For non-compartmental analyses, no adjustment was made for the residual effect of oral olanzapine concentrations on formulation 1. This approach was considered effective because olanzapine residues were expected to dissipate within hours of administration of formulation 1 following the last oral dose. Therefore, its effect on the PK parameters of formulation 1 was expected to be minimal.

[0665] Oral olanzapine pharmacokinetics

[0666] Healthy subjects (2.5 and 5 mg / day) and patients (10, 15 and 20 mg / day) were given subtherapeutic doses of olanzapine orally. The treatment lasted for 7 days. Following the last oral dose, a comprehensive PK collection protocol was employed to fully characterize PK at steady state.

[0667] The obtained oral pharmacokinetic (PK) parameters are shown in Figure 3. The PK parameters and inter-individual variability are related to oral olanzapine. The data is consistent with the published data.

[0668] The systemic exposure of olanzapine (i.e., C) 最大 AUC τ,ss The dosage increases proportionally with the dose in the range of 2.5 to 20 mg.

[0669] Pharmacokinetics of Formulation 1 (Single-dose subjects and patients)

[0670] The p-value curve of olanzapine after a single escalation dose of formulation 1 administered subcutaneously is shown below. Figure 4 (healthy subjects) and Figure 5 (The patient) is shown.

[0671] Overall, the pharmacokinetic (PK) characteristics of formulation 1 were qualitatively similar in healthy subjects and patients. In patients enrolled in cohorts 4–6, olanzapine plasma concentrations of formulation 1 initially increased rapidly within 1–2 days after administration to clinically relevant levels (≥10 ng / mL; Meyer and Stahl 2021). The curves showed an initial immediate release characteristic with a gradual increase in plasma concentration, and no sudden spikes or unexplained increases in olanzapine exposure, indicating no dose dumping following subcutaneous injection of formulation 1, consistent with preclinical studies.

[0672] Olanzapine plasma levels gradually increase, reaching their maximum value within 11 to 14 days (i.e., 264 to 336 hours) after administration of doses ranging from 318 mg to 531 mg (C). 最大 The slow absorption of olanzapine following subcutaneous administration of formulation 1 was reflected in a longer apparent terminal half-life (flip-flop kinetics). The arithmetic mean t1 / 2 values ​​for single-dose cohorts of formulation 1 (cohorts 4–6) ranged from 11 to 17 days (264 to 406 hours), depending on the dose. For clinically relevant doses, therapeutic levels were maintained over a 28-day dosing interval; thereafter, concentrations decreased in a markedly multiphasic manner until the last sample collection time point of 84 days (cohorts 1–4) or 42 days (cohorts 5 and 6).

[0673] Injection site interchangeability

[0674] In this study, 105 mg of formulation 1 was subcutaneously injected into the abdomen (cohort 2) and upper arm (cohort 3) to investigate the comparability of exposures. The pharmacokinetic (PK) curves for the two injection sites were similar. The absorption rate of olanzapine in the abdomen was similar to that in the arm, with a median t0. 最大 The values ​​were 263 and 264 hours, respectively. C after subcutaneous injection in the upper arm 最大 and AUC 0-28d The average ratios were approximately 38% and 20% higher, respectively, than the corresponding values ​​after subcutaneous abdominal injection. Importantly, the AUC... 0-t and AUC 0-∞ Similar exposures were observed at both injection sites. Therefore, the exposure to Formulation 1 after administration through these two injection sites was considered comparable.

[0675] Pharmacokinetics of Formulation 1 at Multiple Doses (Patients)

[0676] Multiple-dose pharmacokinetic (PK) studies of olanzapine were evaluated after three consecutive q1m injections of 283 mg or 566 mg formulation 1 (cohorts 8 and 9, respectively). The mean concentration versus time following the third subcutaneous injection of olanzapine is shown in the figure. Figure 6 and Figure 7 As shown.

[0677] In the multi-dose cohort, formulation 1 was administered three times on day 1, day 29 (week 4), and day 57 (week 8), respectively.

[0678] Following subcutaneous injection of 3q1m, the median time to reach peak plasma concentrations was 11 days and 10 days (262 and 236 hours) for cohorts 8 and 9, respectively. After reaching peak concentrations, olanzapine levels declined slowly until the last sample collection. Increased olanzapine exposure appeared to be proportional to the increase in dose in the multi-dose cohorts. Data used to calculate the arithmetic mean t1 / 2 value between cohorts 8 and 9 after the last dose of formulation 1 (third dose) ranged from 22 to 25 days (539 to 589 hours). AUC 0-tau and C 最大 The cumulative ratio (3 injections / 1 injection) indicates that in cohorts 8 and 9, the AUC 0-tau C accumulated only moderately at 1.30 and 1.14 respectively. 最大 The values ​​are 1.09 and 0.90 respectively. This can be verified by checking C. 谷值 AUC tau and C 最大 Both NCA and popPK analyses were used to estimate the attainment of steady state. Steady state was determined once the observed and simulated steady-state values ​​were reached. As previously stated, in cohorts 8 and 9, formulation 1 showed the lowest cumulative olanzapine levels after the second or third dose. The conclusion is that steady state was rapidly reached within two injections at the end of the second administration on day 57 (week 8). Figure 6 and Figure 7 ).

[0679] β-elimination phase half-life

[0680] In multi-compartment kinetic sustained-release scenarios, using the relevant β-elimination phase half-life instead of the observed terminal elimination phase (the observed best-fit λZ) may be beneficial for estimating the time to steady state (Gidal et al., 2017; Krause et al., 2021). The relevance of using the terminal half-life may be limited if the drug concentration decreases slowly at low levels at the end of the tested pharmacokinetic curve, as this has a small impact on overall drug exposure.

[0681] Due to the multiphase distribution of formulation 1, the β-elimination phase half-life correlated better with the steady state of formulation 1 compared to the terminal elimination phase half-life (the observed best-fit λZ). For the single-dose patient cohort, the mean β-half-life of formulation 1 was 5 to 7 days, and for the multiple-dose patient cohort, the mean β-half-life of formulation 1 was 8 to 10 days (Table 5.2).

[0682] Table 5.2: Estimated terminal (λZ) elimination half-life and β half-life

[0683]

[0684] We investigated other characteristics of formulation 1 under steady-state exposure using Pop PK modeling and simulation.

[0685] Dosage ratio

[0686] According to C 最大 Based on AUC assessment, systemic exposure increased in approximately dose-proportional manner within the treatment dose range of 283 mg to 566 mg, except for cohort 6 (531 mg formulation, 1 sc dose). In cohort 6, AUC 0-28d and AUC 0-∞ Slightly lower than expected based on exposure at other dose levels; however, this change was not clinically significant and is likely related to faster olanzapine clearance in individuals after oral administration of olanzapine and formulation 1, and a smaller sample size.

[0687] Although this study lacked the ability to assess dose proportionality, and despite the high variability of PK parameters observed, a clear trend indicated dose proportionality. This finding was also supported by popPK analysis. The observed median PK curves and PK variability of oral olanzapine and formulation 1 are shown below. Figure 8 As shown. Furthermore, PK / PD simulations correlated olanzapine concentration with D2 receptor occupancy and determined the dose at which D2 receptor occupancy occurred. The simulations also confirmed that the target dose was to achieve a D2RO ranging from 60% to 80% D2 receptor occupancy, which is related to the balance between antipsychotic efficacy and minimal side effects.

[0688] Comparability of Formulation 1 with Oral Olanzapine

[0689] Following the third injection of formulation 1 (day 57), when olanzapine plasma levels were considered to be at steady state at doses of 283 and 566 mg, the range of systemic exposure over 28 days (C) was [not specified]. 最大 ,ss, the trough plasma drug concentration on day 28 [C28d / C 谷值 [,ss] and mean plasma concentration [C 平均 The steady-state systemic exposure observed after oral olanzapine in the 10 to 20 mg dose range is comparable to that observed after oral olanzapine.

[0690] Figure 8 The median concentrations of olanzapine observed after the third dose of formulation 1 (q1m; 283 mg) and the seventh dose of oral olanzapine (10 mg / day) are shown, including the 5th and 95th percentiles, both considered as steady state. Formulation 1 (q1m; 566 mg) and oral olanzapine (20 mg / day) are shown as... Figure 8 middle.

[0691] Overall, Figure 8The figures show that the pharmacokinetic variability of formulation 1 over a 28-day dosing interval is comparable to that of oral olanzapine over a 24-hour dosing interval in terms of the 5th and 95th percentiles. Similarly, the overall exposure (i.e., AUC) is comparable and exhibits similar variability.

[0692] Relative bioavailability

[0693] Table 5.3 lists the relative bioavailability of formulation 1 and oral olanzapine. The relative bioavailability at steady state is calculated using a single dose of formulation 1 (as the steady-state AUC). tau (alternatives) after AUC inf The dose-normalized ratio divided by the AUC of oral olanzapine tau The relative bioavailability of the subcutaneous olanzapine formulation was 112%, with a 90% confidence interval close to the bioequivalence acceptance criteria (0.969, 1.291) after a single dose in patient cohorts (cohorts 4 and 6). After multiple doses in patient cohorts (cohorts 8 and 9), the relative bioavailability of formulation 1 compared to oral olanzapine was 95%, with 90% CIs of 0.855 and 1.059, respectively. Although the sample size of this study was insufficient to support a bioavailability analysis, these results support the overall similarity between formulation 1 and oral olanzapine at comparable doses.

[0694] Table 5.3: Relative bioavailability of Formulation 1 and oral olanzapine (dose normalized)

[0695]

[0696] a. Assess the relative bioavailability of olanzapine AUC normalized to dose (ln-converted AUC of formulation 1) 0-∞ AUC of ln conversion with oral olanzapine 0-tau (Both are treated as a single result).

[0697] b. Assess the relative bioavailability of olanzapine dose-normalized AUC (ln-converted AUC of the third formulation and the interval between multiple administrations). 0-tau [Formulation 1], AUC of oral olanzapine dose-normalized ln transformation was calculated. 0-tau28d Both reflect the steady-state AUC over the 28-day application interval and are treated as a single result.

[0698] AUC = Area under the plasma drug concentration-time curve; AUC 0-∞ =AUC (Area under the plasma drug concentration-time curve extrapolated to infinity) 0-tau = Area under the plasma drug concentration-time curve until the end of the administration phase; CI = Confidence interval; Geo = Geometric curve;

[0699] GMR = Geometric Mean Ratio; LS = Least Squares; Ref = Reference.

[0700] Note: GMR calculation: AUC normalized to formulation 1 dose. 0-∞ (Based on pooled data from single-dose cohorts) and AUC normalized to oral olanzapine dose. 0-tau (Multiplied by 28 days) ratio.

[0701] Security assessment

[0702] Safety was assessed during the study by evaluating adverse events (AEs), clinical laboratory results (serum, hematology, urinalysis, and prolactin), vital sign measurements, ECG, physical examination, injection site pain, local tolerance, and leakage assessment. In addition, psychiatric, neurological, and clinical symptom assessments included:

[0703] • Abnormal Involuntary Movement Scale (AIMS)

[0704] • Barnes' Inability to Sit Rating Scale (BARS)

[0705] • Clinical Global Impression Scale - Disease Severity (CGI-S)

[0706] • Columbia Suicide Severity Rating Scale (C-SRS)

[0707] • Extrapyramidal Symptom Rating Scale (ESRS)

[0708] • Epworth Sleepiness Scale (ESS)

[0709] • Positive and Negative Syndrome Scale (PANSS)

[0710] According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 guidelines, the severity of adverse events (AEs) is graded, ranging from Grade 1 (mild, asymptomatic, or mildly symptomatic) to Grade 5 (AE-related death).

