Rasagiline Citrate Delayed Release Coating
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Solution Overview
Problem
The commercially available form of rasagiline mesylate has concerns such as the risk of hypertensive crises due to peripheral MAO inhibition and delayed gastric emptying, which can contribute to the 'cheese effect, and potential formation of alkyl mesylates, and previous formulations did not adequately address these issues or provide bioequivalence to immediate release formulations.
Innovation Solution
A stable oral dosage form of rasagiline citrate is developed, comprising a core of rasagiline base and citric acid with a pharmaceutically acceptable excipient, coated with an acid-resistant coating to prevent stomach absorption and achieve bioequivalence with immediate release formulations, using a process that includes wet granulation, drying, milling, and compression, with specific excipients like methacrylic acid-ethyl acrylate copolymer and triethyl citrate to ensure delayed release in the duodenum or jejunum.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rasagiline mesylate is used to treat Parkinson's disease, then the therapeutic effect is achieved, but the risk of hypertensive crises and cheese effect increases due to peripheral MAO inhibition
Solution Approach 1:
The patent segments the drug delivery system into two distinct parts: an acid-resistant coating layer that prevents drug release in the stomach, and a core containing rasagiline base and citric acid that releases the drug in the small intestine. This spatial segmentation ensures the drug is delivered only to the intended site, avoiding peripheral MAO inhibition in the stomach while maintaining therapeutic efficacy in the brain.
Solution Approach 2:
The acid-resistant coating acts as an intermediary barrier between the rasagiline drug and the stomach environment. This coating layer prevents direct contact between the drug and gastric MAO, thereby eliminating the cheese effect while allowing the drug to reach the small intestine where it can be absorbed and transported to the brain for therapeutic action.
2Reliability
If rasagiline is released in the stomach, then absorption occurs, but delayed gastric emptying prolongs gastric residence time and increases peripheral MAO inhibition
Solution Approach 1:
The patent applies preliminary action by pre-coating the rasagiline core with an acid-resistant layer before administration. This coating is designed to resist gastric acid and prevent drug release during gastric residence, ensuring that even if the drug remains in the stomach for an extended period due to delayed gastric emptying, it will not be released or absorbed until the tablet reaches the small intestine.
Solution Approach 2:
The patent changes the physical-chemical parameters of the drug delivery system by using an acid-resistant coating that alters the dissolution characteristics of rasagiline. The coating maintains structural integrity at gastric pH levels but dissolves at the higher pH of the small intestine, thereby controlling the timing and location of drug release independent of gastric emptying rate.
3Speed
If immediate release formulation is used, then rapid absorption occurs, but peripheral MAO inhibition and cheese effect occur
Solution Approach 1:
The patent applies local quality by creating a drug delivery system with different properties in different locations: the acid-resistant coating provides protection in the stomach environment, while the core formulation ensures rapid dissolution and absorption in the small intestine. This localized functional differentiation allows the drug to avoid harmful interactions in the stomach while maintaining rapid absorption characteristics in the intestine.
4Object-affected harmful factors
If delayed release coating is applied, then stomach absorption is prevented, but formulation complexity increases
Solution Approach 1:
The patent uses composite materials by combining rasagiline base with citric acid in the core formulation, and coating this core with an acid-resistant polymer layer. This composite structure integrates multiple functions: the citric acid stabilizes the rasagiline base, while the acid-resistant coating provides site-specific release. The composite approach achieves complex functionality through the synergistic combination of simpler materials rather than requiring a single complex substance.
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 achieves bioequivalence with immediate release rasagiline, reducing the risk of peripheral MAO inhibition and the 'cheese effect by delaying rasagiline release until the small intestine, while maintaining stability and efficacy, with enhanced pharmacokinetic profiles and reduced impurity levels.
Implementation Method 1
an acid resistant pharmaceutically acceptable coating
Implementation Method 2
using a process that includes wet granulation, drying, milling, and compression
Data Source
AI summary
Disclosed are formulations of rasagiline base which are designed to delay release of rasagiline while maintaining specific pharmacokinetic properties. Also, disclosed are rasagiline citrate salt and the use and process of manufacture thereof.