Olanzapine compositions and methods of use
Inventors
CARLUER, Mélodie • Ferrand, Maria • Cherniakov, Irina • VALITSKY, Anna Elgart
Assignees
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Publication Number
US-12220418-B2
Publication Date
2025-02-11
Expiration Date
Abstract
The disclosure provides pharmaceutical compositions for subcutaneous administration comprising olanzapine, and organic solvent, and a triblock copolymer, and a diblock copolymer, as well as methods of treating psychiatric diseases and disorders using such compositions.
Core Innovation
The disclosed invention relates to olanzapine-containing pharmaceutical compositions for subcutaneous long-acting depot administration to treat schizophrenia. The compositions comprise a defined mixture of dimethyl sulfoxide (DMSO) and a diblock PLA-PEG copolymer and a triblock PLA-PEG copolymer, with specified weight percentages of olanzapine, DMSO, and the copolymers.
The method involves subcutaneously administering the composition to the abdomen or upper arm once per 28±5 days using 0.9-1.5 mL of the pharmaceutical composition. The subcutaneous injection results in defined olanzapine plasma pharmacokinetic outcomes, including that the olanzapine plasma Cmax occurs within 11-14 days after administration and is less than 100 ng/mL after any subcutaneous injection.
The disclosed outcomes also include a dose-normalized ratio of AUC∞ after any subcutaneous dose relative to AUCτ of oral olanzapine for 28 days between 0.97-1.29, together with sustained olanzapine plasma concentration requirements for at least a defined duration following injection. The patent further links these pharmacokinetic targets to schizophrenia treatment outcomes and safety characterization.
Claims Coverage
The patent contains one independent claim directed to a schizophrenia treatment method with specific composition parameters, dosing schedule and injection sites, and pharmacokinetic exposure outcomes; dependent claims further refine quantitative composition and plasma concentration constraints.
Once-per-28-day subcutaneous schizophrenia treatment with abdominal or upper arm administration
A method of treating schizophrenia comprising subcutaneously administering to the abdomen or upper arm once per 28±5 days 0.9-1.5 mL of a pharmaceutical composition comprising olanzapine.
Specific olanzapine/solvent and PLA-PEG diblock/triblock composition ranges for a long-acting depot
A pharmaceutical composition comprising 30%-32% (w/w) olanzapine, 52%-54% (w/w) dimethyl sulfoxide, 12%-14% (w/w) of a diblock copolymer comprising polylactic acid and polyethylene glycol, and 3%-3.5% (w/w) of a triblock copolymer comprising polylactic acid and polyethylene glycol, wherein the diblock and triblock copolymers together comprise 15%-17.5% (w/w) of the composition.
Pharmacokinetic Cmax timing and threshold after any subcutaneous injection
Administration results in an olanzapine plasma Cmax within 11-14 days after the administration and an olanzapine plasma Cmax of less than 100 ng/mL after any subcutaneous injection.
Dose-normalized AUC∞/AUCτ ratio and sustained olanzapine plasma concentration
Administration results in a dose-normalized ratio of AUC∞ after any subcutaneous dose to AUCτ of oral olanzapine calculated for 28 days between 0.97-1.29, and an olanzapine plasma concentration of at least 10 ng/mL for at least 21 days of the 30 days following any of the subcutaneous injections.
Overall claim coverage centers on an olanzapine long-acting subcutaneous method for schizophrenia using a composition defined by quantitative ranges of olanzapine, dimethyl sulfoxide, and PLA-PEG diblock and triblock copolymers, together with pharmacokinetic constraints including Cmax timing and ceiling, AUC∞/AUCτ ratio versus oral olanzapine, and sustained plasma concentration duration within the 30-day interval.
Stated Advantages
Defined pharmacokinetic exposure characteristics for subcutaneous administration, including Cmax timing, Cmax ceiling, dose-normalized AUC∞/AUCτ ratio versus oral olanzapine, and sustained plasma concentrations over portions of the 30-day period.
Improvement on schizophrenia rating scales including PANSS and CGI-I/CGI-S.
Safety characterization includes injection site reactions and lack of PDSS events.
Documented Applications
Treating schizophrenia in a patient in need thereof using subcutaneous administration to the abdomen or upper arm once per 28±5 days of an olanzapine pharmaceutical composition defined by specified components and proportions.
Clinical/PK evaluation support for subcutaneous extended-release olanzapine over approximately 30 days, including plasma concentration duration thresholds, dopamine D2 receptor occupancy measurement by PET, and assessment of schizophrenia outcomes using PANSS, CGI-I/CGI-S, PGI-I, PSP, SQLS, and EQ-5D-3L.
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