In-situ forming PLGA implants: Towards less toxic solvents.

In-situ forming poly(lactic-co-glycolic acid) (PLGA) implants offer a great potential for controlled drug delivery for a variety of applications, e.g. periodontitis treatment. The polymer is dissolved in a water-miscible solvent. The drug is dissolved or dispersed in this solution. Upon contact with aqueous body fluids, the solvent diffuses into the surrounding tissue and water penetrates into the formulation. Consequently, PLGA precipitates, trapping the drug. Often, N-methyl-2-pyrrolidine (NMP) is used as a water-miscible solvent. However, parenteral administration of NMP raises toxicity concerns. The aim of this study was to identify less toxic alternative solvent systems for in-situ forming PLGA implants. Various blends of polyethylene glycol 400 (PEG 400), triethyl citrate (TEC) and ethanol were used to prepare liquid formulations containing PLGA, ibuprofen (as an anti-inflammatory drug) and/or chlorhexidine dihydrochloride (as an antiseptic agent). Implant formation and drug release kinetics were monitored upon exposure to phosphate buffer pH 6.8 at 37 °C. Furthermore, the syringeability of the liquids, antimicrobial activity of the implants, and dynamic changes in the latter's wet mass and pH of the release medium were studied. Importantly, 85:10:5 and 60:30:10 PEG 400:TEC:ethanol blends provided good syringeability and allowed for rapid implant formation. The latter controlled ibuprofen and chlorhexidine release over several weeks and assured efficient antimicrobial activity. Interestingly, fundamental differences were observed concerning the underlying release mechanisms of the two drugs: Ibuprofen was dissolved in the solvent mixtures and partially leached out together with the solvents during implant formation, resulting in relatively pronounced burst effects. In contrast, chlorhexidine dihydrochloride was dispersed in the liquids in the form of tiny particles, which were effectively trapped by precipitating PLGA during implant formation, leading to initial lag-phases for drug release.

In-situ forming implants for the treatment of periodontal diseases: Simultaneous controlled release of an antiseptic and an anti-inflammatory drug.

Different types of in-situ forming implants based on poly(lactic-co-glycolic acid) (PLGA) for the controlled dual release of an antiseptic drug (chlorhexidine) and an anti-inflammatory drug (ibuprofen) were prepared and thoroughly characterized in vitro. N-methyl-pyrrolidone (NMP) was used as water-miscible solvent, acetyltributyl citrate (ATBC) as plasticizer and hydroxypropyl methylcellulose (HPMC) was added to enhance the implants' stickiness/bioadhesion upon formation within the periodontal pocket. Different drug forms exhibiting substantially different solubilities were used: chlorhexidine dihydrochloride and digluconate as well as ibuprofen free acid and lysinate. The initial drug loadings were varied from 1.5 to 16.1%. In vitro drug release, dynamic changes in the pH of the surrounding bulk fluid and in the systems' wet mass as well as polymer degradation were monitored. Importantly, the release of both drugs, chlorhexidine and ibuprofen, could effectively be controlled simultaneously during several weeks. Interestingly, the tremendous differences in the drug forms' solubilities (e.g., factor >5000) did not translate into major differences in the resulting release kinetics. In the case of ibuprofen, this can likely (at least in part) be attributed to significant drug-polymer interactions (ibuprofen acts as a plasticizer for PLGA). In the case of chlorhexidine, the release of the much less soluble dihydrochloride was even faster compared to the more soluble digluconate (when combined with ibuprofen free acid). In the case of ibuprofen, at higher initial drug loadings also limited solubility effects within the implants seem to play a role, in contrast to chlorhexidine. In the latter case, instead, increased system porosity effects likely dominate at higher drug loadings.

Physical key properties of antibiotic-free, PLGA/HPMC-based in-situ forming implants for local periodontitis treatment.

In-situ forming implants (ISFI) offer an interesting potential for the treatment of periodontitis, allowing for time-controlled drug release directly at the site of action (which is difficult to reach). For this purpose, ISFI loaded with antibiotics have been reported in the literature. But the use of antibiotic drugs at low doses over prolonged periods of time can lead to the development of bacterial resistances. This risk should be avoided. The aim of this study was to develop a novel type of in-situ forming implants, loaded with the antiseptic drug chlorhexidine. Special emphasis was placed on the physical properties of the systems, assuring a reliable residence time in the periodontal pockets of patients suffering from periodontitis. In particular, the risk of premature, accidental loss of the formulations due to mechanical stress (e.g. during tooth brushing and chewing) was to be reduced. Two commercially available drug products for local periodontitis treatment were studied for reasons of comparison: Chlo-site and Parocline. The syringeability and swelling behavior of the formulations were investigated, and the hardness, springiness, resilience and "stickiness" of the systems determined using extracted human teeth. Interestingly, the novel in-situ forming implants, based on PLGA/HPMC and being free of antibiotics, exhibit highly promising physical key properties: They are intensively sticking to teeth' surfaces and provide adequate mechanical strength to assure reliable and prolonged residence times in periodontal pockets. In contrast, the commercial drug products showed limited adhesion and either rapidly shrank (Chlo-site), or substantially swelled and were mechanically very weak (Parocline).

Periodontal manifestations of inflammatory bowel disease: emerging epidemiologic and biologic evidence.

Inflammatory bowel disease and periodontitis are both described as a disproportionate mucosal inflammatory response to a microbial environment in susceptible patients. Moreover, these two conditions share major environmental and lifestyle-related risk factors. Despite this intriguing pathogenic parallel, large-scale studies and basic research have only recently considered periodontal outcomes as relevant data. There are mounting and consistent arguments, from recent epidemiologic studies and animal models, that these two conditions might be related. This article is a comprehensive and critical up-to-date review of the current evidence and future prospects in understanding the biologic and epidemiologic relationships between periodontal status and inflammatory bowel disease.