[0711] Formulation 1 Research Overview

[0712] The safety and risk-benefit profile of formulation 1 was assessed using clinical safety data available to date in this study. All study cohorts have been completed. Cutoff data include all safety and pharmacokinetic (PK) data from the single-dose cohorts (cohorts 1 through 6). For the multi-dose cohorts (cohorts 8 and 9), partial PK and safety data after the third dose are available, as all patients had received three consecutive q1m injections of formulation 1 and completed the treatment phase (day 85). In cohort 8, 11 patients were in the FU phase, and 1 patient completed the study. In cohort 9, 6 patients were in the FU phase, 6 patients completed the study, and 1 patient terminated the study early during the FU phase.

[0713] Results from laboratory tests, vital signs, ECG, clinical scales, and adverse events (AEs) indicated that formulation 1 did not present any new systemic safety signals and remained consistent with the safety profile of olanzapine. No PDSS events or suspected PDSS events were observed during the study.

[0714] The injection site reactions observed in the study were related to the route of administration and did not appear to significantly alter the benefit-risk profile of formulation 1.

[0715] Safety conclusions

[0716] Safety endpoints for this study included the incidence of adverse events, changes in ECG parameters compared to baseline, selected clinical laboratory values ​​(including prolactin) and vital signs, changes in neurological and clinical symptom assessments (e.g., PANSS, ESRS, AIMS, BARS, CGI-S, C-SRS), and other safety measures assessed throughout the study.

[0717] Overall, subcutaneous administration of olanzapine extended-release injection suspension (formulation 1) in healthy subjects and patients diagnosed with schizophrenia or schizoaffective disorder was well tolerated. Its safety profile, except for ISR, was similar to that of oral olanzapine.

[0718] No deaths or treatment-related serious adverse events occurred in this study. During the washout period following oral olanzapine administration, 4 / 127 (3.1%) participants withdrew from the study due to adverse events (2 cases of elevated LDL cholesterol, 1 case of neutropenia, and 1 case of rash); all participants were healthy subjects. In Phase 2 of the study, only 1 patient receiving a clinically relevant dose of formulation 1 (cohort 4; formulation 1 425 mg) withdrew from the study due to a Grade 3 serious adverse event of psychiatric disorder, and 1 patient in cohort 9 (multiple q1m formulation 1 566 mg) experienced a Grade 2 serious adverse event of schizophrenia during the study. The investigators and sponsor considered these two serious adverse events to be unrelated to formulation 1.

[0719] In all treatment cohorts of Phase 2, 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 to the single-dose patient cohort (23.8%), while the incidence was highest in the multi-dose patient cohort (44.8%). The most frequently reported treatment-related adverse events (occurring in more than 4% of healthy subjects or patients) in the single-dose healthy subject cohort were injection site erythema (6.7%) and headache (6.7%); in the single-dose patient cohort, these were headache (4.8%), somnolence (4.8%), increased appetite (4.8%), or weight gain (4.8%); and in the multi-dose patient cohort, these were obesity (13.8%) and injection site pruritus (10.3%). Treatment-related adverse events were typically grade 1 or 2 in severity. Only three healthy subjects or patients experienced grade 3 treatment-related events (one healthy subject in cohort 3 [formula 1, 105 mg, upper arm] experienced elevated ALT, one patient in cohort 5 [formula 1, 318 mg] experienced injection site abscess, and one patient in cohort 9 [multiple q1m doses of formulation 1, 566 mg] experienced injection site erythema). No grade 4 or 5 adverse events were reported during the study.

[0720] Adverse events of particular concern as defined in the protocol included ISRs (only those defined as adverse events). ISRs were observed in all treatment cohorts except for Cohort 6 (Formula 1, 531 mg). Among injection site adverse events, the most frequently reported were injection site abscesses (5 patients in all cohorts), injection site erythema (4 patients in all cohorts), and injection site pruritus (3 patients in all cohorts). Most of these injection site adverse events were grade 1 or 2 in severity; except for one grade 3 injection site abscess in Cohort 5 (Formula 1, 318 mg) and one grade 3 injection site erythema in Cohort 9 (multiple q1m Formula 1, 566 mg). Seven of these events were classified as purulent lesions: one reported 5 cases of injection site abscesses with prior inflammation, and two cases of injection site infections without a clear dose response. One injection site infection (1 patient in Cohort 4) was not considered an ISR or related to Formula 1 administration because the infection was caused by patient irritation / scratching and was therefore classified as injection site irritation. None of these incidents were classified as serious, and all have recovered and been resolved after receiving systemic antibiotic treatment.

[0721] The distribution and incidence of purulent lesions varied at each injection site; specifically, 3 / 11 (27.3%) of healthy subjects received 3 injections out of 11 arm injections, and 3 / 71 (4.2%) of patients received 3 injections out of 129 abdominal injections. None of these events affected the pharmacokinetics of formulation 1.

[0722] As expected for this type of drug, an initial increase in mean prolactin levels was observed in both treatment phases (oral olanzapine and formulation 1). However, no adverse events associated with hyperprolactinemia were observed during the study.

[0723] Overall, the injections were generally well tolerated. In cohort 6 (1531 mg dosage form), one patient had an NPRS score of 10 immediately after injection pain, one patient in cohort 5 (single dose of 1318 mg dosage form) had a score of 9, one patient in cohort 4 (1425 mg dosage form) had a score of 9, two patients in cohort 6 had scores of 8, and one patient in cohort 5 had a score of 8; all other patients had NPRS scores ≤7. Minimal and sporadic injection site pain scores were recorded after day 8. Injection site reactions were generally grade 1 or 2 in severity and transient in nature.

[0724] Clinical laboratory tests (including clinical chemistry, hematology, and urinalysis), vital signs, and physical examination results showed no clinically significant trend in mean change from baseline, nor any clinically significant outcome in these assessments. However, occasional increases in creatine kinase appeared to be dose-independent in both treatment phases. 38% of patients randomized to the multi-dose cohort experienced a weight gain ≥7% from baseline. ECG results were slightly worse in all treatment cohorts, although these were generally considered clinically insignificant. Only one patient in the single-dose cohort (cohort 5; formulation 1318 mg) experienced an adverse event of tachycardia.

[0725] No clinically significant changes were observed in PANSS, ESRS, AIMS, BARS, or ESS scores during the study. Overall, patients' CGI-S and C-SRS scores remained stable throughout the study. No confirmed or suspected PDSS events (protocol-defined adverse events used for rapid reporting) occurred during the study.

[0726] Formulation 1 Safety Overview

[0727] Safety data for formulation 1 were evaluated in 71 patients and 30 healthy subjects at doses ranging from 70 to 566 mg. Six healthy subjects receiving a carrier dose of formulation 1 were also evaluated. The systemic safety profile derived from these data was consistent with other formulations of olanzapine. In this study, there were no clinically significant changes in the assessment scales of mental, neurological, and clinical symptoms compared to baseline, including in clinically stable patients who had previously received oral olanzapine. This supports the sustained release of olanzapine after injection in formulation 1, and therefore its pharmacodynamics and systemic safety profile are comparable to oral olanzapine. Most identified ISR AEs were mild to moderate in severity and not serious. These ISR AEs did not significantly alter the benefit-risk profile of formulation 1.

[0728] Example 6

[0729] A multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study with an open-label, long-term safety profile was conducted to evaluate the efficacy, safety, and tolerability of olanzapine extended-release suspension (formulation 1) for subcutaneous injection in adult patients with schizophrenia.

[0730] Table 6.1: Goals and End Points

[0731]

[0732] Overall Design

[0733] Patients whose schizophrenia worsened ≤8 weeks prior to screening, and those requiring psychiatric hospitalization or continued hospitalization due to schizophrenia symptoms, may be included. The study consists of two phases: Phase 1 (double-blind, placebo-controlled, efficacy and safety phase) and Phase 2 (open-label safety phase). For each patient, Phase 1 lasts 8 weeks, and Phase 2 lasts up to 48 weeks. Randomization was performed up to 8 days prior to screening. In Phase 1, patients were randomly assigned to one of the three treatment groups of Formulation 1 (318 mg once monthly [q1m], 425 mg q1m, or 531 mg q1m) or a placebo group q1m in a 1:1:1:1 ratio. To maintain blinding in Phase 1, all patients were re-randomized between Phase 1 and Phase 2; patients previously assigned to the active treatment group retained their Phase 1 treatment group in Phase 2, and patients previously assigned to the placebo group were randomly assigned to one of the active treatment groups in a 1:1:1 ratio in Phase 2. Treatment ended and follow-up was conducted 4 weeks and 8 weeks after the last dose of the clinical trial drug, respectively.

[0734] Research interventions and intervention methods

[0735] This study aimed to evaluate the efficacy, safety, and tolerability of subcutaneous olanzapine extended-release injection suspension (formulation 1) in patients with schizophrenia compared to placebo. The total study duration was up to 61 weeks, with a treatment duration of up to 56 weeks.

[0736] Number of participants:

[0737] Approximately 985 patients were screened to obtain approximately 640 randomized patients.

[0738] This study enrolled patients diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The diagnosis was confirmed using a structured assessment tool (DSM-5 Structured Clinical Interview Clinical Trial Version [SCID-5-CT]).

[0739] An acute condition is defined as a total PANSS score of 80 to 120 (inclusive) at screening and baseline (before randomization) and a score ≥4 on at least two of the following four items on the PANSS positive subscale: hallucinatory behavior, delusions, conceptual confusion or suspicion / persecution, and a CGI-S score ≥4 at screening and baseline (before randomization) (moderate disease).

[0740] Patient inclusion criteria

[0741] Only patients who meet all of the following criteria will be randomly assigned to groups in this study:

[0742] a. The patient is a male or female of any race, and is 18 to 65 years old (inclusive) at the time of screening.

[0743] b. The patient is able to provide a signed informed consent form. Unless prohibited by local regulations, patients will be asked to consent to share their information with the vendor, who will verify that they are not currently or recently involved in another clinical study. Additionally, patients will be asked to consent to have their PANSS assessments recorded (which will be reviewed if necessary to monitor the quality of the scores).

[0744] c. According to DSM-5, the patient is currently diagnosed with schizophrenia, with a duration of >1 year. The diagnosis must be confirmed by SCID-5-CT.

[0745] d. Patients with a total PANSS score of 80 to 120 (inclusive) at screening and baseline examination (before randomization) and scores ≥4 on at least two of the following four items of the PANSS positive subscale: hallucinatory behavior, delusions, conceptual confusion, or suspicion / persecution.

[0746] e. Patients who begin to experience worsening of schizophrenia ≤8 weeks prior to screening and will benefit from psychiatric hospitalization or continued hospitalization due to schizophrenic symptoms.

[0747] f. Patients with a CGI-S score ≥4 (moderate prevalence) at screening and baseline examination (before randomization).

[0748] g. Patients who have received antipsychotic medication (excluding clozapine) in the past year must be deemed to have responded to treatment based on the investigator's judgment (and discussions with family members, caregivers, or healthcare professionals, if applicable).

[0749] h. The patient has a designated responsible person (referred to as a caregiver) who agrees to provide information about the patient's location, condition, and overall status during the outpatient portion of the study in Phase 1. Field staff must identify the caregiver during the screening visit and consider them a reliable contact. The caregiver must have regular contact with the patient (defined as at least three direct contacts per week), and this frequency of contact is expected to continue in the outpatient portion of Phase 1 (and is also recommended for the remainder of the study, including Phase 2 and FU). Regular contact with the patient is not mandatory during the Phase 1 hospitalization. The patient's caregiver will be required to sign a caregiver ICF.

