Ibrutinib Microsphere Formulations for Sustained Release

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Solution Overview

Problem

Current BTK inhibitors, such as ibrutinib, have low bioavailability and require frequent oral dosing, which can be inconvenient and variable in effectiveness.

Innovation Solution

Development of microsphere formulations comprising ibrutinib and biodegradable polymers, allowing for sustained release through intramuscular or subcutaneous injection, with a drug load of over 30% and particle sizes less than 110 μm, minimizing initial burst release.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If oral formulations of BTK inhibitors are used, then the drug can be administered conveniently, but the bioavailability is low and variable (e.g., ibrutinib has only 2.9% oral bioavailability in fasted state)

Engineering Contradiction:

ImprovebioavailabilityVSAvoiddosing convenience

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent changes the physical form and administration route of ibrutinib from oral solid dosage to injectable microsphere suspension, fundamentally altering how the drug is delivered to achieve sustained release and improved bioavailability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses composite microsphere formulations consisting of ibrutinib encapsulated in biodegradable polymer matrices (such as PLGA), creating a composite material system that enables controlled release and sustained delivery of the drug

Inventive Principle:

Principle #40Composite materials

2Reliability

If oral formulations require closely timed successive dosages, then the drug can maintain therapeutic levels, but patient compliance becomes difficult and dosing frequency increases

Engineering Contradiction:

Improvetherapeutic level maintenanceVSAvoiddosing frequency

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The microsphere formulation provides continuous sustained release of ibrutinib over extended periods (weeks to months), eliminating the need for frequent intermittent dosing while maintaining therapeutic drug levels through continuous delivery

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The drug is pre-loaded into microsphere carriers that are designed to release the medication over time, so the therapeutic action is already prepared and will occur automatically at the required rate without needing repeated patient intervention

Inventive Principle:

Principle #10Preliminary action

3Quantity of substance

If microsphere formulations with high drug load are created, then the injection volume is reduced, but the initial burst release increases

Engineering Contradiction:

Improvedrug loadVSAvoidrelease control

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent creates microspheres with heterogeneous internal structures where ibrutinib is distributed throughout the polymer matrix with different local concentrations and accessibility, creating zones of rapid release near the surface and zones of sustained release deeper within the microsphere

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The biodegradable polymer forms a matrix structure that acts as a flexible barrier controlling drug release rates, with the polymer degradation providing a controlled mechanism to regulate the transition from initial burst to sustained release phases

Inventive Principle:

Principle #30Flexible shells and thin films

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The microsphere formulations provide a long-acting, sustained release of ibrutinib, improving bioavailability and reducing the need for frequent dosing, ensuring consistent drug levels and enhanced patient compliance.

Implementation Method 1

The microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) ibrutinib; and (ii) a biodegradable polymer

Methodology Applied

Scientific EffectDiffusion: Diffusion

Implementation Method 2

a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the ibrutinib of greater than 30% by weight

Methodology Applied

Scientific EffectBiodegradation: Decomposition (biological)

Implementation Method 3

combining the dispersed phase with the continuous phase in a homogenizer

Methodology Applied

Scientific EffectMechanical mixing: Stirring

Implementation Method 4

mixing: (i) water; and (ii) a surfactant, to form a continuous phase

Methodology Applied

Scientific EffectSurfactant action: Surfactant

Data Source

PatentUS20230404922A1Microsphere formulations comprising BTK inhibitors and methods for making and using the same

Publication Date: 2023.12.21 OAKWOOD LABORATORIES LLC

AI summary

Extended-release microsphere formulations comprising a BTK inhibitor are provided. In one aspect, the microsphere formulations are characterized in that the BTK inhibitor is ibrutinib, and the ibrutinib is released in vivo in humans over a period of from about 7 to about 28 days. Methods for making and using the formulations are also provided.