Lenalidomide Polymer Conjugates for Sustained Release

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Solution Overview

Problem

Lenalidomide, a drug used for treating multiple myeloma and myelodysplastic syndromes, has limitations due to its short half-life, variable absorption, and significant side effects, including gastrointestinal issues and neurotoxicity, which affect its efficacy and patient compliance.

Innovation Solution

Development of prodrugs and polymer conjugates of lenalidomide with biocompatible polymers to create sustained-release formulations, enhancing bioavailability and reducing dosing frequency, and using nanoparticle/microparticle formulations to improve bioavailability and minimize side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If lenalidomide is administered orally with standard formulations, then the drug can be absorbed and reach therapeutic concentrations, but the short half-life requires frequent dosing and leads to variable plasma concentrations

Engineering Contradiction:

Improvehalf-lifeVSAvoiddosing frequency

Core Design Contradiction:

Duration of action of moving objectVSProductivity

Solution Approach 1:

The patent converts lenalidomide into a prodrug form where the active drug is pre-loaded onto polymer carriers (such as polyethylene glycol derivatives). This preliminary preparation allows the drug to be delivered in a controlled manner over time, extending the effective duration of action from hours to days, thereby reducing dosing frequency from daily to less frequent administrations.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent introduces polymer carriers (intermediaries) that bind to lenalidomide and facilitate its controlled release in the body. These polymer intermediaries protect the drug from rapid clearance, enable sustained release kinetics, and improve solubility and bioavailability, thereby extending half-life and reducing the need for frequent dosing.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If higher doses of lenalidomide are administered to maintain therapeutic levels, then efficacy is improved, but side effects such as gastrointestinal issues and neurotoxicity increase

Engineering Contradiction:

ImproveefficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent creates formulations where the drug is delivered with localized control over release kinetics and tissue distribution. The polymer-prodrug conjugates exhibit improved solubility and targeted delivery characteristics, ensuring that therapeutic concentrations are maintained in relevant tissues while minimizing peak plasma concentrations that cause systemic side effects, thus improving the therapeutic index.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The sustained-release formulations create periodic drug release patterns that maintain stable plasma concentrations within the therapeutic window. This avoids the peaks and troughs associated with standard dosing, preventing both sub-therapeutic periods (reducing efficacy) and supratherapeutic peaks (reducing side effects), thereby improving the reliability of treatment while minimizing harmful effects.

Inventive Principle:

Principle #19Periodic action

3Quantity of substance

If oral absorption is enhanced to improve bioavailability, then more drug reaches circulation, but absorption variability increases due to food effects and gastrointestinal conditions

Engineering Contradiction:

ImprovebioavailabilityVSAvoidabsorption consistency

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The patent uses polymer intermediaries (such as polyethylene glycol chains) that improve the solubility and dissolution characteristics of lenalidomide. These intermediaries create a more stable and predictable release profile that is less susceptible to variations in gastrointestinal conditions and food effects, thereby improving both bioavailability and absorption consistency.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the physicochemical parameters of lenalidomide by converting it to a prodrug form with altered solubility, stability, and release characteristics. These parameter changes result in more consistent absorption kinetics that are less affected by gastrointestinal variability, food intake, and other external factors, thereby improving both the quantity and stability of drug delivery.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20230248696A1Lenalidomide prodrugs, polymeric conjugates, and formulations thereof, and their uses for the treatment of multiple myeloma

Publication Date: 2023.08.10 DYNAMIC BIOLOGICS INC

AI summary

Compounds of formula I and II:or a pharmaceutically acceptable salt thereof, and their compositions including polymer encapsulated micro/nano particle compositions are provided, wherein:R1 is —CH2—, a C2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof;R2 is hydrogen or —(C═O)R3 wherein R3 is a C2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; andR4 is a pharmaceutically acceptable polymeric moiety comprising a pharmaceutically acceptable polymer chain such that R1 is linked to the polymer chain through an ester, carbonate or carbamate bond including the oxygen atom linking R1 and R4.The compositions are useful for treatment of multiple myeloma, mantle cell lymphoma, and transfusion-dependent anemia due to myelodysplastic syndromes.