Inhaled Nintedanib Formulation for Pulmonary Delivery
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Solution Overview
Problem
Development of advanced nintedanib formulations for inhalation delivery poses challenges that have not been completely overcome, including achieving optimal target organ dose, pharmacokinetic profile, and safety profile for treating pulmonary and extrapulmonary diseases.
Innovation Solution
The formulation of nintedanib or its salts, along with indolinone derivatives, in aqueous solutions for nebulized inhalation, utilizing specific concentrations of nintedanib (0.005 mg/mL to 10 mg/mL), osmolality adjusting agents, inorganic salts, and buffers to optimize delivery to the lungs, central nervous system, and systemic compartment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If nintedanib is formulated for inhaled delivery to improve target organ dose and reduce systemic toxicity, then safety profile is improved, but formulation complexity increases due to need for specific excipients and delivery system optimization
Solution Approach 1:
The formulation is divided into distinct functional components: nintedanib active ingredient, permeant ions (sodium chloride, magnesium chloride, calcium chloride, potassium chloride) for membrane penetration, buffers (phosphate, citrate, acetate) for pH control, and osmolality adjusting agents (mannitol, sorbitol, glycerin) for isotonicity. This segmentation allows each component to be optimized independently for its specific function while maintaining overall formulation safety and efficacy.
Solution Approach 2:
Permeant ions serve as intermediaries that facilitate the transport of nintedanib across pulmonary epithelial membranes. The formulation includes specific concentrations of sodium chloride (15-300 mM), magnesium chloride (15-300 mM), calcium chloride (15-300 mM), and potassium chloride (15-300 mM) to create an ionic environment that enhances drug permeation while maintaining physiological compatibility and reducing systemic toxicity.
2Quantity of substance
If aqueous solution concentration of nintedanib is increased to improve therapeutic efficacy, then target organ dose is improved, but solubility and stability challenges worsen
Solution Approach 1:
The formulation employs parameter changes in pH and ionic composition to enhance nintedanib solubility and stability at therapeutic concentrations. Buffers are included to maintain pH between 3.0-7.0, with preferred ranges of 4.0-6.0, optimizing the ionization state of nintedanib for maximum solubility. The ionic strength and composition are adjusted to prevent precipitation and maintain formulation stability throughout storage and administration.
Solution Approach 2:
The formulation creates a composite aqueous solution system where nintedanib is dissolved in a multi-component medium containing permeant ions, buffers, and osmolality adjusting agents. This composite formulation approach allows the system to achieve both high drug concentration for therapeutic efficacy and enhanced stability through synergistic interactions between formulation components.
3Reliability
If inorganic salts are added to adjust osmolality and provide permeant ions, then pharmacokinetic profile is improved, but formulation complexity increases
Solution Approach 1:
The inorganic salts in the formulation serve multiple functions simultaneously: sodium chloride, magnesium chloride, calcium chloride, and potassium chloride each contribute to osmolality adjustment, provide essential permeant ions for pulmonary epithelial transport, and maintain ionic balance for physiological compatibility. This multi-functionality reduces the need for separate additive systems and simplifies the overall formulation approach while optimizing pharmacokinetic delivery.
Solution Approach 2:
The formulation utilizes controlled variations in inorganic salt concentrations to optimize multiple parameters: osmolality is adjusted to isotonic levels (280-320 mOsm/kg), ionic strength is controlled to enhance drug solubility and stability, and specific ion ratios are maintained to facilitate permeation. These parameter optimizations are achieved within defined concentration ranges that balance pharmacokinetic performance with formulation simplicity.
Data Source
AI summary
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.