Dry powder treprostinil for the treatment of pulmonary hypertension
Inventors
Roscigno, Robert Frank • Farrer, Brian T. • Sprague, Jacob J. • Maynor, Benjamin
Assignees
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Publication Number
US-11744835-B2
Publication Date
2023-09-05
Expiration Date
Abstract
A dry powder inhalation treatment for pulmonary arterial hypertension includes a dose of dry particles comprising greater than 25 micrograms of treprostinil enclosed in a capsule. The dry particles can include treprostinil, a wetting agent, a hydrophobicity modifying agent, a pH modifying agent and a buffer. A method of treating a patient having pulmonary arterial hypertension includes providing a patient a dry powder inhaler, providing the patient at least one capsule for use in the dry powder inhaler, the capsule including at least 25 micrograms of treprostinil.
Core Innovation
The disclosed invention relates to a dry powder treatment for treating pulmonary arterial hypertension. The treatment includes a dose of dry powder particles comprising treprostinil or a pharmaceutically acceptable salt thereof, together with an excipient matrix. The dry powder particles are filled into one or more dosage units configured to be inserted into a dry powder inhaler for administration to a patient.
The dry powder particles are formed from a solution comprising a pH modifying agent and a bulking agent. The document further characterizes the dry powder formulation as comprising treprostinil sodium together with excipients including trehalose dihydrate, polysorbate 80, L-leucine, sodium citrate dihydrate, and sodium chloride, within a PRINT® Technology-produced particle concept. The particles are described as pollen-/pollen-shaped and are filled into capsule dosage units.
The disclosed dry powder treatment is defined by predetermined treprostinil amount per dosage unit, and by aerosol-related particle characteristics. The document describes dose presentation concepts, particle/deliverability targets, and performance and stability evaluation, including aerosol performance measures, batch uniformity, and stability under low-humidity conditions.
The document also reports nonclinical and early clinical bridging information for LIQ861 compared with nebulized treprostinil, including inhaled treprostinil (PRINT-Tre) dry powder/particles versus PRINT placebo and a randomized, placebo-controlled single-ascending dose study in healthy volunteers.
Claims Coverage
The independent claim coverage centers on one inventive feature set for a dry powder treprostinil treatment for pulmonary arterial hypertension, with dependent claims adding formulation and product-configuration limitations.
Dry powder treprostinil dose for pulmonary arterial hypertension
A dry powder treatment for treating pulmonary arterial hypertension comprising a dose of dry powder particles comprising treprostinil or a pharmaceutically acceptable salt thereof and an excipient matrix.
Particle formation from pH modifying agent and bulking agent solution
The dry powder particles are formed from a solution comprising a pH modifying agent and a bulking agent.
Dosage units configured for insertion into a dry powder inhaler
The dry powder particles are filled into one or more dosage units configured to be inserted into a dry powder inhaler for administration to a patient.
Predetermined treprostinil amount per dosage unit
The one or more dosage units include a total predetermined amount of the treprostinil or the pharmaceutically acceptable salt thereof in the range of 100 µg to 350 µg.
Specific excipient matrix including trehalose, L-leucine, polysorbate 80, sodium citrate, and sodium chloride
The excipient matrix contains trehalose, L-leucine, polysorbate 80, sodium citrate, and sodium chloride.
Low water content powder with water content less than 5%
The dry powder particles are dried to achieve a water content of less than 5%.
Aerosol particle aerodynamic size constraint between 1 µm and 5 µm
The dry powder particles have a mass median aerodynamic diameter between 1 µm and 5 µm.
Dose per dosage unit constrained to 50 µg to 220 µg
Each dosage unit contains treprostinil or a pharmaceutically acceptable salt thereof at 50 µg to 220 µg.
Capsule dosage unit presentation
The one or more dosage units are in the form of one or more capsules.
Overall, the claim coverage centers on treprostinil-containing dry powder particles formed using a solution with a pH modifying agent and a bulking agent, packaged into dosage units for insertion into a dry powder inhaler with a total predetermined treprostinil amount of 100 µg to 350 µg, and further refined by dependent limitations including specific excipient components, moisture and aerodynamic size constraints, a treprostinil per-unit dose range, and capsule-based dosage units.
Stated Advantages
The document describes aerosol performance measures, batch uniformity, and stability under low-humidity conditions.
The document reports tolerability up to 1.37 mg/kg/day in a 7-day rat inhalation study.
The document reports treprostinil PK increasing with dose across 25–150 µg administered by DPI as capsules in healthy volunteers.
Documented Applications
Treatment of pulmonary arterial hypertension.
Nonclinical inhalation study of PRINT-Tre dry powder/particles versus PRINT placebo.
Randomized, placebo-controlled single-ascending dose study in healthy volunteers.
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