Rapamycin Cyclic Hydrocarbon Esters for Stent Coating Integrity
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Solution Overview
Problem
Rapamycin stents face issues with coating instability and cracking during expansion, leading to reduced drug release and potential clotting hazards, along with high rates of restenosis after percutaneous transluminal coronary angioplasty (PTCA) due to poor drug stability and flaking coatings.
Innovation Solution
Development of a rapamycin 40-O-cyclic hydrocarbon ester with enhanced ductility, incorporated into a bioerodable polymer coating for stents, which reduces cracking and improves drug stability and release, using a stent with a polymer coating containing 40%-80% polymer and 20%-60% rapamycin compound with a 40-O—OH or —O(CH)nOH substituent, where n=1 to 5, to prevent flaking and enhance drug delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rapamycin is coated on stent using conventional methods, then drug delivery function is achieved, but coating cracks and flakes during stent expansion
Solution Approach 1:
The patent modifies the chemical structure of rapamycin by converting the 40-OH group to various ester derivatives (cyclic carbonate, cyclic carbamate, cyclic carboxylate esters) and further to cyclic hydrocarbon esters. These parameter changes in molecular structure improve the drug's compatibility with polymer coatings, enhancing coating ductility and preventing cracking during stent expansion while maintaining therapeutic efficacy.
Solution Approach 2:
The patent creates composite coating systems combining modified rapamycin derivatives with bioerodable polymers (polyesters, polyamides, polyanhydrides). These composite materials provide both structural integrity during stent expansion and controlled drug release functionality, resolving the contradiction between coating durability and drug delivery.
2Reliability
If high concentration of rapamycin is used in coating, then restenosis inhibition is improved, but coating stability decreases and drug loss increases
Solution Approach 1:
The patent employs parameter changes by modifying rapamycin's chemical structure to create esters with improved stability profiles. The cyclic hydrocarbon ester derivatives maintain high potency for restenosis prevention while exhibiting enhanced stability in polymer coatings, allowing higher effective concentrations without compromising coating integrity or experiencing excessive drug loss.
3Productivity
If conventional rapamycin coating is applied, then initial drug release occurs, but drug stability is poor with less than 40% active drug recovered
Solution Approach 1:
The patent applies parameter changes through systematic modification of rapamycin's 40-OH group to create a series of ester derivatives with optimized stability-release profiles. The cyclic hydrocarbon esters particularly excel by providing both enhanced stability (maintaining >80% active drug recovery) and sustained release capability, directly addressing the contradiction between drug stability and release efficiency.
Data Source
AI summary
A new class of rapamycin 40-O-cyclic hydrocarbon esters is disclosed. The 40-O position of the rapamycin ester has the form 40-O—R, where R is C(O)—(CH2)n-X, n is 0, 1 or 2, and X is a cyclic hydrocarbon having 3-8 carbons, optionally containing one or more unsaturated bonds, and one or more linear (CH2)) and/or cyclic (X) carbon atoms may have an OH or halide group. Also disclosed are therapeutic compositions and methods that employ the novel analogs.