[0750] i. At the time of screening, the body mass index was between 18.0 and 40.0 kg / m². 2 (Including end values).

[0751] j. Only women who test negative for β-human chorionic gonadotropin (β-HCG) at screening and baseline (serum testing should be performed and negative if urine test results are borderline) or who are infertile (documented hysterectomy, bilateral oophorectomy, or bilateral salpingectomy or congenital infertility) or postmenopausal can be included.

[0752] k. Women of childbearing age must agree not to attempt pregnancy unless they have a monogamous partner, and must agree to use a highly effective method of contraception before the first dose of IMP, and to continue using this method during the study period and for 70 days after the last dose of IMP. Highly effective methods of contraception include the following:

[0753] 1. Combined hormonal contraception with estrogen and progestin (oral, vaginal, transdermal) associated with ovulation suppression; these should be initiated during the screening visit prior to the first dose of IMP.

[0754] m. Progestin-only hormonal contraceptives (oral, injectable, implantable) associated with ovulation suppression; these should be initiated during the screening visit prior to the first dose of IMP.

[0755] n. Intrauterine devices and intrauterine hormone-releasing systems; these need to be inserted at least 2 months before screening.

[0756] o. Bilateral fallopian tube obstruction.

[0757] p. Vasectomy of the partner, provided that he is the only sexual partner and undergoes a medical evaluation of the procedure.

[0758] q. Abstinence (avoiding heterosexual intercourse) for a prescribed period is also considered a very effective method. The reliability of abstinence needs to be evaluated based on the duration of clinical studies and the patient's preferred and daily lifestyle.

[0759] r. The patient (if an adult male) is surgically infertile, or if capable of fathering children, has only a same-sex partner, or is currently using an approved method of contraception and agrees to continue using this method during the study period (and for 70 days after the last dose of IMP). Male patients whose sexual partners are women of childbearing age must use condoms, even if they are sterilized. Furthermore, male patients are prohibited from donating sperm during the study period and for 70 days after the last dose of IMP.

[0760] s. The patient is able to understand the nature of the study and comply with the protocol requirements, including the prescribed dosage regimen (oral and subcutaneous), the avoidance of concomitant medications, and hospitalization at the clinical site for at least 4 weeks; be able to read and understand written text in order to complete the patient-reported outcome measurement independently; and be able to reliably score on the assessment scale.

[0761] Patients must be willing and able to comply with the study restrictions, the required time spent at the research center during the study phase (including at least 4 weeks of on-site hospitalization), and must be willing to return to the research center for further visits (if applicable), as well as the FU procedures and assessments as specified in this agreement.

[0762] u. Patients had a stable place of residence for about 3 months prior to screening and were not expected to change their place of residence during the study participation process.

[0763] v. Based on medical history and psychiatric history, physical examination, electrocardiogram (ECG), serum chemistry, hematology, coagulation urine test and serology, the patient's health condition is determined to be good.

[0764] Patient exclusion criteria

[0765] Patients meeting any of the following criteria will not be randomly assigned in this study:

[0766] a. The patient’s current DSM-5 diagnosis is clinically significant, except for schizophrenia (the current primary diagnosis is a disease other than schizophrenia, or a comorbid diagnosis that is the primary cause of the current symptoms and functional impairment).

[0767] b. The patient has a known medical history of: (a) borderline personality disorder, antisocial personality disorder, or bipolar disorder; (b) traumatic brain injury resulting in persistent cognitive difficulties, Alzheimer's disease or another form of dementia, or any chronic organic disease of the central nervous system; and (c) intellectual disability of a degree that would affect the ability to participate in research.

[0768] c. From screening to day 1 (baseline [randomized] visit), patients' total PANSS score improved (decreased) by ≥20%.

[0769] d. Prior to screening, the patient had been hospitalized for more than 14 days during the current acute phase (excluding social or administrative hospitalization).

[0770] e. Based on the patient's medical history or the researcher's judgment, the patient is at significant risk of engaging in violent behavior.

[0771] f. Based on the patient's medical history or C-SRS and the researcher's judgment, the patient is at significant risk of suicide.

[0772] Patients who have shown a positive C-SRS response for suicidal ideation 3, 4 or 5 and / or a positive response for suicidal behavior in the past 6 months are not eligible.

[0773] g. The patient meets the criteria for moderate to severe substance use disorder (based on DSM-5 criteria) within the past 6 months, such as chronic alcohol abuse or drug abuse (excluding caffeine or nicotine-related drug abuse). A positive urine drug test result is not exclusionary if, in the investigator's judgment, the patient does not meet the criteria for substance use disorder. In the case of such a positive result without medical interpretation, the patient's eligibility will be determined by the investigator based on the patient's background, drug use history, and discussions with family, caregivers, or healthcare professionals (if applicable).

[0774] h. The patient is currently using an antipsychotic drug with a specific LAI, or is still within the coverage phase of a particular LAI at the time of screening.

[0775] i. The patient has taken clozapine or received electroconvulsive therapy within 12 months prior to the screening.

[0776] j. The patient is currently taking olanzapine orally every day at a dose >20 mg / day.

[0777] k. The patient currently has or has a known history of allergy to olanzapine or any excipient of formulation 1 or oral olanzapine formulations.

[0778] 1. Based on medical and psychiatric history, the investigator determines that the patient has treatment-resistant schizophrenia or has a documented failure of two or more antipsychotic medications (administered at the maximum tolerated dose for at least 6 weeks per medication). Participants who respond to antipsychotic medications only when used in combination with clozapine are also considered treatment-resistant.

[0779] m. Based on medical history, mental illness history, and the researcher's judgment, the patient develops significant sedation or delirium after receiving antipsychotic medication, or delirium occurs due to some disease.

[0780] n. Any medical or psychiatric condition in which the researcher believes the patient may jeopardize or impair the patient's ability to participate in the study.

[0781] o. The patient has known risk factors for undiagnosed / unstable arrhythmia, congenital long QT interval, hypokalemia, hypomagnesemia, or autonomic dysfunction (most of whom are accompanied by clinically significant orthostatic hypotension).

[0782] p. The patient has any clinically significant uncontrolled disease (treated or untreated).

[0783] q. Any condition that may interfere with the absorption, metabolism, or elimination of olanzapine.

[0784] r. The patient's non-fasting blood glucose level at the time of screening is ≥200 mg / dL.

[0785] s. The patient changed their diabetes treatment regimen within 4 weeks prior to their first IMP injection.

[0786] t. The patient's serum triglyceride level is ≥500 mg / dL.

[0787] u. The patient's low-density lipoprotein level is ≥190 mg / dL.

[0788] v. The patient has a history of ketoacidosis or hyperosmolar coma.

[0789] w. The patient has a known alanine aminotransferase (ALT) / serum alanine aminotransferase level ≥2 × upper limit of normal (ULN), aspartate aminotransferase / serum aspartate aminotransferase level ≥2 × ULN, and total bilirubin level ≥1.5 × ULN.

[0790] The isolation exclusion parameters are as follows:

[0791] -ALT or AST>5×ULN

[0792] -ALT or AST > 3 × ULN, in addition, total bilirubin level > 2 × ULN or international normalized ratio > 1.5 (if the increase in international normalized ratio is not caused by anticoagulant).

[0793] -ALT or AST > 3 × ULN, with symptoms such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and

[0794] / or eosinophilia (>5%)

[0795] x. Patient's neutrophil count <1200 / mm 3 .

[0796] y. Patient's platelet count ≤75×10 3 μL.

[0797] z. Patient's serum creatinine >2.5 mg / dL.

[0798] aa. The patient is serologically positive for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B surface antigen, and / or hepatitis C. If the hepatitis C serological test is positive, but the ribonucleic acid (RNA) test is negative, and the patient has no history of liver disease or symptoms of active liver disease, admission will be permitted based on clinical judgment.

[0799] bb. Patients are pregnant or breastfeeding women, or plan to become pregnant during the study.

[0800] cc. The patient had previously participated in this study (except for rescreening).

[0801] dd. The patient is currently using or has previously used or taken any medications prohibited under this agreement.

[0802] ee. Patients who have used the investigational drug (new chemical entity) or medical device in a clinical study within 30 days or 5 half-lives (whichever is longer) prior to the first administration of formulation 1, or in the case of a biological investigational drug, within 3 months or 5 half-lives (whichever is longer).

[0803] ff. Patients who have donated or received any blood, plasma, or platelet transfusions within 30 days prior to the study, or who plan to donate during the study or within 6 months of the last dose of IMP.

[0804] The patient may have a pending trial that could lead to imprisonment.

[0805] Phase 2 eligibility criteria

[0806] To proceed to Phase 2, patients must meet the following eligibility criteria:

[0807] 1. The patient has completed Phase 1.

[0808] 2. Based on the researchers' judgment, the patient was considered to have sufficient clinical stability.

[0809] 3. The patient is an outpatient (i.e., meets the RDQ criteria and is discharged before Phase 2).

[0810] Patients who do not meet the RDQ criteria but whose clinical stability is deemed sufficient to transition to Phase 2 and who may benefit from continued participation in the study may continue as inpatients in Phase 2 for up to 8 weeks. For these 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 hospital stay (week 16), the patient will discontinue study treatment and be required to complete ET and FU visits.

[0811] Intervention group and duration

[0812] The screening phase included two consecutive days of oral olanzapine administration prior to randomization to Phase 1 to determine tolerability (for patients who had not received oral olanzapine treatment in the past year). During Phase 1 (8 weeks), patients received 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 received up to 12 monthly injections of formulation 1.

[0813] Clinical trial drugs used in the study

[0814] IMP is defined as the test IMP and the placebo IMP matched with the test IMP.

[0815] The descriptions of the IMP (formulation 1) and placebo IMP tests are shown in Table 6.3.

[0816] Testing drugs for clinical trials

[0817] Formulation 1 mentioned in the examples is a pharmaceutical composition disclosed herein, comprising: 30% to 32% (w / w) olanzapine; 52% to 54% (w / w) dimethyl sulfoxide; 12% to 14% (w / w) a diblock copolymer comprising polylactic acid and polyethylene glycol, the diblock copolymer having a number average molecular weight of 6.5 to 12.5 kg / mol and comprising 75% to 84% (w / w) polylactic acid by weight; and 3% to 3.5% (w / w) a triblock copolymer comprising polylactic acid and polyethylene glycol, the triblock copolymer having a number average molecular weight of 6 to 13 kg / mol and comprising 83% to 88% (w / w) polylactic acid by weight; wherein the diblock copolymer and the triblock copolymer together comprise 15% to 17.5% (w / w) of the composition by weight.

[0818] Pharmaceuticals are used for reconstitution. Carriers containing excipients are used for reconstitution.

[0819] Formulation 1 requires reconstitution from the following two components: one vial containing olanzapine active pharmaceutical ingredient powder and one PFS containing a carrier (two block copolymer excipients dissolved in an organic solvent containing dimethyl sulfoxide). Prior to administration, Formulation 1 is reconstituted in the vial by adding the carrier from the PFS and mixing.

[0820] Formulation 1 is administered subcutaneously to the abdomen at q1m intervals, at a dose equivalent to 10, 15, or 20 mg / day of oral olanzapine, converted according to Table 6.2. After reconstitution, each gram of total formulation 1 contains 305 mg of olanzapine. The dosage is selected by inhaling a specific prescribed volume into the injection syringe.

[0821] Inject alternately into the right and left sides of the navel. Subsequent monthly injections should be administered in a clockwise rotation between the abdominal quadrants.

[0822] Dosage group

[0823] In this study, formulation 1 was administered at three doses: low dose (318 mg q1m), medium dose (425 mg q1m), and high dose (531 mg q1m).

