Specially formulated compositions of inhaled nintedanib and nintedanib salts
Inventors
SURBER, Mark William • Pham, Stephen
Assignees
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Publication Number
US-12090225-B2
Publication Date
2024-09-17
Expiration Date
Abstract
Disclosed herein are formulations of nintedanib and salts thereof, indolinone derivative compounds and salts thereof for aerosolization and use of such formulations for the prevention or treatment of various fibrotic, carcinogenic, vascular and viral infectious diseases, including diseases associated with the lung, heart, kidney, liver, eye, central nervous system and surgical sites. Formulations and delivery options described herein allow for efficacious local delivery of nintedanib or a indolinone derivative compound or salt thereof. Methods include inhalation procedures, indications and manufacturing processes for production and use of the compositions described. Also included are methods for identifying compounds and indications that benefit by reformulation and inhalation administration.
Core Innovation
The invention provides a sealed, sterile two-solution system of nintedanib configured to be combined to form an admixture. The first solution contains dissolved nintedanib salt at a nintedanib concentration less than 1.5 mg/mL, with the salt counterion selected from esylate, chloride, and bromide and combinations thereof, and a buffer selected from lysinate, acetylcysteine, glycine, glutamate, borate, succinate, tartrate, phosphate, or Tris and combinations thereof.
The second solution comprises permeant ions and adjusts the permeant ion concentration of the admixture to between 30 mM and 150 mM. Either or both of the first and second solutions further comprise a non-ionic osmolality adjusting agent that increases the osmolality of the admixture and avoids precipitation of the nintedanib salt. The formulation maintains solubility and stability through controlled mixing of the two sealed solutions.
The invention is associated with aerosol administration of nintedanib-containing admixtures, including nebulizer-based delivery with specified aerosol parameters and delivery timing after combining the first and second solutions. The partial content also identifies pirfenidone as a stabilizing co-active in inhaled combination formulations and describes formulation development relating to storage stability and compatibility with container and filter materials.
Claims Coverage
The independent claim covers a sealed, sterile two-solution nintedanib formulation with a first solution containing dissolved nintedanib salt and a buffer, and a second solution containing permeant ions that set the admixture permeant ion concentration. The claim set further includes an optional non-ionic osmolality adjusting agent to avoid precipitation, and dependent subject matter adds aerosol delivery constraints and pirfenidone.
Sealed, sterile two-solution nintedanib formulation
A sealed, sterile first solution of a dissolved nintedanib salt at a nintedanib concentration less than 1.5 mg/mL, and a separate sealed, sterile second solution comprised of permeant ions, where the admixture of the first and second solutions is adjusted by permeant ions to a defined concentration range.
Defined nintedanib salt counterion and buffer system
In the first solution, the nintedanib salt counterion is selected from esylate, chloride, and bromide and combinations thereof, and the buffer is selected from lysinate, acetylcysteine, glycine, glutamate, borate, succinate, tartrate, phosphate, or Tris and combinations thereof.
Permeant-ion adjustment to 30 mM to 150 mM
The second solution adjusts the permeant ion concentration of an admixture of the first and second solution to between 30 mM and 150 mM.
Non-ionic osmolality adjusting agent to avoid precipitation
Either or both of the first or the second solution is further comprised of a non-ionic osmolality adjusting agent that increases the osmolality of an admixture of the first solution and the second solution and avoids precipitation of the nintedanib salt.
Aerosol performance and delivery timing constraints
A nebulizer delivers an admixture having pH between 3.5 and 4.6 and generates an aerosol with MMAD about 1 μm to about 5 μm, GSD about 1.0 to about 2.5, FPF at least about 30% with droplets less than 5 microns, and output rate at least 0.1 mL/min, delivering the aerosol dose within 3 hours of combining the first and second solutions.
Pirfenidone as additional active agent
The formulation further comprises pirfenidone.
Overall, the claim coverage centers on a sealed, sterile two-solution formulation architecture for nintedanib, with a specified first-solution salt/buffer system, a second-solution permeant-ion component that sets the admixture permeant-ion concentration to 30 mM to 150 mM, and an optional non-ionic osmolality adjusting agent to avoid precipitation. Dependent subject matter adds aerosol delivery constraints and pirfenidone.
Stated Advantages
Avoids precipitation of the nintedanib salt.
Maintains solubility and stability through controlled mixing of the two sealed solutions.
Pirfenidone is identified as a stabilizing co-active.
Documented Applications
Aerosol administration of nintedanib-containing admixtures, including nebulizer-based delivery characterized by defined aerosol parameters.
Inhaled combination formulations including pirfenidone as a stabilizing co-active for ready-to-use inhaled compositions.
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