Pharmaceutical Formulation Using TPGS Melt for Dengue API Solubility

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Solution Overview

Problem

There is a need for improved pharmaceutical formulations that address the hydrophobicity and instability of active pharmaceutical ingredients, particularly for dengue viral replication inhibitors, to effectively treat dengue viral infections.

Innovation Solution

A pharmaceutical formulation comprising D-α-tocopherol polyethylene glycol succinate (TPGS), an active pharmaceutical ingredient soluble in molten TPGS, and glyceryl palmitostearate, where the TPGS is heated above its melting point to form a melt, and the active ingredient is dissolved within, resulting in a solid dosage form for treating dengue viral infections.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the active pharmaceutical ingredient is used in conventional formulations, then the formulation can be manufactured, but the solubility and stability of the hydrophobic API are insufficient

Engineering Contradiction:

Improvestability of active pharmaceutical ingredientVSAvoidsolubility of hydrophobic API

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent uses a composite system comprising TPGS (a surfactant) combined with glyceryl palmitostearate (a lipid excipient) to formulate the hydrophobic API. This composite approach allows the API to be solubilized in the lipid component while TPGS provides surface activity to enhance stability and bioavailability, resolving the contradiction between maintaining hydrophobicity for stability and achieving sufficient solubility for efficacy.

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent changes the physical state parameters of the formulation by using TPGS at temperatures above its melting point to form a melt, into which the API is dissolved. This parameter change (temperature-induced phase transition) enables the hydrophobic API to achieve adequate solubility during manufacturing while maintaining stability in the final solid dosage form after cooling and solidification.

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If the active pharmaceutical ingredient has high hydrophobicity, then the formulation can maintain stability, but the solubility and bioavailability are reduced

Engineering Contradiction:

Improvestability of hydrophobic APIVSAvoidsolubility of active pharmaceutical ingredient

Core Design Contradiction:

Stability of the object's compositionVSQuantity of substance

Solution Approach 1:

TPGS acts as an intermediary substance between the hydrophobic API and the aqueous environment. The surfactant molecules form micelles or mixed micelles with the lipid excipient, allowing the hydrophobic API to be incorporated in the core while the hydrophilic outer surface of the micelle provides solubility in aqueous media, thus maintaining both stability and solubility.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The formulation creates a microstructural environment where the lipid excipient and surfactant form a matrix with micellar structures that provide nanoscale domains for API dissolution. This porous-like microstructure at the molecular level increases the effective surface area and solubility of the hydrophobic API without compromising its stability.

Inventive Principle:

Principle #31Porous materials

3Ease of manufacture

If conventional formulation methods are used, then the manufacturing process is simple, but the therapeutic effectiveness against dengue virus replication is insufficient

Engineering Contradiction:

Improveformulation manufacturing processVSAvoidtherapeutic effectiveness

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The manufacturing process utilizes temperature parameter changes to simplify formulation: TPGS is heated above its melting point to form a melt, the API is dissolved in this melt, and then the mixture is cooled to form a solid dosage form. This parameter-based approach (temperature cycling) achieves effective drug delivery while maintaining manufacturing simplicity, as it avoids complex processing steps.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The use of the TPGS-glyceryl palmitostearate composite system enhances therapeutic effectiveness against dengue virus replication while maintaining ease of manufacture. The composite provides superior API solubilization and stability, leading to better bioavailability and antiviral activity, all through a relatively simple melt-based manufacturing process.

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 formulation provides a therapeutically effective solid dosage form that enhances the solubility and stability of the active pharmaceutical ingredient, enabling effective inhibition of dengue virus replication and treatment of dengue viral infections.

Implementation Method 1

heating TPGS to a temperature above its melting point

Methodology Applied

Scientific EffectMelting: Melting

Implementation Method 2

an active pharmaceutical ingredient that is soluble in molten TPGS

Methodology Applied

Scientific EffectSolvation: Solvation

Data Source

PatentUS20230301924A1Pharmaceutical formulation

Publication Date: 2023.09.28 JANSSEN PHARMACEUTICALS INC

AI summary

The invention relates to pharmaceutical formulations comprising an active pharmaceutical ingredient, glyceryl palmitostearate, and D-α-tocopherol polyethylene glycol succinate (TPGS). Solid dosage forms comprising said pharmaceutical formulations, processes for preparing these and their use in methods of treatment are also described.