[0824] Table 6.2: Dosage Conversion Between Oral Olanzapine and Formulation 1

[0825] Olanzapine oral dosage Formulation 1 Olanzapine dosage Application volume of Formulation 1 10mg 318mg 0.9mL 15mg 425mg 1.2mL 20mg 531mg 1.5mL

[0826] Placebo clinical trial drugs

[0827] Formulation 1, the placebo, consists of two components: one empty vial and one PFS containing a carrier (two block copolymer excipients dissolved in DMSO). Prior to administration, the placebo product is prepared in the vial by adding the carrier from the PFS and mixing. The dosage of Formulation 1, the placebo, is 0.8 mL.

[0828] Other components

[0829] The kits for IMP and placebo IMP contain the following:

[0830] • Two 16-gauge needles: one for adding the carrier to the vial for reconstitution, and the other for drawing the drug into the administration syringe after reconstitution.

[0831] • A 3mL Luerlock disposable syringe with a Luerlock tip

[0832] • A 21-gauge, 16mm (5 / 8-inch) safety needle for subcutaneous injection, with a needle protection device.

[0833] Table 6.3: Clinical Trial Drugs Used in the Study

[0834]

[0835] IMP = Clinical Trial Drug; INN = International Nonproprietary Name; q1m = Once a Month; sc = Subcutaneous Injection.

[0836] Permitted concomitant medication

[0837] rescue drugs

[0838] Permitted rescue medications include zolpidem, zopiclone, zaleplon, or diphenhydramine for treating insomnia; benzalkonium chloride, trihexyphenidyl, or diphenhydramine for Parkinson's disease symptoms; and propranolol and benzodiazepines for akathisia.

[0839] In addition, during the screening phase and in Phase 1, lorazepam may be used as needed, except for akathisia (anxiety) (up to 6 mg / day or not exceeding the local maximum permitted daily dose [whichever is lower]). In this case, use must be limited to no more than 72 consecutive hours, and lorazepam must not be taken within 8 hours prior to the assessment of the rating scale.

[0840] In Phase 2, lorazepam (at the locally labeled approved dose) will be permitted for use as needed for indications other than akathisia (anxiety disorder). During the study, antihistamines and anticholinergics will be permitted for the treatment of agitation and insomnia.

[0841] Antidepressants and mood stabilizers

[0842] Screening phase and phase 1 Patients who have been receiving antidepressants and / or mood stabilizers for at least 3 months prior to screening and whose dosage has not changed for at least 4 weeks prior to screening (except for indications that exclude patients from the study, such as schizoaffective disorder) may continue treatment during screening phase / phase 1. Dosage changes or initiation of new treatments with these medications are not permitted during screening phase / phase 1.

[0843] Phase 2 During Phase 2, patients who received mood stabilizers and antidepressants for at least 3 months prior to screening and whose dosage remained unchanged for at least 4 weeks prior to screening, and who continued treatment during Phase 1, will be allowed to continue treatment. New mood stabilizers are not permitted; however, the dosage of mood stabilizers may be adjusted based on specific circumstances after discussion with the MM (Medical Analyst).

[0844] Phase 2 will allow for adjustments to antidepressant dosages based on the investigator's clinical judgment. Patients who have not previously received antidepressants will be permitted to begin treatment with some antidepressants (including selective serotonin reuptake inhibitors [except fluvoxamine], serotonin and norepinephrine reuptake inhibitors, and trazodone) in Phase 2, based on the investigator's clinical judgment. Investigators are encouraged to contact MM or the sponsor before initiating any new antidepressant treatment. The use of other antidepressants (such as tricyclic and tetracyclic antidepressants and bupropion) is prohibited.

[0845] Screening period (up to 8 days before randomization to enter Phase 1) :

[0846] Patients underwent screening and assessment up to 8 days prior to randomization to Phase 1. Informed consent was provided during the screening visit prior to any study-related procedures. Patients were asked to consent to share their information with the vendor, who would verify that they were not currently or recently involved in another clinical study, unless prohibited by local regulations. Furthermore, patients were asked to consent to the recording of their PANSS assessments (for review if necessary to monitor the quality of the scores). Patients willing to participate in optional pharmacogenetic and biomarker sampling, as well as optional recorded exploratory assessments, signed separate informed consent forms (ICFs) for this purpose.

[0847] Patients whose condition worsened ≤8 weeks prior to screening (investigators should confirm the worsening based on the patient's medical records and / or medical history) and patients who benefited from schizophrenia hospitalization or continued hospitalization due to schizophrenia symptoms were eligible for inclusion in this study.

[0848] During screening, patients should have a total score of 80 to 120 (inclusive) on the Positive and Negative Syndrome Scale (PANSS) and a score of ≥4 on at least two of the following four items on the PANSS positive subscale: hallucinatory behavior, delusions, conceptual confusion, or suspicion / persecution.

[0849] Patients must have a designated responsible person (referred to as a caregiver) who agrees to provide information about the patient's location, condition, and overall status during the outpatient portion of the Phase 1 study. Field staff must identify the caregiver during the screening visit and consider them a reliable contact. Caregivers must maintain regular contact with patients (defined as at least three direct contacts per week), and this frequency of contact is expected to continue during 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 is required to sign the caregiver ICF at the time of screening.

[0850] Patients who have not yet been hospitalized will be admitted during the screening phase (for details on length of stay and discharge criteria, see the description of “Phase 1” below).

[0851] Patients gradually reduced their previous oral antipsychotic medication at a rate determined by the investigator. The tapering process should be completed before randomization.

[0852] During the screening phase, patients enrolled in the study who had not previously received oral olanzapine received two doses of oral olanzapine over two consecutive days (the second dose should be taken at least 24 hours before randomization) to assess tolerability (oral olanzapine 10 mg / day or higher [but not exceeding 20 mg / day], at the investigator's discretion). PANSS and Clinical Global Impression-Severity (CGI-S) were completed before oral olanzapine administration.

[0853] Patients who have received olanzapine treatment within the past year do not need to receive two doses of oral therapy. Researchers verified prior use, tolerability, and duration of olanzapine treatment to ensure prior tolerability.

[0854] If a patient meets all study inclusion criteria and no study exclusion criteria, but the results of the blood sample collected during the 8-day screening period are not available by day 8, the screening period can be extended by 2 days (until day 10) to obtain results to confirm the patient's eligibility. If no results are available by day 10, the patient is considered to have failed the screening, and rescreening may be considered.

[0855] Phase 1 (8 weeks) :

[0856] Phase 1 is an 8-week double-blind, placebo-controlled efficacy and safety phase (acute treatment phase).

[0857] Randomized patients had a total PANSS score of 80 to 120 (inclusive) at baseline (before randomization) and a score ≥4 on at least two of the following four items on the PANSS positive subscale: hallucinatory behavior, delusions, conceptual confusion, or suspicion / persecution.

[0858] Patients whose total PANSS score decreased by ≥20% between screening and baseline (randomized) visit were not eligible for randomization to the study.

[0859] Randomized patients received either formulation 1 (low dose [318 mg q1m], medium dose [425 mg q1m], or high dose [531 mg q1m]) or placebo subcutaneously at their second visit (week 0) and seventh visit (week 4).

[0860] At the 2nd and 7th visits, prior to administration of the clinical trial drug (IMP), the PANSS, Columbia Suicide Severity Rating Scale (C-SRS), CGI-S, and Clinical Global Impression-Improvement (CGI-I; 7th visit only [week 4]) scales were completed; all other scales and questionnaires were completed before or after IMP administration. Any assessments performed after IMP administration were completed on the day of IMP administration.

[0861] Prior to screening, patients were either outpatients or inpatients. All patients were hospitalized upon entry into the study (screening period) and remained hospitalized during the screening phase and for the first 4 weeks after randomization (until the second IMP administration). After the second injection, patients were discharged if they met all discharge criteria and the investigators deemed discharge appropriate.

[0862] Throughout Phase 1 (including inpatient and outpatient care), a window of ±3 days is permitted around the planned visit date for administration of the visit; a window of ±2 days is permitted for all other visits (during inpatient care, every effort will be made to keep the assessment on the planned date). The visit date is calculated from the date of the last IMP administration. In exceptional circumstances, at the investigator's discretion and with the permission of the Medical Supervisor (MM) or the sponsor, administration of the visit should be performed (and recorded accordingly) 5 days prior to the planned visit date.

[0863] Phase 2 (up to 48 weeks) :

[0864] After completing Phase 1 (8 weeks), eligible patients proceed to Phase 2, the safety phase (long-term safety period; up to 48 weeks). During this period, patients receive monthly subcutaneous injections of Formulation 1.

[0865] The 11th visit (week 8) was the final visit for Phase 1 and the first visit for Phase 2. To maintain blinding in Phase 1, all patients were re-randomized between Phase 1 and Phase 2; patients previously assigned to the active treatment group retained their Phase 1 treatment group (the re-randomization of patients in the Formulation 1 group was solely for maintaining blinding in Phase 1 and was, in effect, a deterministic grouping, not a randomization), while patients previously assigned to the placebo group were randomly assigned to one of the active treatment groups in a 1:1:1 ratio. At this visit, the Treatment 1 group was assigned to Phase 2 and proceeded according to the re-randomized treatment grouping. Scales, questionnaires, and other assessments were completed only once. Treatment grouping in Phase 2 was revealed on a patient-by-patient basis only after the study procedures related to the assessment of the Phase 1 efficacy and safety endpoints were completed and reported. The re-disclosure of Phase 2 treatment grouping was conducted by the sponsor or representative from weeks 8 to 12 according to a predefined procedure in the relevant study plan, provided that all requirements specified in this procedure were met. Therefore, although the administration in week 8 was grouped into phase 2, all parties were treated in a blinded manner, similar to the administration in phase 1.

[0866] The study will continue on an outpatient basis (or with inpatient care for patients requiring up to 8 weeks), with weekly telephone contact (or other similar forms of remote communication) between monthly outpatient visits. If the investigator determines that a patient's condition may worsen or pose a danger to themselves or others, the patient will be invited for ad hoc appointments and / or hospitalization if necessary, and will be treated according to the investigator's judgment. If treatment with prohibited medications, including antipsychotics other than Formulation 1, is required, the patient will discontinue study treatment and be required to complete ET and FU visits.

[0867] Complete the PANSS, C-SRS, CGI-S, and CGI-I scales before IMP administration; all other scales and questionnaires may be completed before or after IMP administration (except for the 11th visit [week 8], where all assessments must be completed before IMP administration). Any assessments conducted after IMP administration should be completed on the same day as IMP administration.

[0868] Throughout Phase 2 (including any telephone visits), a window of ±3 days is permitted around the planned visit date for administration of the visit; for any patient hospitalized at the start of Phase 2, every effort shall be made to assess them on the planned date during their hospitalization. The visit date is calculated from the date of the last IMP administration. In exceptional circumstances, at the investigator's discretion and with the permission of the MM or the sponsor, administration of the visit may be performed up to 5 days before the planned visit date (and recorded accordingly).

[0869] Patients entering Phase 2 receive up to 48 weeks of treatment. The End-of-Treatment (EOT) visit is completed 4 weeks after the patient's last injection.

[0870] Dosage adjustment :

[0871] During Phase 2, researchers may, based on clinical judgment, adjust the dosage of Formulation 1 starting from the 12th visit (week 12) (to one of the dosages provided in the protocol). Dosage adjustments are recorded in the case report form.

