A Novel Chlorhexidine and Ibuprofen In-Situ Forming Depot for Periodontal Regeneration: A Proof of Concept Study

Objectives:
Sustained infection and inflammation hinder periodontal wound healing and regeneration. Herein, a novel in-situ forming depot (CHX-IBU/PLGA) was characterized, combining antimicrobial chlorhexidine dihydrochloride (CHX) and anti-inflammatory ibuprofen (IBU) in Poly Lactic-co-Glycolic Acid (PLGA). The drug release from depots in vitro and their impact on periodontal wound healing in vivo were investigated.
Methods:
Two depots (with 0.5% or 2% drug loadings) were prepared by dissolving PLGA in N-methyl pyrrolidone, plasticizer (acetyltributyl citrate), mucoadhesive polymer (hydroxypropyl methylcellulose) and two drugs (CHX and IBU: each 0.5% or 2% w/w, based on total liquid formulation without drug). The depots were formed by solvent exchange (at 37 °C and 80 rpm) and their drug content was determined using HPLC-UV. The relative mass change was calculated by weighing depots at pre-determined time points after removing excess water (blotting with precision wipes). The formulations were also tested in a P.gingivalis induced periodontitis mouse model. Periodontal wound healing after intra-pocket administration of the formulations in 4 groups (untreated, placebo, 0.5%, 2%) was histomorphometrically studied at 7 days (n=16) and 15 days (n=16) respectively.
Results: In vitro, drug release studies showed that 20mg and 90mg of IBU were released from 0.5 and 2% depots respectively, whereas, 150mg (from 0.5% depot) and 400mg CHX (from 2% depot) were released during 2 days, reaching desired drug concentrations and further peaking over time. 2% depot showed a decrease in mass over time, while, 0.5% depot followed a similar pattern as the placebo. In vivo, histomorphometry showed that treatment with the depots (0.5% and 2%) significantly reduced the length of junctional epithelium and increased connective tissue attachment on root surface.
Conclusions: This study showed that CHX-IBU/PLGA depots maybe an efficient local drug delivery system that could allow time and dose controlled diffusion of anti-microbial and anti-inflammatory drugs, improving periodontal wound healing by decreasing inflammation at the soft tissue level.