In-situ forming implants for periodontitis treatment – Imperio

The basic idea is to dissolve the drug (or a combination of drugs) together with a biodegradable matrix former in a common solvent. This liquid is administered using standard syringes into the patients’ pockets. Once in contact with aqueous body fluids, the solvent diffuses out of the system, causing the precipitation of the matrix former and drug entrapment. The latter is subsequently released in time-controlled manner at the target site. This leads to optimized therapeutic efficacy and reduced drug exposure to the rest of the human body, thus, minimized side effects. Due to the biodegradability of the in-situ formed implant, empty remnants do not need to be removed after drug exhaust. A highly interdisciplinary consortium encompassing pharmacists, dentists, microbiologists, immunologists, physicists, chemists etc., offers the whole range of innovation: from clinical expertise to advanced research, through technological development, up to cutting-edge evaluation in animal models. New types of in-situ forming implants will be prepared and thoroughly characterized in vitro as well as in vivo (periodontitis mouse model). For instance, MS imaging (MALDI) will allow getting deeper insight into the underlying mass transport mechanisms, drug release kinetics and pharmacodynamic efficacy of the systems, mapping for example the spatial distribution of the drug and inflammation markers in the animal tissue.

In-situ forming implants loaded with an antiseptic drug (chlorhexidine) and an anti-inflammatory drug (ibuprofen) were prepared and thoroughly characterized. Particular attention was paid to the impact of the type of drug salts and drug loadings on system performance. It could be shown that both parameters not only affected the resulting drug release kinetics, but also the injectability of the formulations. In addition the mechanical and swelling properties of the implants could be altered and, hence, the risk of uncontrolled and premature expulsion out of the periodontal pocket. Simultaneous diffusion of chlorhexidine and ibuprofen could be monitored using MALDI imaging in a gel mimicking in vivo tissues. Microbiological assays highlighted the antibacterial activity against samples obtained from patients suffering from periodontitis, as well as against isolated bacterial strains. The rapid bactericide and anti-biofilm activity, demonstrated in vitro, should contribute to the eradication of the parodontal pathogenic flora and hamper recolonization of the site in vivo. Moreover, ibuprofen seems to present an additional antimicrobial activity, added to that of chlorhexidine. The most promising implants (chlorhexidine dihydrochloride/ibuprofen 0.5% - 2%) were investigated in vivo in a periodontitis mouse model. The first histological analyses have shown very promising results with respect to attachment level.

The project will open up new horizons for innovative medicines: - Imperio will provide new, powerful tools allowing for more efficient local treatments of periodontitis. - The project will overcome a fundamental current drawback of in-situ forming implants for advanced periodontitis treatment: their lack of bioadhesion. - Imperio will allow identifying novel drug combinations and optimized release kinetics, combating the development of bacterial resistances against antibiotics. Specific expected outcomes include: -Know-how to prepare innovative in-situ forming implants for improved periodontitis treatment (protocols and prototypes). - Comprehensive database on the key characteristics of these new types of drug delivery systems (e.g., stickiness, drug release periods, drug release rates). - Comprehensive databases on the in vivo performances (animals) of the innovative drug delivery systems. This information will serve as a basis for the conduction of clinical trials, envisaged as follow-up studies of this ANR project. Hence, Imperio will allow transferring new knowledge obtained in the fundamental sciences into practical/industrial applications. All partners in this consortium have prior experience in securing intellectual property rights. Partner 5 is a French SME and medical doctors are part of the consortium. The scientific findings of the project will also be disseminated by the means of publications in scientific journals and will be presented orally and as posters at international and national scientific meetings. Importantly, non-antibiotic drugs will be studied, thus, the project will also contribute to the combat against the development of bacterial resistances.