[0872] Procedures for potential post-injection delirium / sedation syndrome

[0873] During Phase 1 and Phase 2, patients should remain in the clinic for at least 3 hours for observation following IMP administration. In the event of a potential PDSS event, vital signs and blood samples (for patients who consent to biomarker collection) should be collected immediately upon suspicion of a potential PDSS event to determine plasma drug concentrations and biomarkers. If a suspected PDSS event is reported, toxicological blood tests should be performed on the patient immediately upon suspicion of a PDSS event. Additional pharmacokinetic samples should be collected at 3, 6, 12, and 24 hours after the event and at 24 hours after resolution, or as feasible. Additional biomarker samples should be collected at 24 hours after the event and at 24 hours after resolution, or as feasible. Vital signs should be measured concurrently with the collection of additional pharmacokinetic samples.

[0874] The total duration of patient participation in this study includes screening for up to 8 days, during which time patients will take olanzapine orally for 2 consecutive days (to determine tolerability), treatment with formulation 1 or placebo for 8 weeks (Phase 1 [Acute Treatment Period]), treatment with formulation 1 for up to 48 weeks (Phase 2 [Long-Term Safety Period]), and 4 weeks of FU.

[0875] The end of the study was defined as the last visit to the last patient.

[0876] Research diagram as follows Figure 9 As shown.

[0877] efficacy assessment

[0878] The primary efficacy endpoint of the study was the change in the total PANSS score from baseline to week 8.

[0879] The key secondary efficacy endpoint was the change in the Clinical Global Impression-Disease Severity Scale (CGI-S) score from baseline to week 8.

[0880] The key secondary efficacy endpoint was the change in the Personal and Social Functioning Scale (PSP) from baseline to week 8.

[0881] Other secondary efficacy and safety endpoints that need to be measured include:

[0882] • Changes in the total PANSS score from baseline to weeks 1, 2, and 4;

[0883] • Change in Clinical Global Impression-I (CGI-I) score compared to baseline

[0884] • Change in Patient Overall Impression-I (PGI-I) score compared to baseline

[0885] • Change in Schizophrenia Quality of Life Scale (SQLS) score compared to baseline

[0886] • Report the number of participants using at least one concomitant medication

[0887] • Number of participants who suspended the trial

[0888] • Number of participants who discontinued the trial due to adverse events

[0889] • Change in total score of the Abnormal Involuntary Movement Scale (AIMS) compared to baseline

[0890] • Change in mean score of the Simpson-Angus Scale (SAS) compared to baseline

[0891] • Change in total score of Barnes Inability to Sit (BARS) compared to baseline

[0892] • The number of participants with any suicidal ideation or behavior, according to the Columbia Suicide Severity Rating Scale (C-SRS).

[0893] • Change in Calgary Schizophrenia Depression Scale (CDSS) from baseline

[0894] Other assessments may include the DSM-5 Structured Clinical Interview Clinical Trial Version (SCID-5-CT) or the EuroQol Level 3 five-dimensional questionnaire.

[0895] For a description of the Positive and Negative Syndrome Scale (PANSS), see paragraph

[0418] above. Audio recordings of PANSS assessments may be made (and will be reviewed as necessary to monitor the quality of the scores).

[0896] PANSS is administered by the investigator / trained rater at screening and at all time points specified in Tables 6.4 and 6.5.

[0897] Table 6.4: Phase 1

[0898]

[0899] Table 6.5: Phase 2

[0900]

[0901] For a description of the Clinical Global Impression-I (CGI-I) scale, see paragraph

[0420] above. The CGI-I is administered by the investigator / trained rater at the time points specified in Tables 6.4 and 6.5. The CGI-I during Phase 1 and Phase 2 is related to the CGI-S score at the baseline visit (Visit 2 of Phase 1).

[0902] The Clinical Global Impression-Disease Severity (CGI-S) scale is described in paragraph

[0422] above. Investigators / trained raters completed the CGI-S at the time points specified in Tables 6.4 and 6.5.

[0903] The Patient Overall Impression-Improvement (PGI-I) scale is as described in paragraph

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

[0904] The Personal and Social Performance (PSP) scale is used to manage patients at the time points specified in Tables 6.4 and 6.5. It is a tool for clinician assessment, as described in paragraph

[0426] .

[0905] Other assessments

[0906] DSM-5 Structured Clinical Interview Clinical Trial Version (SCID-5-CT)

[0907] SCID-5-CT is a semi-structured interview guideline for the diagnosis of DSM-5. It is administered by clinicians familiar with the DSM-5 classification and diagnostic criteria or by trained mental health professionals during screening.

[0908] SCID-5-CT can be used to ensure a systematic review of the primary diagnoses of DSM-5, ensure that all study patients meet the inclusion and exclusion criteria of DSM-5, and characterize the study population based on current and previous psychiatric diagnoses.

[0909] Quality of life scale

[0910] The quality of life scale used in this study includes the following two indicators.

[0911] The Schizophrenia Quality of Life Scale (SQLS) Revision 4 (see paragraph

[0428] ) was administered at the time points specified in Tables 6.4 and 6.5 to record quality of life.

[0912] The Level 3 EuroQol five-dimensional questionnaire (EQ-5D-3L; see paragraph

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

[0913] Security assessment

[0914] In this study, qualified investigators assessed safety 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 body temperature), weight, laboratory tests, ECG, concomitant medications, all-cause discontinuation time, all-cause discontinuation rate and discontinuation rate due to adverse events (tolerance), and rating scales (including AIMS, BARS, SAS, C-SRS and CDSS).

[0915] Post-injection delirium / sedation syndrome monitoring

[0916] Patients receiving formulation 1 (based on the time points in Tables 6.4 and 6.5) will be clinically observed for at least 3 hours after administration to monitor for symptoms of potential PDSS events.

[0917] If a potential PDSS event is suspected, the Medical Management Department (MM) and the sponsor should be contacted immediately. Once a potential PDSS event is suspected, vital signs and blood samples should be collected as soon as possible to determine plasma drug concentrations and biomarkers (for patients who consent to biomarker collection). If a suspected PDSS event is reported, toxicological blood tests should be performed on the patient immediately after PDSS is suspected.

[0918] Additional pharmacokinetic samples should be collected at 3, 6, 12, and 24 hours after the event and at 24 hours after its resolution, or as practicable. Additional biomarker samples should be collected at 24 hours after the event and at 24 hours after its resolution, or as practicable. Vital signs should be measured concurrently with the collection of additional pharmacokinetic samples.

[0919] Any potential PDSS event needs to be evaluated by researchers according to the following criteria.

[0920] If a potential PDSS event occurs, IDMC will review the case and determine whether it meets all five criteria of the following PDSS clinical diagnostic definition:

[0921] 1. One or both of the conditions listed in (a) and (b):

[0922] a. At least one of the following three symptom clusters is a sign or symptom consistent with olanzapine overdose, and more than one of them is at least moderately severe:

[0923] - Seizure

[0924] -Sedation / Sleepiness

[0925] - Delirium / Confusion / Disorientation / Other cognitive impairments

[0926] - Articulation disorders / other speech disorders

[0927] - Ataxia / other movement disorders

[0928] -Extrapyramidal symptoms

[0929] -Excited / Irritable / Anxious / Uneasy

[0930] - Dizziness / weakness / general malaise

[0931] b. Any of the following signs and symptoms that lead to the patient's:

[0932] - Unable to wake up, unconscious, comatose or comatose

[0933] 2. The condition appeared within 24 hours after administration of formulation 1.

[0934] 3. This situation cannot be explained by a significant increase (i.e., overdose) in the dose of formulation 1, the initiation or addition of oral olanzapine (or other forms of olanzapine) or other sedatives.

[0935] 4. Underlying medical conditions have been ruled out, including concomitant medications or drug abuse.

[0936] 5. Olanzapine plasma levels >100 ng / mL within ≤3 hours after injection.

[0937] Example 7

[0938] In vitro release from human plasma

[0939] Commercially available human plasma was placed in a well-sealed conical flask and placed on a rail-shaking water bath. Throughout the test, the temperature was maintained at 37°C and the rotation speed was set to 100 RPM. Formulation 1 and ZYPREXA Reconstitute according to the instructions and inject directly into human plasma. At designated time points during the 72-hour period, aliquot the sample solution from the conical flask and immediately filter through a 0.45 μm syringe filter. Replace the sampled plasma volume with the same volume of fresh plasma and incubate at 37°C to maintain a constant total plasma volume in the flask. Quantify olanzapine in the collected in vitro released samples using LC-MS / MS with an ESI ion source. Studies have shown that the PDSS risk is minimized using Formulation 1 technology. See [link to documentation]. Figure 10 .

[0940] The invention will now be further described with reference to the following terms:

[0941] 1. A pharmaceutical composition for administration via subcutaneous injection, wherein the composition comprises:

[0942] 20% to 45% (w / w) of olanzapine;

[0943] 35% to 65% (w / w) of an organic solvent, said organic solvent comprising dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP) or combinations thereof;

[0944] A diblock copolymer comprising polylactic acid and polyethylene glycol, wherein the number average molecular weight of the diblock copolymer is 6 to 15 kg / mol and comprises 70% to 90% (w / w) polylactic acid by weight; and

[0945] The triblock copolymer comprises polylactic acid and polyethylene glycol, the number average molecular weight of the triblock copolymer being 6 to 19 kg / mol and containing 80% to 90% (w / w) polylactic acid by weight;

[0946] The diblock copolymer and the triblock copolymer together comprise 10% to 25% (w / w) of the composition by weight.

[0947] 2. The pharmaceutical composition according to Clause 1, wherein the composition comprises 20% to 24% (w / w) olanzapine by weight.

[0948] 3. The pharmaceutical composition according to Clause 2, wherein the composition comprises 20.5% (w / w) olanzapine by weight.

[0949] 4. The pharmaceutical composition according to Clause 2, wherein the composition comprises 22% (w / w) olanzapine by weight.

[0950] 5. The pharmaceutical composition according to Clause 2, wherein the composition comprises 23.5% (w / w) olanzapine by weight.

[0951] 6. The pharmaceutical composition according to Clause 1, wherein the composition comprises 22% to 34% (w / w) olanzapine by weight.

[0952] 7. The pharmaceutical composition according to Clause 6, wherein the composition comprises 30% to 32% (w / w) olanzapine by weight.

[0953] 8. The pharmaceutical composition according to Clause 6, wherein the composition comprises 26.5% (w / w) olanzapine by weight.

[0954] 9. The pharmaceutical composition according to Clause 6, wherein the composition comprises 29.0% (w / w) olanzapine by weight.

[0955] 10. The pharmaceutical composition according to Clause 6 or Clause 7, wherein the composition comprises 30.5% (w / w) olanzapine by weight.

[0956] 11. The pharmaceutical composition according to Clause 6 or Clause 7, wherein the composition comprises 32.0% (w / w) olanzapine by weight.

[0957] 12. The pharmaceutical composition according to Clause 6, wherein the composition comprises 33.5% (w / w) olanzapine by weight.

[0958] 13. The pharmaceutical composition according to Clause 1, wherein the composition comprises 40% to 45% (w / w) olanzapine by weight.

[0959] 14. The pharmaceutical composition according to Clause 13, wherein the composition comprises 40.7% (w / w) olanzapine by weight.

[0960] 15. The pharmaceutical composition according to Clause 13, wherein the composition comprises 42.0% (w / w) olanzapine by weight.

[0961] 16. The pharmaceutical composition according to Clause 13, wherein the composition comprises 43.5% (w / w) olanzapine by weight.

[0962] 17. The pharmaceutical composition according to any one of the preceding clauses, wherein the organic solvent is dimethyl sulfoxide (DMSO).

[0963] 18. The pharmaceutical composition according to any one of clauses 1 to 16, wherein the organic solvent is N-methyl-2-pyrrolidone (NMP).

[0964] 19. The pharmaceutical composition according to any one of clauses 1 to 16, wherein the organic solvent is a mixture of dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP).

