Weakly Basic Drug Delivery via Segmented Particle Release

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Solution Overview

Problem

Conventional oral dosage forms for weakly basic, poorly soluble drugs face challenges in maintaining consistent drug release due to pH-dependent solubility profiles, leading to inadequate plasma concentrations and increased side effects, particularly in the intestinal tract where drugs become insoluble, making once-daily dosing difficult.

Innovation Solution

The development of pharmaceutical compositions comprising a combination of rapid release (RR) and timed pulsatile release (TPR) particles, where RR particles release at least 80% of the drug within 5 minutes and TPR particles provide sustained plasma levels over an extended period, using a core coated with a TPR layer containing a weakly basic drug and a pharmaceutically acceptable organic acid separated by a sustained release (SR) layer, ensuring controlled drug release.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Speed

If conventional immediate-release dosage forms are used, then the drug is released quickly into solution, but the plasma concentration rapidly rises to peak and then declines, requiring multiple doses to maintain therapeutic levels

Engineering Contradiction:

Improvedrug release rateVSAvoidduration of therapeutic effect

Core Design Contradiction:

SpeedVSDuration of action of moving object

Solution Approach 1:

The dosage form is segmented into multiple particles with different release characteristics (immediate-release particles and sustained-release particles), allowing simultaneous rapid and prolonged drug delivery to maintain therapeutic plasma levels without requiring multiple doses

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The system dynamically adjusts drug release rates through pH-dependent solubility changes of the weakly basic drug and organic acid, transitioning from rapid release in acidic stomach environment to controlled release in neutral intestinal environment

Inventive Principle:

Principle #15Dynamics

2Duration of action of moving object

If sustained-release dosage forms are used, then the number of doses is minimized, but the drug release rate is reduced, potentially failing to achieve adequate plasma concentrations

Engineering Contradiction:

Improveduration of therapeutic effectVSAvoiddrug release rate

Core Design Contradiction:

Duration of action of moving objectVSSpeed

Solution Approach 1:

The formulation combines immediate-release particles (providing rapid drug release) with sustained-release particles (providing prolonged drug release), ensuring both adequate peak plasma concentrations and extended therapeutic duration with once-daily dosing

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The system exploits pH-dependent solubility parameter changes of the weakly basic drug and organic acid to control release kinetics, achieving rapid release in acidic conditions and sustained release in neutral conditions

Inventive Principle:

Principle #35Parameter changes

3Reliability

If weakly basic drugs are administered in the intestinal tract, then the drug becomes insoluble at pH >6, but conventional dosage forms fail to release the drug in the high pH environment

Engineering Contradiction:

Improvedrug release reliabilityVSAvoidpH-dependent solubility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

An organic acid intermediary is incorporated into the dosage form, which reacts with the weakly basic drug to form a soluble salt that releases the drug in the intestinal tract, overcoming the insolubility issue at high pH

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The system utilizes pH parameter changes throughout the gastrointestinal tract to control drug release, with the organic acid maintaining drug solubility in neutral pH intestinal environment

Inventive Principle:

Principle #35Parameter changes

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

This approach enables improved drug release profiles for once-daily dosing, maintaining clinically effective plasma levels while minimizing side effects by synchronizing drug and acid release, ensuring complete absorption and reducing the need for multiple doses.

Implementation Method 1

Basic and acidic drugs exhibit pH-dependent solubility profiles varying by more than 2 orders of magnitude in the physiological pH range

Methodology Applied

Scientific EffectpH-dependent solubility:

Implementation Method 2

The TPR layer comprises a weakly basic, poorly soluble drug and a pharmaceutically acceptable organic acid

Methodology Applied

Scientific EffectAcid-base reaction:

Data Source

PatentUS8133506B2Drug delivery systems comprising weakly basic drugs and organic acids

Publication Date: 2012.03.13 ADARE PHARMACEUTICALS INC

AI summary

The present invention is directed to pharmaceutical compositions, and methods of making such compositions, wherein the compositions comprise a plurality of TPR and RR particles, wherein: the TPR particles each comprise a core coated with a TPR layer; the core comprises a weakly basic, poorly soluble drug and a pharmaceutically acceptable organic acid separated from each other by an SR layer; the RR particles each comprise the weakly basic, poorly soluble drug, and release at least about 80 wt. % of the weakly basic, poorly soluble drug in about 5 minutes when dissolution tested using United States Pharmacopoeia (USP) dissolution methodology (Apparatus 2—paddles@50 RPM and a two-stage dissolution medium at 37° C. (first 2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8).