Specially formulated compositions of inhaled nintedanib and nintedanib salts
Inventors
SURBER, Mark William • Pham, Stephen
Assignees
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Publication Number
US-11123290-B2
Publication Date
2021-09-21
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 relates to therapeutic administration of aerosol formulations of nintedanib comprising nintedanib salts delivered by inhalation to lungs. A sealed, sterile first solution contains a dissolved nintedanib salt in a non-glass container with a buffer, and a separate sealed, sterile second solution comprised of permeant ions is combined at the point of use to form an admixture for aerosol delivery.
The permeant-ion concentration of the admixture is adjusted to a defined range, and either or both solutions may further include a non-ionic osmolality adjusting agent to increase osmolality and avoid precipitation of the nintedanib salt. The formulation work addresses compatibility and stability of inhalable nintedanib salt formulations with excipients and packaging/filter components.
The prepared admixture is contained in the reservoir of a nebulizer and used for inhalation dosing to the lungs. The document emphasizes inhalation pharmacokinetics and pharmacodynamics, including lung epithelial lining fluid and lung tissue exposure metrics, while reducing systemic exposure compared with oral dosing.
Claims Coverage
The independent claim coverage centers on a point-of-use mixing method using two sealed sterile solutions, nebulizer-based inhalation, and a defined functional endpoint. Four inventive features are reflected across the claim set.
Point-of-use sealed sterile two-solution aerosol nintedanib admixture
Combining at the point of use a sealed, sterile first solution of a dissolved nintedanib salt at a nintedanib concentration less than 1.5 mg/mL in a non-glass container with a buffer, where the salt counterion is selected from esylate, chloride, and bromide and combinations thereof, with a separate sealed, sterile second solution comprised of permeant ions to adjust the permeant ion concentration of an admixture of the first and second solution to between 30 mM and 150 mM.
Non-ionic osmolality adjustment to avoid precipitation
Including a non-ionic osmolality adjusting agent in either or both solutions to increase the osmolality of the admixture and avoid precipitation of the nintedanib salt.
Nebulizer containment and timely activation
Containing the admixture in the reservoir of a nebulizer and activating the nebulizer within 2 hours of forming the admixture.
Inhalation dosing to reduce progression of decline in lung function
Delivering by inhalation an aerosol dose of the nintedanib salt to the lungs of a patient to reduce progression of a decline in Forced Vital Capacity or Forced Expiratory Volume.
Overall, the claims focus on preparing a nintedanib salt aerosol admixture at the point of use using two sealed sterile solutions with defined permeant-ion concentration and optional non-ionic osmolality adjustment to prevent precipitation, followed by nebulizer containment and timely activation to deliver inhaled nintedanib to the lungs for reducing progression of decline in Forced Vital Capacity or Forced Expiratory Volume.
Stated Advantages
Reduces progression of a decline in Forced Vital Capacity or Forced Expiratory Volume through inhalation delivery of a nebulized aerosol dose of nintedanib to the lungs.
Avoids precipitation of the nintedanib salt by increasing osmolality using a non-ionic osmolality adjusting agent.
Uses sealed sterile solutions for combining at the point of use prior to nebulization.
Targets delivery to the lungs and downstream tissues while reducing systemic exposure.
Provides inhalation pharmacokinetics and pharmacodynamics characterized by lung Cmax and AUC enhancement compared with oral dosing.
Documented Applications
Administration of an aerosol formulation of nintedanib by inhalation to lungs of a patient to reduce progression of decline in Forced Vital Capacity or Forced Expiratory Volume.
In-line nebulization within a mechanical ventilator system where the resulting aerosol is delivered through the ventilator forced air circuit to the patient [procedural detail omitted for safety].
Therapeutic administration for conditions including multiple sclerosis.
Therapeutic administration for fibrotic and inflammatory diseases, including pulmonary fibrosis and ILD, using aerosol.
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