[0965] 20. The pharmaceutical composition according to any one of the preceding clauses, wherein the composition comprises 35% to 40% (w / w) of an organic solvent by weight.

[0966] 21. The pharmaceutical composition according to Clause 20, wherein the composition comprises 35% (w / w) of an organic solvent by weight.

[0967] 22. The pharmaceutical composition according to Clause 20, wherein the composition comprises 37.1% (w / w) of an organic solvent by weight.

[0968] 23. The pharmaceutical composition according to Clause 20, wherein the composition comprises 38% (w / w) of an organic solvent by weight.

[0969] 24. The pharmaceutical composition according to any one of clauses 1 to 19, wherein the composition comprises 50% to 55% (w / w) of an organic solvent by weight.

[0970] 25. The pharmaceutical composition according to Clause 24, wherein the composition comprises 50% (w / w) of an organic solvent by weight.

[0971] 26. The pharmaceutical composition according to Clause 24, wherein the composition comprises 52% (w / w) of an organic solvent by weight.

[0972] 27. The pharmaceutical composition according to Clause 24, wherein the composition comprises 53.5% (w / w) of an organic solvent by weight.

[0973] 28. The pharmaceutical composition according to Clause 24, wherein the composition comprises 54% (w / w) of an organic solvent by weight.

[0974] 29. The pharmaceutical composition according to Clause 24, wherein the composition comprises 55% (w / w) of an organic solvent by weight.

[0975] 30. The pharmaceutical composition according to any one of clauses 1 to 19, wherein the composition comprises 58% to 62% (w / w) of an organic solvent by weight.

[0976] 31. The pharmaceutical composition according to Clause 30, wherein the composition comprises 58.5% (w / w) of an organic solvent by weight.

[0977] 32. The pharmaceutical composition according to Clause 30, wherein the composition comprises 60% (w / w) of an organic solvent by weight.

[0978] 33. The pharmaceutical composition according to Clause 30, wherein the composition comprises 61.5% (w / w) of an organic solvent by weight.

[0979] 34. The pharmaceutical composition according to any one of the preceding clauses, wherein the diblock copolymer comprises 75% to 84% (w / w) polylactic acid by weight.

[0980] 35. The pharmaceutical composition according to Clause 34, wherein the diblock copolymer comprises 76% (w / w) polylactic acid by weight.

[0981] 36. The pharmaceutical composition according to Clause 34, wherein the diblock copolymer comprises 80% (w / w) polylactic acid by weight.

[0982] 37. The pharmaceutical composition according to Clause 34, wherein the diblock copolymer comprises 82% (w / w) polylactic acid by weight.

[0983] 38. The pharmaceutical composition according to any one of clauses 1 to 37, wherein the diblock copolymer comprises 73% to 77% (w / w) polylactic acid by weight.

[0984] 39. The pharmaceutical composition according to Clause 38, wherein the diblock copolymer comprises 73% (w / w) polylactic acid by weight.

[0985] 40. The pharmaceutical composition according to Clause 38, wherein the diblock copolymer comprises 75% (w / w) polylactic acid by weight.

[0986] 41. The pharmaceutical composition according to Clause 38, wherein the diblock copolymer comprises 77% (w / w) polylactic acid by weight.

[0987] 42. The pharmaceutical composition according to any one of clauses 1 to 33, wherein the diblock copolymer comprises 84% ​​to 88% (w / w) polylactic acid by weight.

[0988] 43. The pharmaceutical composition according to Clause 42, wherein the diblock copolymer comprises 84% ​​(w / w) polylactic acid by weight.

[0989] 44. The pharmaceutical composition according to Clause 42, wherein the diblock copolymer comprises 86% (w / w) polylactic acid by weight.

[0990] 45. The pharmaceutical composition according to Clause 42, wherein the diblock copolymer comprises 88% (w / w) polylactic acid by weight.

[0991] 46. ​​The pharmaceutical composition according to any one of the preceding clauses, wherein the number average molecular weight of the diblock copolymer is 6.5 to 13.5 kg / mol, optionally 7.0 to 13.5 kg / mol.

[0992] 47. The pharmaceutical composition according to any one of the preceding clauses, wherein the number-average molecular weight of the diblock copolymer is about 9 kg / mol.

[0993] 48. The pharmaceutical composition according to any one of clauses 1 to 47, wherein the number-average molecular weight of the diblock copolymer is about 10 kg / mol.

[0994] 49. The pharmaceutical composition according to any one of clauses 1 to 47, wherein the number-average molecular weight of the diblock copolymer is about 11 kg / mol.

[0995] 50. The pharmaceutical composition according to any one of clauses 1 to 49, wherein the weight ratio of the diblock copolymer to the triblock copolymer is 6:1 to 2:1, optionally about 4:1.

[0996] 51. The pharmaceutical composition according to any one of the preceding clauses, wherein the composition comprises 10% to 17% (w / w) of a diblock copolymer by weight.

[0997] 52. The pharmaceutical composition according to any one of Clause 51, wherein the composition comprises 10% to 15% (w / w) of a diblock copolymer by weight.

[0998] 53. The pharmaceutical composition according to Clause 51, wherein the composition comprises 12.2% (w / w) of a diblock copolymer by weight.

[0999] 54. The pharmaceutical composition according to Clause 51, wherein the composition comprises 12.8% (w / w) of a diblock copolymer by weight.

[1000] 55. The pharmaceutical composition according to Clause 51, wherein the composition comprises 13.2% (w / w) of a diblock copolymer by weight.

[1001] 56. The pharmaceutical composition according to Clause 51, wherein the composition comprises 13.6% (w / w) of a diblock copolymer by weight.

[1002] 57. The pharmaceutical composition according to Clause 51, wherein the composition comprises 14.0% (w / w) of a diblock copolymer by weight.

[1003] 58. The pharmaceutical composition according to Clause 51, wherein the composition comprises 14.4% (w / w) of a diblock copolymer by weight.

[1004] 59. The pharmaceutical composition according to any one of the preceding clauses, wherein the triblock copolymer comprises 85% to 88% (w / w) polylactic acid by weight.

[1005] 60. The pharmaceutical composition according to Clause 59, wherein the triblock copolymer comprises 87% (w / w) polylactic acid by weight.

[1006] 61. The pharmaceutical composition according to Clause 59, wherein the triblock copolymer comprises 85% (w / w) polylactic acid by weight.

[1007] 62. The pharmaceutical composition according to any one of the preceding clauses, wherein the number average molecular weight of the triblock copolymer is 6.0 to 13.0 kg / mol, optionally 7.0 to 12.0 kg / mol.

[1008] 63. The pharmaceutical composition according to any one of the preceding clauses, wherein the number-average molecular weight of the triblock copolymer is about 9.5 kg / mol.

[1009] 64. The pharmaceutical composition according to any one of clauses 1 to 62, wherein the number-average molecular weight of the triblock copolymer is about 14 kg / mol.

[1010] 65. The pharmaceutical composition according to any one of the preceding clauses, wherein the composition comprises 3% to 5% (w / w) of a triblock copolymer by weight.

[1011] 66. The pharmaceutical composition according to any one of the preceding clauses, wherein the composition comprises 3% to 4% (w / w) of a triblock copolymer by weight.

[1012] 67. The pharmaceutical composition according to any one of the preceding clauses, wherein the composition comprises 3.0% (w / w) of a triblock copolymer by weight.

[1013] 68. The pharmaceutical composition according to any one of clauses 1 to 66, wherein the composition comprises 3.2% (w / w) of a triblock copolymer by weight.

[1014] 69. The pharmaceutical composition according to any one of clauses 1 to 66, wherein the composition comprises 3.5% (w / w) of a triblock copolymer by weight.

[1015] 70. The pharmaceutical composition according to any one of clauses 1 to 66, wherein the composition comprises 3.6% (w / w) of a triblock copolymer by weight.

[1016] 71. The pharmaceutical composition according to any one of clauses 1 to 66, wherein the composition comprises 3.7% (w / w) of a triblock copolymer by weight.

[1017] 72. The pharmaceutical composition according to any one of clauses 1 to 65, wherein the composition comprises 4.5% (w / w) of a triblock copolymer by weight.

[1018] 73. The pharmaceutical composition according to any one of the preceding clauses, wherein the diblock copolymer and the triblock copolymer together constitute 10% to 20% (w / w), optionally 14% to 20% (w / w), of the composition by weight.

[1019] 74. The pharmaceutical composition according to Clause 73, wherein the diblock copolymer and the triblock copolymer together constitute 12% (w / w) of the composition by weight.

[1020] 75. The pharmaceutical composition according to Clause 73, wherein the diblock copolymer and the triblock copolymer together constitute 14% (w / w) of the composition by weight.

[1021] 76. The pharmaceutical composition according to Clause 73, wherein the diblock copolymer and the triblock copolymer together constitute 16% (w / w) of the composition by weight.

[1022] 77. The pharmaceutical composition according to Clause 73, wherein the diblock copolymer and the triblock copolymer together constitute 18% (w / w) of the composition by weight.

[1023] 78. The pharmaceutical composition according to Clause 73, wherein the diblock copolymer and the triblock copolymer together constitute 20% (w / w) of the composition by weight.

[1024] 79. The pharmaceutical composition according to any one of clauses 1 to 72, wherein the diblock copolymer and the triblock copolymer together constitute 22% (w / w) of the composition by weight.

[1025] 80. The pharmaceutical composition according to any one of the preceding clauses, wherein each gram of the composition contains about 220 to about 340 mg of olanzapine.

[1026] 81. The pharmaceutical composition according to any one of the preceding clauses, wherein each gram of the composition contains about 265 mg of olanzapine.

[1027] 82. The pharmaceutical composition according to any one of clauses 1 to 80, wherein each gram of the composition contains about 290 mg of olanzapine.

[1028] 83. The pharmaceutical composition according to any one of clauses 1 to 80, wherein each gram of the composition contains about 305 mg of olanzapine.

[1029] 84. The pharmaceutical composition according to any one of clauses 1 to 80, wherein each gram of the composition contains about 320 mg of olanzapine.

[1030] 85. The pharmaceutical composition according to any one of clauses 1 to 80, wherein each gram of the composition contains about 335 mg of olanzapine.

[1031] 86. A reagent kit comprising:

[1032] A container containing approximately 318 to approximately 950 mg of olanzapine; and

[1033] A container containing about 0.73 to about 2.5 g of a mixture, said mixture being a mixture of an organic solvent, a diblock copolymer, and a triblock copolymer, said organic solvent being dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or a combination thereof, said diblock copolymer comprising polylactic acid and polyethylene glycol, said diblock copolymer having a number average molecular weight of 6 to 15 kg / mol and containing 70% to 90% (w / w) polylactic acid by weight, said triblock copolymer comprising polylactic acid and polyethylene glycol, said triblock copolymer having a number average molecular weight of 6 to 19 kg / mol and containing 80% to 90% (w / w) polylactic acid by weight.

[1034] 87. The kit according to Clause 86, wherein the container containing olanzapine contains approximately 318 mg of olanzapine.

[1035] 88. The kit according to Clause 86, wherein the container containing olanzapine contains approximately 575 mg of olanzapine.

[1036] 89. The kit according to Clause 86, wherein the container containing olanzapine contains approximately 600 mg of olanzapine.

[1037] 90. The kit according to Clause 86, wherein the container containing olanzapine contains approximately 710 mg of olanzapine.

[1038] 91. The kit according to Clause 86, wherein the container containing olanzapine contains approximately 815 mg of olanzapine.

[1039] 92. The kit according to Clause 86, wherein the container containing olanzapine contains approximately 885 mg of olanzapine.

