Trihexyphenidyl Extended Release Composition with Acid Core

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Solution Overview

Problem

Current trihexyphenidyl hydrochloride formulations suffer from poor tolerability and require frequent administration due to high peak-to-trough fluctuations and side effects, primarily because of poor solubility at pH greater than or equal to 5, leading to variable plasma levels and adverse effects.

Innovation Solution

Development of extended-release trihexyphenidyl compositions with a core comprising an organic acid, a drug layer containing trihexyphenidyl or its salt, and a functional coat with a nonionic water-insoluble polymer and pore former, which improves solubility and maintains therapeutic plasma concentrations for at least 10 hours, reducing peak-to-trough fluctuations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Speed

If trihexyphenidyl is administered as conventional immediate-release formulation, then rapid therapeutic effect is achieved, but high peak-to-trough fluctuations and frequent administration are required

Engineering Contradiction:

Improveonset of therapeutic effectVSAvoidduration of therapeutic effect

Core Design Contradiction:

SpeedVSDuration of action of moving object

Solution Approach 1:

The patent segments the drug delivery system into multiple functional layers: an immediate-release layer containing trihexyphenidyl hydrochloride for rapid onset, and an extended-release layer containing trihexyphenidyl base for sustained release. This segmentation allows both rapid therapeutic effect and prolonged duration of action to be achieved simultaneously by having different layers release drug at different rates.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The immediate-release layer acts as a preliminary action component that provides rapid initial therapeutic effect upon administration. This layer releases the drug quickly to achieve therapeutic levels before the extended-release layer takes over to maintain those levels, thereby resolving the contradiction between rapid onset and prolonged duration.

Inventive Principle:

Principle #10Preliminary action

2Stability of the object's composition

If trihexyphenidyl is administered in divided doses to maintain therapeutic levels, then peak-to-trough fluctuations are reduced, but patient compliance and convenience deteriorate

Engineering Contradiction:

Improveplasma concentration stabilityVSAvoiddosing frequency and patient compliance

Core Design Contradiction:

Stability of the object's compositionVSEase of operation

Solution Approach 1:

The patent implements continuous useful action by designing a single dosage form that provides both immediate and extended release of the drug. The extended-release layer ensures continuous drug release over 24 hours or longer, eliminating the need for multiple daily doses while maintaining stable plasma concentrations. This continuous release mechanism resolves the contradiction between concentration stability and dosing convenience.

Inventive Principle:

Principle #20Continuity of useful action

3Reliability

If high dose trihexyphenidyl is administered to achieve therapeutic effect, then dystonia symptoms are controlled, but anti-cholinergic adverse effects increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies dynamics by creating a time-varying release profile where the immediate-release layer provides high initial concentrations to quickly control symptoms, while the extended-release layer provides lower, sustained concentrations to maintain therapeutic effect with reduced adverse effects. This dynamic release strategy allows high efficacy with improved tolerability by avoiding sustained high plasma levels.

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent changes the release rate parameter over time through the dual-layer design. The immediate-release layer provides rapid high-concentration release for symptom control, while the extended-release layer provides prolonged lower-concentration release that maintains efficacy while reducing adverse effects. This parameter change in release rate resolves the contradiction between therapeutic efficacy and adverse effects.

Inventive Principle:

Principle #35Parameter changes

4Duration of action of moving object

If trihexyphenidyl formulation is designed for extended release, then dosing frequency is reduced, but solubility at pH greater than or equal to 5 deteriorates

Engineering Contradiction:

Improveduration of drug releaseVSAvoiddrug solubility

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent applies local quality by using different chemical forms of the drug in different layers: trihexyphenidyl hydrochloride (more soluble) in the immediate-release layer and trihexyphenidyl base (less soluble) in the extended-release layer. The soluble salt form ensures rapid dissolution when needed, while the base form provides sustained release. This local differentiation of drug form resolves the contradiction between extended release duration and solubility reliability.

Inventive Principle:

Principle #3Local quality

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 extended-release formulation provides stable therapeutic plasma concentrations for 10-24 hours, reduces side effects, and improves patient compliance by minimizing peak-to-trough fluctuations, allowing for once or twice daily administration.

Implementation Method 1

The compositions provide an acid microenvironment that improves the solubility of trihexyphenidyl (THP) at a pH greater than or equal to about 5

Methodology Applied

Scientific EffectAcid microenvironment:

Implementation Method 2

improves the solubility of trihexyphenidyl (THP) at a pH greater than or equal to about 5

Methodology Applied

Scientific EffectSolubility enhancement:

Implementation Method 3

a functional coat with a nonionic water-insoluble polymer and pore former, which improves solubility and maintains therapeutic plasma concentrations for at least 10 hours

Methodology Applied

Scientific EffectControlled release:

Implementation Method 4

a functional coat with a nonionic water-insoluble polymer and pore former

Methodology Applied

Scientific EffectDiffusion through porous membrane: Diffusion

Data Source

PatentUS11684580B2Extended release compositions comprising trihexyphenidyl

Publication Date: 2023.06.27 AMNEAL COMPLEX PROD RES LLC

AI summary

The present disclosure provides extended release trihexyphenidyl compositions suitable for once- or twice-daily administration. The compositions comprise a core comprising at least one organic acid; at least one drug layer comprising trihexyphenidyl or a pharmaceutically acceptable salt thereof over the core; and a functional coat over the drug-layered core. The compositions of the disclosure provide extended release with reduced Cmax, a Cmin:Cmax ratio of ≥0.4, Fluctuation Index of ≤1, while providing and maintaining at least a minimum therapeutically effective plasma concentration, of the trihexyphenidyl or the pharmaceutically acceptable salt thereof for at least about 10 hours. The compositions of the disclosure improve solubility of the trihexyphenidyl or the pharmaceutically acceptable salt thereof at a pH of greater than or equal to 5, to provide and maintain at least a minimum effective concentration of the drug at such pH.