Soft Gelatin Tacrolimus Formulation for Stable Pulmonary Hypertension Dosing
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Solution Overview
Problem
Current tacrolimus formulations for treating pulmonary hypertension, particularly pulmonary arterial hypertension, exhibit variable bioavailability and initial drug concentration spikes, leading to unwanted side effects and suboptimal therapeutic profiles.
Innovation Solution
Development of a soft gelatin capsule formulation containing an ascomycin class compound, such as tacrolimus, dissolved in a solvent, which increases BMPR2 signaling to treat pulmonary hypertension, offering a therapeutically effective and controlled release profile.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If immediate release capsule formulation of tacrolimus is used, then rapid absorption is achieved, but bioavailability is variable and low
Solution Approach 1:
The gastrointestinal tract is segmented into different absorption regions (small intestine, ileum, colon), and the formulation is designed to target specific segments. The soft gelatin capsule with controlled release properties enables the drug to be released and absorbed progressively through different intestinal segments, optimizing bioavailability while maintaining rapid initial absorption.
Solution Approach 2:
The formulation transitions from static immediate release to dynamic controlled release. The soft gelatin capsule structure provides time-dependent drug release, adapting the absorption rate to match the transit time through different intestinal regions, thereby improving both speed and reliability of bioavailability.
2Reliability
If extended release tablet formulation is used, then bioavailability is improved, but initial drug concentration spikes occur causing side effects
Solution Approach 1:
Different regions of the formulation have different release properties. The soft gelatin capsule contains tacrolimus dissolved in a lipid vehicle, creating a concentration gradient that provides higher initial concentration for rapid absorption followed by sustained lower concentrations, thereby improving bioavailability while reducing side effects from excessive initial dosing.
Solution Approach 2:
The formulation implements periodic drug release patterns through the soft gelatin capsule structure. The lipid vehicle enables initial rapid release followed by sustained release over time, creating a periodic concentration profile that maintains therapeutic levels without causing harmful spikes.
3Reliability
If tacrolimus is dissolved in lipid vehicle for soft gelatin capsule, then bioavailability and pharmacokinetic profile are improved, but formulation complexity increases
Solution Approach 1:
The formulation uses composite materials combining tacrolimus with specific lipid vehicles (medium-chain triglycerides, long-chain triglycerides, or mixed triglycerides) enclosed in soft gelatin capsules. This composite approach improves pharmacokinetic profile through enhanced solubility and controlled release, while the soft gelatin capsule provides a familiar, relatively simple delivery format that masks the complexity of the lipid-tacrolimus composite.
Data Source
AI summary
The present invention provides compositions and methods for the treatment or prevention of pulmonary hypertension comprising administering an ascomycin, or a pharmaceutically acceptable salt, solvate, analog, or prodrug thereof to the patient with pulmonary hypertension. Described herein are liquid formulations which deliver an ascomycin. The liquid formulation can be placed in a soft gelatin capsule.