[1040] 93. The kit according to any one of clauses 86 to 92, wherein the container containing the mixture of the organic solvent, the diblock copolymer and the triblock copolymer contains about 0.73 g of the mixture.

[1041] 94. The kit according to any one of clauses 86 to 92, wherein the container containing the mixture of the organic solvent, the diblock copolymer and the triblock copolymer contains about 1.5 g of the mixture.

[1042] 95. The kit according to any one of clauses 86 to 92, wherein the container containing the mixture of the organic solvent, the diblock copolymer and the triblock copolymer contains about 1.7 g of the mixture.

[1043] 96. The kit according to any one of clauses 86 to 92, wherein the container containing the mixture of the organic solvent, the diblock copolymer and the triblock copolymer contains about 2.0 g of the mixture.

[1044] 97. The kit according to any one of clauses 86 to 96, wherein the container containing olanzapine is a glass vial.

[1045] 98. The kit according to any one of claims 86 to 97, wherein the container comprising an organic solvent, a diblock copolymer comprising polylactic acid and polyethylene glycol, and a triblock copolymer comprising polylactic acid and polyethylene glycol is a syringe.

[1046] 99. The kit according to Clause 98, wherein the kit further includes a needle capable of being attached to a syringe.

[1047] 100. The kit according to Clause 99, wherein the needle is a 21-gauge needle.

[1048] 101. The kit according to Clause 99 or Clause 100, wherein the needle is 5 / 8 inch in length.

[1049] 102. The kit according to any one of clauses 86 to 101, wherein the kit is used to prepare the composition according to any one of clauses 1 to 84.

[1050] 103. A method for preparing the composition of any one of clauses 1 to 85, the method comprising: adding an organic solvent, a mixture of a diblock copolymer comprising polylactic acid and polyethylene glycol and a triblock copolymer comprising polylactic acid and polyethylene glycol to solid olanzapine.

[1051] 104. The method according to Clause 103, wherein the organic solvent, a mixture of a diblock copolymer comprising polylactic acid and polyethylene glycol, and a triblock copolymer comprising polylactic acid and polyethylene glycol are added to a vial of solid olanzapine via a syringe.

[1052] 105. The kit according to any one of clauses 86 to 102 or the method according to clauses 103 or 104, wherein the particle size distribution of olanzapine is 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 about 0.44 g / mL, or any combination thereof.

[1053] 106. The kit or method according to Clause 105, wherein the particle size distribution of olanzapine is characterized by D(90) being from 20 μm to about 37 μm.

[1054] 107. The kit or method according to Clause 106, wherein the particle size distribution of olanzapine is characterized by D(90) being about 24 μm to about 35 μm.

[1055] 108. The kit or method according to Clause 106, wherein the particle size distribution of olanzapine is characterized by D(3,2) being about 5.5 μm to about 7.5 μm.

[1056] 109. The kit or method according to Clause 106, wherein the particle size distribution of olanzapine is characterized by D(3,2) being about 5.8 μm to about 7.0 μm.

[1057] 110. The kit or method according to any one of clauses 105 to 109, wherein the olanzapine tap density is about 0.35 g / mL to about 0.44 g / mL.

[1058] 111. The kit or method according to Clause 105, wherein the particle size distribution of olanzapine is characterized by D(90) being about 20 μm to about 37 μm and D(3,2) being about 5.5 μm to about 7.5 μm.

[1059] 112. The kit or method according to Clause 105, wherein the particle size distribution of olanzapine is 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.

[1060] 113. The kit or method according to Clause 105, wherein the particle size distribution of olanzapine is 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.

[1061] 114. The kit or method according to Clause 105, wherein the particle size distribution of olanzapine is 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 a tap density of about 0.35 g / mL to about 0.44 g / mL.

[1062] 115. The kit or method according to any one of clauses 86 to 114, wherein the olanzapine is polymorph II.

[1063] 116. A method of administering olanzapine to a patient, the method comprising: subcutaneously injecting the patient with any one of the compositions described in clauses 1 to 85.

[1064] 117. A method for treating a disease or condition in a patient in need, wherein the disease or condition is schizophrenia, schizoaffective disorder, bipolar disorder, or depression, the method comprising: subcutaneously administering the composition of any one of clauses 1 to 85 to the patient.

[1065] 118. The method according to Clause 117, wherein the disease or condition is schizophrenia.

[1066] 119. The method according to Clause 117, wherein the disease or condition is schizoaffective disorder.

[1067] 120. The method according to Clause 117, wherein the disease or condition is bipolar disorder.

[1068] 121. The method according to Clause 117, wherein the disease or condition is depression.

[1069] 122. The method according to any one of clauses 116 to 121, wherein the patient has a total PANSS score of 80 to 120 (inclusive) at baseline (before randomization) and scores ≥4 on at least two of the following four items of the PANSS positive subscale: hallucinatory behavior, delusions, conceptual confusion or suspicion / persecution.

[1070] 123. The method according to any one of clauses 116 to 122, wherein the subcutaneously administered composition comprises 300 to 600 mg of olanzapine.

[1071] 124. The method according to Clause 123, wherein the subcutaneously administered composition comprises 300 to 350 mg, optionally 310 to 320 mg, of olanzapine.

[1072] 125. The method according to Clause 124, wherein the subcutaneously administered composition comprises about 318 mg of olanzapine.

[1073] 126. The method according to Clause 123, wherein the subcutaneously administered composition comprises 400 to 450 mg, optionally 415 to 435 mg, of olanzapine.

[1074] 127. The method according to Clause 126, wherein the subcutaneously administered composition comprises about 425 mg of olanzapine.

[1075] 128. The method according to Clause 123, wherein the subcutaneously administered composition comprises 500 to 550 mg, optionally 520 to 540 mg, of olanzapine.

[1076] 129. The method according to Clause 128, wherein the subcutaneously administered composition comprises about 531 mg of olanzapine.

[1077] 130. The method according to any one of clauses 116 to 129, wherein the volume of the subcutaneously administered composition is about 0.5 to 1.8 mL.

[1078] 131. The method according to any one of clauses 116 to 130, wherein the volume of the subcutaneously administered composition is about 0.9 to 1.5 mL.

[1079] 132. The method according to Clause 131, wherein the volume of the composition is about 0.9 mL.

[1080] 133. The method according to Clause 131, wherein the volume of the composition is about 1.2 mL.

[1081] 134. The method according to Clause 131, wherein the volume of the composition is about 1.5 mL.

[1082] 135. The method according to any one of clauses 116 to 134, wherein the composition is applied once a month.

[1083] 136. The method according to any one of clauses 116 to 135, wherein the composition is applied once every 28 ± 5 days.

[1084] 137. The method according to any one of clauses 116 to 136, wherein the composition is applied once every 28 ± 3 days.

[1085] 138. The method according to any one of clauses 116 to 137, wherein the composition is applied once every 28 days.

[1086] 139. The method according to any one of clauses 116 to 138, wherein the AUC after a single subcutaneous dose of the composition is... ∞ AUC of oral olanzapine calculated over 28 days tau The dose normalization ratios ranged from 0.97 to 1.29.

[1087] 140. The method according to any one of clauses 116 to 139, wherein the AUC after a single subcutaneous dose of the composition is... ∞ AUC of oral olanzapine calculated over 28 days tau The dose normalization ratio is approximately 1.1.

[1088] 141. The method according to any one of clauses 116 to 140, wherein administering the composition to a patient via subcutaneous injection results in the patient having olanzapine plasma C10 levels within 11 to 14 days after administration. 最大 .

[1089] 142. The method according to any one of clauses 116 to 141, wherein administering the composition to the patient via subcutaneous injection results in the patient having increased olanzapine plasma C levels after the first subcutaneous injection. 最大 Less than 100 ng / mL.

[1090] 143. The method according to any one of clauses 116 to 142, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after a second subcutaneous injection. 最大 Less than 100 ng / mL.

[1091] 144. The method according to any one of clauses 116 to 143, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after the first subcutaneous injection. 最大 Less than 90 ng / mL.

[1092] 145. The method according to any one of clauses 116 to 144, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after a second subcutaneous injection. 最大 Less than 90 ng / mL.

[1093] 146. The method according to any one of clauses 116 to 145, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after the first subcutaneous injection. 最大 Less than 80 ng / mL.

[1094] 147. The method according to any one of clauses 115 to 146, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after a second subcutaneous injection. 最大 Less than 80 ng / mL.

[1095] 148. The method according to any one of clauses 116 to 147, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after the first subcutaneous injection. 最大 Less than 70 ng / mL.

[1096] 149. The method according to any one of clauses 116 to 148, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after a second subcutaneous injection. 最大 Less than 70 ng / mL.

[1097] 150. The method according to any one of clauses 116 to 149, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after the first subcutaneous injection. 最大 Less than 60 ng / mL.

[1098] 151. The method according to any one of clauses 116 to 150, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after a second subcutaneous injection. 最大 Less than 60 ng / mL.

[1099] 152. The method according to any one of clauses 116 to 151, wherein administering the composition to the patient via subcutaneous injection results in the patient having increased olanzapine plasma C levels after the first subcutaneous injection. 最大 Less than 50 ng / mL.

[1100] 153. The method according to any one of clauses 116 to 152, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after a second subcutaneous injection. 最大 Less than 50 ng / mL.

[1101] 154. The method according to any one of clauses 116 to 153, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after the first subcutaneous injection. 最大 Less than 40 ng / mL.

[1102] 155. The method according to any one of clauses 116 to 154, wherein administering the composition to the patient via subcutaneous injection results in the patient having elevated olanzapine plasma C levels after a second subcutaneous injection. 最大 Less than 40 ng / mL.

[1103] 156. The method according to any one of clauses 116 to 155, wherein administering the composition to a patient via subcutaneous injection results in a plasma concentration of olanzapine of at least 10 ng / mL in the patient for at least 21 days out of 30 days following the subcutaneous injection.

[1104] 157. The method according to any one of clauses 116 to 156, wherein administering the composition to a patient via subcutaneous injection results in a plasma concentration of olanzapine of at least 20 ng / mL in the patient for at least 21 days out of 30 days following the subcutaneous injection.

[1105] 158. The method according to any one of clauses 116 to 157, wherein administering the composition to a patient via subcutaneous injection results in a plasma concentration of olanzapine of at least 10 ng / mL in the patient at least 30 days after the subcutaneous injection.

[1106] 159. The method according to any one of clauses 116 to 158, wherein administering the composition to a patient via subcutaneous injection results in a plasma concentration of olanzapine of at least 20 ng / mL in the patient at least 30 days after the subcutaneous injection.

[1107] 160. A method of treating a patient with olanzapine, the method comprising:

[1108] a) Provide a kit as described in any one of clauses 86 to 102 or 105 to 115;

[1109] b) Remove the mixture from the container containing the mixture of organic solvent, diblock copolymer, and triblock copolymer in the kit;

[1110] c) Add the mixture from b) to the container containing olanzapine in the kit, then mix to form a subcutaneous olanzapine drug composition; and

[1111] d) Subcutaneously administer the olanzapine subcutaneous pharmaceutical composition to patients requiring olanzapine treatment;

[1112] The treatment lasts effectively for about a month.

[1113] 161. The method according to any one of clauses 116 to 160, wherein the treatment results in the patient scoring lower on the Positive and Negative Syndrome Scale (PANSS) than the patient scored before receiving the treatment.

[1114] 162. The method according to any one of clauses 116 to 161, wherein the treatment results in the patient scoring lower on the Clinical Global Impression-Improvement (CGI-I) scale than the patient scored before receiving the treatment.

[1115] 163. The method according to any one of clauses 116 to 162, wherein the treatment results in the patient scoring lower on the Clinical Global Impression-Disease Severity Scale (CGI-S) than the patient scored before receiving the treatment.

