Amorphous GaQ3 Oral Dosage Form for Enhanced Bioavailability

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Solution Overview

Problem

The development of oral dosage forms for gallium (III) complexes, specifically tris(8-quinolinolato) gallium (III) (GaQ3), is hindered by poor aqueous solubility and instability in acidic gastric conditions, leading to poor bioavailability and non-linear pharmacokinetics.

Innovation Solution

Formulating GaQ3 in an amorphous or nanocrystalline form and using an enteric or delayed release coating to protect it from gastric acid, combined with a dispersant to maintain the non-crystalline state and ensure controlled release in the intestinal tract.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If GaQ3 is formulated in conventional crystalline form with enteric coating, then gastric acid stability is improved, but aqueous solubility remains poor leading to low bioavailability

Engineering Contradiction:

Improvegastric acid stabilityVSAvoidaqueous solubility

Core Design Contradiction:

Stability of the object's compositionVSQuantity of substance

Solution Approach 1:

The patent changes the physical state parameter of GaQ3 from crystalline to amorphous form. This parameter change dramatically improves aqueous solubility while the enteric coating maintains gastric acid stability. The amorphous form achieves solubility enhancement without sacrificing the stability provided by the coating system.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite formulation combining amorphous GaQ3 with specific excipients and polymers in the enteric coating matrix. This composite approach allows simultaneous achievement of high solubility (from amorphous state) and acid stability (from coating protection), resolving the contradiction between these two properties.

Inventive Principle:

Principle #40Composite materials

2Device complexity

If GaQ3 is administered orally in crystalline form, then formulation simplicity is improved, but bioavailability is poor due to low solubility and non-linear pharmacokinetics

Engineering Contradiction:

Improveformulation simplicityVSAvoidbioavailability

Core Design Contradiction:

Device complexityVSReliability

Solution Approach 1:

The patent changes the physical state from crystalline to amorphous, which fundamentally improves bioavailability through enhanced solubility. The enteric coating parameter addition protects the amorphous form during gastric transit, enabling reliable oral bioavailability while maintaining a relatively simple tablet or capsule formulation.

Inventive Principle:

Principle #35Parameter changes

3Stability of the object's composition

If enteric coating is applied to crystalline GaQ3, then gastric stability is improved, but absorption is limited due to poor solubility of the crystalline compound

Engineering Contradiction:

Improvegastric stabilityVSAvoidabsorption efficiency

Core Design Contradiction:

Stability of the object's compositionVSProductivity

Solution Approach 1:

The patent changes the physical state parameter from crystalline to amorphous, which dramatically improves dissolution and absorption rates. The enteric coating is applied to this amorphous form, allowing it to survive gastric transit and then rapidly dissolve in intestinal fluid, achieving high absorption efficiency that was impossible with crystalline form alone.

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 significantly enhances bioavailability, achieving plasma Cmax at least 100 times and AUC at least 200 times that of crystalline GaQ3, with improved solubility and stability, facilitating effective oral administration.

Implementation Method 1

GaQ3 formulations for oral administration comprise an amorphous or nanocrystalline form of GaQ3

Methodology Applied

Scientific EffectAmorphous state:

Implementation Method 2

GaQ3 formulations for oral administration comprise an amorphous or nanocrystalline form of GaQ3

Methodology Applied

Scientific EffectNanocrystalline state:

Implementation Method 3

protected by an enteric or delayed release coating

Methodology Applied

Scientific EffectEnteric coating: Coatings

Implementation Method 4

The complexed structure of GaQ3 is disrupted completely at pH values below the pKa of 8-hydroxyquinoline (8-HQ; pKa = 5.01)

Methodology Applied

Scientific EffectpH-dependent stability:

Implementation Method 5

The GaQ3 or its derivative is admixed with a dispersant to maintain its amorphous or nanocrystalline form

Methodology Applied

Scientific EffectDispersion: Dispersion (of waves)

Implementation Method 6

The formulations of the invention result in desirable pharmacokinetics wherein when said encapsulated GaQ3 is administered to dogs at a dose of 10 mg/kg the Cmax in plasma is at least 100 times the Cmax in plasma of dogs administered 10 mg/kg of crystalline GaQ3 and the AUC in plasma is at least 200 times that of dogs administered comparable amounts of crystalline GaQ3

Methodology Applied

Scientific EffectBioavailability enhancement:

Data Source

PatentEP3582778B1Compositions of gallium (III) complexes for oral administration

Publication Date: 2022.10.05 MEDMELIOR INC

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AI summary

The present invention relates to dosage forms of gallium complexes suitable for oral very and methods of preparation thereof Such dosage forms are useful for the treatment of diseases, including, but not limited to, cancer.