Polymeric prodrugs of ampicillin as antibacterial coatings

Abstract

A novel ampicillin prodrug containing two carboxylic acid functionalities was synthesized by reacting ampicillin with acyl chloride in the presence of base. This prodrug was subsequently converted into a poly(anhydride-amide) via solution polymerization. The polymer, which chemically incorporates the ampicillin prodrug into the polymeric backbone, was developed as a film to prevent infections associated with medical devices by controlled, localized release of antimicrobials. The robust polymer coatings exhibiting strong adhesion to stainless steel were produced under elevated temperature and reduced pressure. The in vitro hydrolytic degradation of the polymer into the ampicillin prodrug was measured and the antibacterial activity of polymer-derived coatings was examined using a Gram-positive bacterium, Staphylococcus aureus. Furthermore, the polymer cytotoxicity was screened using fibroblasts. The ampicillin prodrug demonstrated antibacterial activity and the polymer demonstrated no cytotoxic effects on fibroblasts. Based on these results, the biodegradation of the antimicrobial-based poly(anhydride-amide) into the prodrug displays substantial promise as an implant or implant coating to reduce device failure resulting from bacterial infections.

Polyactives: controlled and sustained bioactive release via hydrolytic degradation

“…83,84 Ampicillin, a commonly used betalactam antibiotic, was chemically incorporated into a poly-(anhydride-amide) backbone using a method similar to that described in section 3.1 (Scheme 6). 85 Bearing a primary amine and a carboxylic acid moiety, ampicillin (23) was reacted with a diacyl chloride (e.g., sebacoyl chloride, 24) to afford the diacid (25). Solution polymerization with triphosgene as a coupling agent resulted in the poly(anhydride- amide) (26).…”

Polyanhydride Chemistry

“…This approach would confer properties such as high drug loading, enhanced processability and better controlled release kinetics to the polymer . Poly­(anhydride-ester) based polyactives can also be employed as prodrug platforms for the controlled release of various therapeutics and bioactive small organic molecules including antioxidants, − anti-inflammatory drugs, , antiseptics, , antibiotics, and antimicrobial drugs . Recently, Madras et al also reported several poly­(anhydride-esters) that contained bioactive molecules such as salicylic acid and aspirin in the polymer main chain. − They studied the release kinetics associated with the hydrolytic degradation of the polymer matrix and subsequently investigated their anti-inflammatory and antibacterial activities.…”

A bio-based pro-antimicrobial polymer network via degradable acetal linkages

“…Poly(actives), or polymeric pro-drugs that rely on degradable linkages for the release of therapeutic agents, can improve chemical stability, enable tunable release profiles, and reduce volatility [15]. Multiple linear poly(actives) have been reported including poly(esters) [16, 17], poly(anhydride-esters) [18–25], poly(anhydride-amides) [26], poly(carbonate-amides) [27], poly(carbonate esters) [28], poly(ketals) [29], and poly(oxalate-acetals) [30]. While linear poly(actives) successfully entrap drugs and allow for tunable release profiles, crosslinked poly(actives) represent a relatively unexplored class of degradable drug-releasing materials where opportunities for greater control over degradation profiles, thermomechanical properties, and sample geometry (particles, thin films, or coatings) are available.…”