[1116] 164. The method according to any one of clauses 116 to 163, wherein the treatment results in the patient scoring lower in Patient Overall Impression-Improvement (PGI-I) than the patient scored before receiving treatment.

[1117] 165. The method according to any one of clauses 116 to 164, wherein the treatment results in the patient scoring higher on the Personal and Social Functioning Scale (PSP) than the patient scored before receiving the treatment.

[1118] 166. The method according to any one of clauses 116 to 165, wherein the treatment results in the patient scoring lower on the Schizophrenia Quality of Life Scale (SQLS) revision 4 than the patient scored before receiving treatment.

[1119] 167. The method according to any one of clauses 116 to 166, wherein the treatment results in the patient scoring lower on the Level 3 EuroQol Five Dimensions Questionnaire (EQ-5D-3L) than the patient scored before receiving the treatment.

[1120] 168. The method according to any one of clauses 116 to 167, wherein the treatment results in a D2 receptor occupancy rate of 60% to 80%, optionally 65% ​​to 80%, optionally 65% ​​to 70%, as measured by positron emission tomography (PET).

[1121] 169. A method of switching a patient from daily oral olanzapine treatment to treatment comprising a composition administered once monthly according to any one of clauses 1 to 85, the method comprising: i) administering the last oral dose of daily oral olanzapine treatment, after which no further oral olanzapine treatment is administered; administering the composition of any one of clauses 1 to 85 subcutaneously to the patient the following day; thereby switching the subject from daily oral olanzapine treatment to treatment comprising a composition administered according to any one of clauses 1 to 84.

[1122] 170. A method for switching a patient from a long-acting intramuscular olanzapine formulation to the composition of any one of clauses 1 to 85 without supplemental oral olanzapine treatment, wherein the method comprises: administering a final dose of the long-acting intramuscular olanzapine formulation; and at the next administration: optionally, one month after the previous dose when the previous dose was a monthly dose, administering the composition of any one of clauses 1 to 85 subcutaneously, or optionally, two weeks after the previous dose when the previous dose was a bi-weekly dose; wherein the method is performed without administering supplemental oral olanzapine treatment to the patient.

[1123] 171. The pharmaceutical composition of any one of the clauses 1 to 85 is used in a pharmaceutical product.

[1124] 172. The pharmaceutical composition of any one of Clauses 1 to 85 is used in the method of any one of Clauses 116 to 170.

[1125] 173. A method of treating a treatment-naïve olanzapine patient, the method comprising: administering to the patient an oral daily dose of olanzapine of 10 mg to 20 mg for two consecutive days to assess the patient's tolerance to olanzapine, and if the patient tolerates oral olanzapine, subcutaneously injecting the pharmaceutical composition of any one of clauses 1 to 86.

Claims

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

2. The pharmaceutical composition according to claim 1, wherein, The composition contains 20% to 24% (w / w) olanzapine by weight, or 30% to 32% (w / w) olanzapine by weight.

3. The pharmaceutical composition according to claim 1, wherein, The composition contains 22% to 34% (w / w) olanzapine by weight.

4. The pharmaceutical composition according to claim 1, wherein, The organic solvent is dimethyl sulfoxide (DMSO) or N-methyl-2-pyrrolidone (NMP) or a mixture thereof.

5. The pharmaceutical composition according to claim 1, wherein, The composition comprises 35% to 40% (w / w) of organic solvent by weight, or 50% to 55% (w / w) of organic solvent by weight, or 58% to 62% (w / w) of organic solvent by weight.

6. The pharmaceutical composition according to claim 1, wherein, The diblock copolymer comprises 75% to 84% (w / w) polylactic acid by weight; and / or The number-average molecular weight of the diblock copolymer is 6.5 to 13.5 kg / mol; and / or The triblock copolymer comprises 85% to 88% (w / w) polylactic acid by weight; and / or The number-average molecular weight of the triblock copolymer is 6.0 to 13.0 kg / mol.

7. The pharmaceutical composition according to claim 1, wherein, The diblock copolymer contains 84% ​​to 88% (w / w) polylactic acid by weight.

8. The pharmaceutical composition according to claim 1, wherein, The composition comprises 10% to 17% (w / w) of a diblock copolymer by weight; and / or The composition comprises 3% to 5% (w / w) of a triblock copolymer; and / or The diblock copolymer and triblock copolymer together constitute 10% to 20% (w / w) of the composition by weight; and / or The weight ratio of the diblock copolymer to the triblock copolymer is 6:1 to 2:

1.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein, The composition contains 220 mg to 340 mg of olanzapine per gram of composition.

10. A reagent kit comprising: The first container contains 318 mg to 950 mg of olanzapine; and A second container containing 0.73 g to 2.5 g of a mixture, said mixture being an organic solvent, a diblock copolymer, and a triblock copolymer, said organic solvent being dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or a combination thereof, said diblock copolymer comprising polylactic acid and polyethylene glycol, said diblock copolymer having a number average molecular weight of 6 to 15 kg / mol and containing 70% to 90% (w / w) polylactic acid by weight, said triblock copolymer comprising polylactic acid and polyethylene glycol, said triblock copolymer having a number average molecular weight of 6 to 19 kg / mol and containing 80% to 90% (w / w) polylactic acid by weight.

11. The kit according to claim 10, wherein, The first container containing olanzapine is a glass vial; and / or The second container containing the mixture is a syringe, the mixture being an organic solvent, a diblock copolymer containing polylactic acid and polyethylene glycol, and a triblock copolymer containing polylactic acid and polyethylene glycol.

12. The kit according to claim 10, wherein, The kit also includes a needle that can be attached to a syringe.

13. The kit according to claim 12, wherein, The needle is a size 21 needle.

14. The kit according to claim 12, wherein, The needle is 16 mm long.

15. A method for preparing the composition according to any one of claims 1 to 9, the method comprising: An organic solvent, a diblock copolymer containing polylactic acid and polyethylene glycol, and a triblock copolymer containing polylactic acid and polyethylene glycol are added to solid olanzapine.

16. The method according to claim 15, wherein, Solid olanzapine was added to a vial using a syringe, consisting of an organic solvent, a diblock copolymer of polylactic acid and polyethylene glycol, and a triblock copolymer of polylactic acid and polyethylene glycol.

17. The method according to claim 15, wherein, The olanzapine is characterized by a particle size distribution of D(90) of 20 μm to 37 μm, a particle size distribution of D(3,2) of 5.5 μm to 7.5 μm, or a tap density of 0.35 g / mL to 0.44 g / mL, or any combination thereof.

18. The kit according to any one of claims 10 to 14, wherein, The olanzapine is characterized by a particle size distribution of D(90) of 20 μm to 37 μm, a particle size distribution of D(3,2) of 5.5 μm to 7.5 μm, or a tap density of 0.35 g / mL to 0.44 g / mL, or any combination thereof.

19. The method according to any one of claims 15 to 17, wherein, The olanzapine in question is polymorph II.

20. The kit according to any one of claims 10 to 14, wherein, The olanzapine in question is polymorph II.

21. Use of the composition of any one of claims 1 to 9 in the preparation of a medicament for treating a disease or condition in a patient in need, said disease or condition being schizophrenia, schizoaffective disorder, bipolar disorder, or depression, said composition being administered to the patient by subcutaneous injection.

22. The use according to claim 21, wherein, The illness or condition referred to is schizophrenia, schizoaffective disorder, bipolar disorder, or depression.

23. The use according to claim 21, wherein, The patients had a total PANSS score of 80 to 120 at baseline prior to randomization and a score ≥4 on at least two of the following four items on the PANSS positive subscale: hallucinatory behavior, delusions, conceptual confusion, or suspicion / persecution.

24. The use according to any one of claims 21 to 23, wherein, The subcutaneously administered composition contains 300 mg to 600 mg of olanzapine; and / or The volume of the composition for subcutaneous application is 0.5 to 1.8 mL.

25. The use according to any one of claims 21 to 23, wherein, The subcutaneously administered composition contains 300 mg to 350 mg of olanzapine.

26. The use according to any one of claims 21 to 23, wherein, The composition is applied once a month or once every 28 days.

27. The use according to any one of claims 21 to 23, wherein, AUC after a single subcutaneous dose of the composition ∞ AUC of oral olanzapine calculated over 28 days tau The dose normalization ratio was 0.97 to 1.29; and / or The composition was administered to patients via subcutaneous injection, resulting in olanzapine-induced plasma C levels in patients within 11 to 14 days after administration. 最大 ; and / or Administering the composition to a patient via subcutaneous injection resulted in a decrease in olanzapine plasma C levels after the first subcutaneous injection. 最大 Less than 100 ng / mL; and / or The administration of the composition to the patient via subcutaneous injection resulted in a decrease in plasma C levels of olanzapine after a second subcutaneous injection. 最大 Less than 100 ng / mL; and / or Subcutaneous administration of the composition to a patient results in an olanzapine plasma concentration of at least 10 ng / mL for at least 21 days out of a 30-day period following the subcutaneous injection; and / or Subcutaneous administration of the composition to a patient results in an olanzapine plasma concentration of at least 10 ng / mL for at least 30 days after the subcutaneous injection.

28. The use according to any one of claims 21 to 23, wherein, The treatment resulted in the patient scoring lower on the Positive and Negative Syndrome Scale (PANSS) than before the treatment; and / or The treatment resulted in the patient scoring lower on the Clinical Global Impression-I (CGI-I) scale than before treatment; and / or The treatment resulted in the patient's score on the Clinical Global Impression-Disease Severity Scale (CGI-S) being lower than the patient's score before treatment; and / or The treatment resulted in the patient's score on Patient Overall Impression-I (PGI-I) being lower than the patient's score before treatment; and / or The treatment resulted in the patient scoring higher on the Personal and Social Functioning Scale (PSP) than before the treatment; and / or The treatment resulted in the patient's score on the Schizophrenia Quality of Life Scale (SQLS) revision 4 being lower than the patient's score before treatment; and / or The treatment resulted in the patient scoring lower on the EuroQol 5D-3L Level 3 questionnaire than before the treatment; and / or The treatment resulted in a D2 receptor occupancy rate of 60% to 80% in the patient, which was measured by positron emission tomography (PET).

29. Use of the composition of any one of claims 1 to 9 in the preparation of a medicament for treating patients treated with daily oral olanzapine, wherein: The patient receives the last dose of daily oral olanzapine treatment, after which no further oral olanzapine treatment will be administered; and The next day, the patient is given a subcutaneous application of the composition according to any one of claims 1 to 9; thereby switching the patient from daily oral olanzapine treatment to treatment including monthly administration of the composition according to any one of claims 1 to 9.

30. Use of the composition of any one of claims 1 to 9 in the preparation of a medicament for treating patients who have been given a long-acting intramuscular olanzapine formulation, wherein: The patient was given the final dose of a long-acting intramuscular olanzapine formulation; and At the next administration, the patient receives a subcutaneous application of the composition of any one of claims 1 to 9, provided that the patient has not received supplemental oral olanzapine treatment.

31. The use according to claim 30, wherein, When the previous dose was once a month, the next administration is one month after the previous dose, or When the previous dose was administered every two weeks, the next administration will be two weeks after the previous dose.

32. Use of the pharmaceutical composition of any one of claims 1 to 9 in the preparation of a medicament for treating olanzapine-naïve patients, said use comprising: Administer 10 mg to 20 mg of olanzapine orally daily to the patient for two consecutive days; assess whether the patient can tolerate the oral daily dose of olanzapine; and administer the pharmaceutical composition of any one of claims 1 to 9 subcutaneously to the patient who is assessed as tolerant to the oral daily dose of olanzapine.

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