Inhalable dry powder cytidine analogue composition and method of use as a treatment for cancer
Inventors
Belinsky, Steven A. • Kuehl, Philip J. • Badenoch, Aaron • Burke, Michael • Dubose, Devon
Assignees
Lovelace Biomedical Research Institute • Bend Research Inc • Lovelace Respiratory Research Institute
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Publication Number
US-11266599-B2
Publication Date
2022-03-08
Expiration Date
Abstract
An embodiment of the present invention provides for a dry powder pharmaceutical composition suitable for dispersion in an aerosol for inhaled administration to a patient with cancer, the composition comprising: a cytidine analogue including salts, solvates, hydrates, and esters thereof; and a pharmaceutically acceptable excipient together forming the dry powder pharmaceutical composition suitable for dispersion in the aerosol for administration via inhalation to the patient with cancer. Another embodiment provides for a method of making the composition and a further embodiment provides for a method a treating a patient in need thereof with the composition.
Core Innovation
The invention relates to an inhaled, cancer-treatment dry powder pharmaceutical composition suitable for dispersion in an aerosol for inhaled administration to a patient with cancer. The dry powder composition includes a cytidine analogue selected from 5-azacytidine, zebularine, 5-Aza-2′-deoxycitidine, SG-10, or pharmaceutically acceptable salt, solvate, hydrate, or esters thereof. The composition further comprises dimethyl sulfoxide (DMSO) and a pharmaceutically acceptable excipient.
A key aspect of the invention is the aerosol-dispersion performance of the dry powder. The composition suitable for dispersion in the aerosol for administration via inhalation has a mass median aerodynamic diameter (MMAD) of between about 1.0 µm to about 5.0 µm and a geometric standard deviation (GSD) of emitted particle size distribution of about 1.0 µm to about 3.4 µm. The described formulation enables inhaled aerosol delivery using device/capsule-based dispersion.
The invention also addresses delivering cytidine analogues in a manner that improves pharmacokinetics and anticancer outcomes while supporting local and systemic toxicity profiles. The disclosed nonclinical data compare inhaled dry powder versus inhaled aqueous and systemic dosing, reporting increases in lung/plasma/brain/liver AUC and Cmax and reductions in tumor burden with improved survival across multiple NSCLC tumor types. The document further discusses that the cytidine deaminase inhibitor tetrahydrouridine (THU) can be used in combination to enhance systemic exposure and to support metastatic disease treatment.
Claims Coverage
The partial content includes one independent claim (clm-00001). It defines a dry powder pharmaceutical composition for aerosol dispersion and inhaled administration in cancer patients and specifies the cytidine analogue selection and aerosol particle-size performance.
Cytidine analogue dry powder inhalable aerosol formulation with DMSO and excipient
A dry powder pharmaceutical composition suitable for dispersion in an aerosol for inhaled administration to a patient with cancer, comprising a cytidine analogue selected from 5-azacytidine, zebularine, 5-Aza-2′-deoxycitidine, SG-10 or a pharmaceutically acceptable salt, solvate, hydrate, or esters thereof, dimethyl sulfoxide (DMSO), and a pharmaceutically acceptable excipient.
Aerosol particle-size performance for inhalation (MMAD and GSD)
The dry powder pharmaceutical composition suitable for dispersion in the aerosol for administration via inhalation has a mass median aerodynamic diameter (MMAD) of between about 1.0 µm to about 5.0 µm and a geometric standard deviation (GSD) of emitted particle size distribution of about 1.0 µm to about 3.4 µm.
Overall, the independent claim covers an inhalable dry powder cytidine-analogue composition that includes DMSO and a pharmaceutically acceptable excipient and is characterized by specified aerosol particle-size distribution parameters (MMAD and GSD).
Stated Advantages
Increased pharmacokinetics after inhaled dry powder compared with inhaled aqueous and systemic dosing, including increased lung/plasma/brain/liver AUC and Cmax.
Reduced tumor burden and improved survival in multiple NSCLC tumor types compared with relevant comparators.
Improved local and systemic toxicity profiles as assessed in the document.
Documented Applications
Inhaled administration for cancer treatment, including NSCLC tumor types studied in orthotopic lung cancer models.
Treatment support for metastatic disease through combination with tetrahydrouridine (THU) to enhance systemic exposure.
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