Two-Layer Rosuvastatin Ezetimibe Tablet Formulation

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Solution Overview

Problem

Current pharmaceutical formulations of rosuvastatin and ezetimibe face challenges in achieving stable two-layer tablets with optimal bioavailability and release rates, due to issues like degradation, interaction between ingredients, and variability in active ingredient content and release.

Innovation Solution

A two-layer tablet composition where each layer contains only one active ingredient, with a weight ratio of rosuvastatin to ezetimibe ranging from 1:2 to 2:1, using stearic acid as a glidant in the ezetimibe layer at 0.15-0.5% by weight, and avoiding basic stabilizing excipients in the rosuvastatin layer, to enhance stability and bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a two-layer tablet formulation is used to separate rosuvastatin and ezetimibe, then stability and bioavailability are improved, but manufacturing complexity increases

Engineering Contradiction:

ImprovestabilityVSAvoidmanufacturing complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The tablet is divided into two distinct layers, with the first layer containing rosuvastatin and the second layer containing ezetimibe. This segmentation prevents interaction between the two active ingredients, improving stability while allowing independent optimization of each layer's formulation and release characteristics.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Each layer is formulated with specific excipients and properties tailored to its active ingredient. The rosuvastatin layer uses basic stabilizing excipients appropriate for that compound, while the ezetimibe layer uses different excipients optimized for ezetimibe's release and stability, allowing local optimization without compromising the other ingredient.

Inventive Principle:

Principle #3Local quality

2Reliability

If basic stabilizing excipients are added to the rosuvastatin layer, then rosuvastatin stability is improved, but ezetimibe degradation increases

Engineering Contradiction:

Improverosuvastatin stabilityVSAvoidezetimibe degradation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

By separating rosuvastatin and ezetimibe into different layers, the patent allows the rosuvastatin layer to contain basic stabilizing excipients without exposing ezetimibe to conditions that cause degradation. The physical barrier of the layer structure prevents harmful interactions.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The layer structure itself acts as an intermediary barrier between rosuvastatin and ezetimibe, preventing the basic excipients in the rosuvastatin layer from contacting and degrading ezetimibe in the second layer.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Ease of manufacture

If the tablet is designed as a single layer containing both active ingredients, then manufacturing is simpler, but bioavailability and release rate control are compromised

Engineering Contradiction:

Improvemanufacturing simplicityVSAvoidbioavailability

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The two-layer structure allows each active ingredient to be released at different rates and under different conditions, optimizing bioavailability for both compounds. The rosuvastatin layer can be formulated for immediate release while the ezetimibe layer can be formulated for sustained release, achieving superior pharmacokinetic profiles compared to a single-layer formulation.

Inventive Principle:

Principle #1Segmentation

4Reliability

If the weight ratio of rosuvastatin to ezetimibe is optimized for therapeutic efficacy, then treatment effectiveness is improved, but formulation stability decreases

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidformulation stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

By placing rosuvastatin and ezetimibe in separate layers, the patent enables independent formulation optimization for each ingredient. Each layer can be designed with the optimal weight ratio and excipient composition for its specific active ingredient, maintaining therapeutic effectiveness while preventing stability issues that arise from suboptimal mixing ratios in single-layer formulations.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS11786526B2Pharmaceutical composition comprising rosuvastatin and ezetimibe and a preparation method thereof

Publication Date: 2023.10.17 SANOFI SA(FR)

AI summary

The invention relates to a pharmaceutical composition comprising the active ingredients rosuvastatin of formula I, with the systematic name (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe of formula II, with the systematic name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one or its pharmaceutically acceptable salts, esters, hydrates or solvates, as well as a preparation method of this pharmaceutical composition. The weight ratio of the layers is 1:2 to 2:1.