5-Fluoropyrimidine Formulations for Sustained Plasma Concentration
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Solution Overview
Problem
Current immediate release (IR) orally administered anticancer fluoropyrimidine drugs, such as capecitabine, fail to maintain plasma drug concentration within the therapeutic effective range, leading to suboptimal therapeutic effects due to concentrations dropping below minimum therapeutic levels approximately 6 hours post-administration.
Innovation Solution
Development of pharmaceutical formulations of 5-fluoropyrimidine derivatives in various release forms, including immediate release, controlled release, and sustained release, designed to maintain therapeutic plasma concentrations for extended periods through optimized dosage regimens and excipient combinations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If immediate release orally administered fluoropyrimidine drugs are used, then the drug is easily absorbed and reaches therapeutic concentration quickly, but the plasma concentration drops below minimum therapeutic level after approximately 6 hours
Solution Approach 1:
The patent divides the single dose into multiple smaller doses administered at intervals, or segments the release mechanism into different phases (immediate release component followed by sustained release component). This segmentation allows the drug to be released in stages, maintaining therapeutic levels throughout the day without requiring a single large dose that would cause peak-trough fluctuations.
Solution Approach 2:
The patent modifies the release parameters of the drug formulation by incorporating sustained release mechanisms that change the release rate over time. This parameter change transforms the rapid single-dose release into a controlled, extended-release profile, maintaining plasma concentration within the therapeutic window for 24 hours or longer.
2Reliability
If higher doses are administered to maintain therapeutic concentration, then the therapeutic effect is improved, but the toxicity and side effects increase
Solution Approach 1:
The patent employs periodic dosing schedules (e.g., twice daily or three times daily) that deliver smaller amounts of drug at regular intervals. This periodic administration maintains steady therapeutic levels without the peak concentrations that cause toxicity, as each dose is spaced enough time apart to allow metabolism of previous doses while preventing subtherapeutic troughs.
Solution Approach 2:
The sustained release formulation provides continuous drug delivery over 24 hours or longer, eliminating the peak-trough fluctuations associated with immediate release formulations. This continuous action maintains plasma concentration within the therapeutic window without exceeding toxic thresholds, thereby improving reliability while reducing harmful effects.
3Duration of action of moving object
If multiple daily doses are administered to maintain therapeutic levels, then the plasma concentration is maintained, but patient compliance and convenience decrease
Solution Approach 1:
The patent segments the dosing frequency into practical intervals (twice daily or three times daily) that balance therapeutic requirements with patient convenience. This segmentation avoids the impracticality of continuous dosing while preventing the subtherapeutic gaps of less frequent dosing, thereby maintaining compliance.
Solution Approach 2:
The patent changes the release time parameter of the formulation to extend drug action from 6 hours to 24 hours or longer. This parameter change allows once-daily or twice-daily dosing to achieve the same therapeutic effect that would otherwise require three or four times daily dosing with immediate release formulations, significantly improving ease of operation and patient compliance.
4Duration of action of moving object
If extended release formulations are developed to maintain therapeutic levels, then the duration of action is improved, but the formulation complexity increases
Solution Approach 1:
The patent employs composite formulation strategies combining immediate release and sustained release components in a single dosage form. This composite approach uses well-established excipients and release mechanisms that are commercially available and manufacturable, avoiding the need for complex novel delivery systems while achieving extended therapeutic coverage.
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 formulations achieve and maintain therapeutic drug levels for the duration of treatment, enhancing the therapeutic efficacy and patient compliance by providing improved solubility, stability, and bioavailability.
Implementation Method 1
Endogenous enzymes convert 5-fluoropyrimidine derivatives to 5-fluorouracil (5-FU)
Implementation Method 2
pharmaceutical formulations of 5-fluoropyrimidine derivatives in various release forms, including immediate release, controlled release, and sustained release, designed to maintain therapeutic plasma concentrations for extended periods
Data Source
AI summary
The present invention relates to a pharmaceutical formulation of 5-fluoropyrimidine derivatives or a salt, solvate, or hydrate thereof for oral administration wherein the formulation is a simple composition for ingestion, simple, safest, convenient, non-invasive, versatility and most importantly, the patient compliance for oral administration with improved compliance, safety, and bioavailability. Further disclosed is a process for the preparation, composition, methods of administration, dosages of the formulation and their use for treating cancers and its associated complications.