HCV Prodrug Formulation with Hydroxypropylcellulose

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Solution Overview

Problem

The development of hepatitis C virus (HCV) polymerase inhibitor prodrug formulations faces challenges due to low bulk density, pH-dependent solubility limitations, and the need for high drug loading, which complicates manufacturing and bioavailability, especially with conventional excipients requiring multiple densification steps and high binder usage.

Innovation Solution

Formulations incorporating hydroxypropylcellulose as a binder at 1-4%w/w level, combined with compound 1 at 50-95%w/w, utilizing hydroxypropylcellulose as a surface-active agent to enhance granule density, compression, and dissolution profiles, achieving 80% release in less than 45 minutes and improved bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Volume of stationary object

If conventional excipients and multiple densification steps are used to improve bulk density, then bulk density is improved, but manufacturing complexity and binder usage increase

Engineering Contradiction:

Improvebulk densityVSAvoidmanufacturing process complexity

Core Design Contradiction:

Volume of stationary objectVSDevice complexity

Solution Approach 1:

The patent extracts and eliminates the need for multiple densification steps by using a self-granulating excipient that provides bulk density improvement in a single step, removing unnecessary manufacturing operations

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The self-granulating excipient performs multiple functions simultaneously: it acts as a filler, provides bulk density, enables granulation, and serves as a binding agent, replacing the need for separate binders and multiple processing steps

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Volume of stationary object

If high amounts of binders are used to improve granule density, then granule density is improved, but dissolution rate and bioavailability decrease

Engineering Contradiction:

Improvegranule densityVSAvoiddissolution rate

Core Design Contradiction:

Volume of stationary objectVSProductivity

Solution Approach 1:

The patent uses a self-granulating excipient that requires minimal binder (1-5% w/w) compared to conventional formulations, allowing the formulation to be easily dissolved and eliminated in the digestive tract, improving bioavailability

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent changes the binder concentration parameter from conventional high levels (5-10% w/w or higher) to low levels (1-5% w/w), which maintains granule integrity during manufacturing while enabling rapid dissolution and absorption

Inventive Principle:

Principle #35Parameter changes

3Volume of stationary object

If multiple densification steps are used to improve bulk density, then bulk density is improved, but manufacturing time and process steps increase

Engineering Contradiction:

Improvebulk densityVSAvoidmanufacturing time

Core Design Contradiction:

Volume of stationary objectVSLoss of time

Solution Approach 1:

The patent merges multiple densification operations into a single granulation step using a self-granulating excipient, achieving bulk density improvement without requiring separate densification steps

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The self-granulating excipient is pre-formulated to possess self-granulating properties, allowing it to automatically form dense granules during mixing without requiring subsequent densification steps

Inventive Principle:

Principle #10Preliminary action

4Quantity of substance

If high drug loading is used to provide high dose, then dose strength is improved, but flow and compression properties worsen due to low bulk density

Engineering Contradiction:

Improvedrug loadingVSAvoidflow and compression properties

Core Design Contradiction:

Quantity of substanceVSEase of manufacture

Solution Approach 1:

The patent creates a composite formulation combining the HCV polymerase inhibitor with a self-granulating excipient, where the excipient provides the necessary bulk density and flow properties while maintaining high drug loading

Inventive Principle:

Principle #40Composite materials

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 use of hydroxypropylcellulose in these formulations provides improved bulk density, granule size, compression, and dissolution profiles, reducing the need for high binder levels and simplifying the manufacturing process while enhancing bioavailability and patient convenience.

Implementation Method 1

hydroxypropylcellulose as a binder at 1-4%w/w level

Methodology Applied

Scientific EffectAdhesion: Adhesive

Implementation Method 2

utilizing hydroxypropylcellulose as a surface-active agent to enhance granule density

Methodology Applied

Scientific EffectSurface activity: Surfactant

Implementation Method 3

fast dissolution profiles

Methodology Applied

Scientific EffectSolvation: Solvation

Data Source

PatentEP2389164B1Pharmaceutical compositions comprising a HCV polymerase inhibitor prodrug

Publication Date: 2014.08.13 F HOFFMANN LA ROCHE & CO AG

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AI summary

The present invention provides novel formulations of isobutyric acid (2R,3R,4R,5R)- 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-2-isobutyryloxymethyl-4-methyl-tetrahydro-furan-3-yl ester) and hydroxypropylcellulose that provide high bulk density, low particle size better suited for improved compression and flow, good compression, and fast dissolution profiles.