Gastro-retentive Nilotinib Dosage Form for Enhanced Bioavailability
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Solution Overview
Problem
Nilotinib's low aqueous solubility and permeability pose challenges in formulating effective oral delivery dosage forms with good bioavailability, as its solubility decreases with increasing pH, leading to reduced absorption.
Innovation Solution
A gastro-retentive solid oral dosage form comprising nilotinib, a rate controlling polymer, and pharmaceutically acceptable excipients such as swelling agents, acidifying agents, and osmogen agents, which can be administered daily and utilize mechanisms like floatation, gas generation, or swelling to prolong stomach retention and enhance solubility and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional oral dosage forms are used, then manufacturing is simple, but solubility and bioavailability are poor
Solution Approach 1:
The dosage form is segmented into multiple functional components: nilotinib core, rate-controlling polymer layer, swelling agents, gas-generating agents, and acidifying agents. Each component performs a specific function to collectively improve bioavailability while maintaining manageable manufacturing complexity through modular formulation design.
Solution Approach 2:
The invention uses composite materials by combining nilotinib with multiple excipients including rate-controlling polymers (HPMC, carbomer), swelling agents (sodium alginate, carboxymethyl cellulose), gas-generating agents (sodium bicarbonate, calcium carbonate), and acidifying agents (citric acid, fumaric acid). This composite formulation creates a gastro-retentive system that maintains acidic pH and enhances drug solubility and bioavailability.
2Reliability
If solubility is improved through formulation, then bioavailability increases, but manufacturing complexity increases
Solution Approach 1:
The invention changes the pH parameter of the gastric environment by incorporating acidifying agents (citric acid, fumaric acid, tartaric acid) that maintain acidic pH (2-4) in the stomach. This parameter change prevents pH-induced precipitation of nilotinib and maintains its solubility, thereby improving bioavailability while using conventional pharmaceutical excipients that are easy to manufacture.
Solution Approach 2:
The formulation incorporates gas-generating agents (sodium bicarbonate, calcium carbonate) that produce carbon dioxide gas in the stomach, creating buoyancy that enhances gastro-retention. This pneumatic mechanism prolongs drug exposure to the absorption site without requiring complex manufacturing processes, as the gas generation occurs automatically upon contact with gastric fluids.
3Reliability
If drug release is accelerated, then absorption improves, but stomach retention time decreases
Solution Approach 1:
The dosage form employs dynamic mechanisms for drug release: initially, gas generation and swelling create buoyancy and prolong retention; then, as the polymer matrix hydrates and swells, it controls drug release through diffusion and erosion. This dynamic behavior allows the system to first retain the drug in the stomach, then release it at a controlled rate to maintain absorption without rapid elimination.
Solution Approach 2:
The rate-controlling polymers (HPMC, carbomer) undergo phase transition from dry powder to hydrated gel matrix upon contact with gastric fluids. This phase transition creates a swelling barrier that controls drug release kinetics while maintaining gastro-retention. The gel layer forms gradually, providing sustained release without compromising stomach retention time.
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 gastro-retentive dosage form effectively prolongs drug retention in the stomach, enhancing the bioavailability of nilotinib by maintaining an acidic pH environment and controlling release, thereby improving absorption and solubility.
Implementation Method 1
the rate controlling polymer is a swelling agent
Implementation Method 2
The gastro-retentive action of the tablet is based on one or more mechanisms, for example, floatation, gas generation, or swelling
Implementation Method 3
The gastro-retentive action of the tablet is based on one or more mechanisms, for example, floatation, gas generation, or swelling
Implementation Method 4
enhancing the bioavailability of nilotinib by maintaining an acidic pH environment
Data Source
AI summary
The present invention relates to a pharmaceutical gastro-retentive solid oral dosage form comprising nilotinib as the active ingredient. The invention is further related to methods of preparing said dosage form.