International publications: Elisei et al. Crystalline Polymorphism Emerging From a Milling-Induced Amorphous Form: The Case of Chlorhexidine Dihydrochloride. J Pharm Sci. Sous presse Agossa et al. Physical key properties of antibiotic-free, PLGA/HPMC-based in-situ forming implants for local periodontitis treatment. Int J Pharm15, 2017, 282-293. Oral presentations: Agossa et al. Mise au point d’un modèle d’évaluation de l’adhésion d’un implant formé in situ pour le traitement des poches parodontales. Congrès national de la SFPIO, Lyon, 2016. Morrand et al. Evaluation in vitro d’une membrane de PCL fonctionnalisée par de l’ibuprofène. Congrès national de la SFPIO, Lyon, 2016. Posters: Agossa et al. Antimicrobial activity of novel in situ forming implants for periodontitis treatment. CED-IADR/NOF Oral Health Research, Vienna, Austria, 2017. Rongthong et al. In-situ forming implants containing drug-loaded microparticles for periodontitis treatment. 10th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Glasgow, UK, 2016. Rongthong et al. Chlorhexidine-loaded, in-situ forming implants for periodontitis treatment: Importance of the drug form. 10th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Glasgow, UK, 2016. Agossa et al. Textural properies and bioadhesion of novel in-situ forming implants for periodontitis treatment. 4th Congress on Innovation in Drug Delivery, Antibes-Juan-les-Pins, 2016. Rongthong et al. Novel in-situ forming implants loaded with antiseptic and anti-inflammatory drugs for periodontitis treatment. 4th Congress on Innovation in Drug Delivery, Antibes-Juan-les-Pins, 2016. Rongthong, et al. Chlorhexidine-loaded, in-situ forming PLGA implants for periodontitis treatment: importance of the type of salt and loading. 2nd European conference on pharmaceutics, Krakow, Poland, 2017.

Periodontitis is a highly prevalent, chronic inflammatory disease of the periodontium, leading to the destruction of the tooth supporting tissues and finally tooth loss. Microorganisms in the patients’ periodontal pockets produce molecules, which directly attack the host tissue, and/or cause an immune response leading to tissue destruction. Periodontitis is the main cause for tooth loss in adults: 47% of the US adults have mild, moderate or severe periodontitis (64% of the population > 65 years). The treatment of periodontitis is highly challenging, since drug partitioning into the periodontal pockets is not very pronounced and gingival fluid flow rapidly eliminates the drug from the site of action. Hence, using conventional administration routes, high systemic drug levels are required, while the drug concentration at the target site remains low. This leads to potentially severe side effects and low therapeutic efficacy, despite the availability of highly potent drugs able to act against the pathogenic flora and inflammation. These hurdles can be overcome using local controlled drug delivery systems: In this case, the drug is directly administered at the site of action and its release is controlled during prolonged periods of time. Different types of systems have been proposed; however most of them contain antibiotic drugs and exhibit insufficient adhesion to the walls of the periodontal pockets, combined with inappropriate mechanical properties. This leads to uncontrolled expulsion of at least parts of the systems during the treatment and, thus, unreliable drug exposure to the target site. The aim of this project is to overcome these severe bottlenecks and to develop innovative in-situ forming implants, which: (i) are easy to inject (as liquid formulations), (ii) readily spread within the patients’ pockets and adapt their geometry and size to the individuals’ needs, (iii) exhibit reliable residence times due to improved bioadhesion and adequate plasticity, and (iv) control the release of non-antibiotic drugs during optimized periods of time. The basic idea is to dissolve the drug (or a combination of drugs) together with a biodegradable matrix former in a common solvent. This liquid is administered using standard syringes into the patients’ pockets. Once in contact with aqueous body fluids, the solvent diffuses out of the system, causing the precipitation of the matrix former and drug entrapment. The latter is subsequently released in time-controlled manner at the target site. This leads to optimized therapeutic efficacy and reduced drug exposure to the rest of the human body, thus, minimized side effects. Due to the biodegradability of the in-situ formed implant, empty remnants do not need to be removed after drug exhaust. A highly interdisciplinary consortium encompassing pharmacists, dentists, microbiologists, immunologists, physicists, chemists etc., offers the whole range of innovation: from clinical expertise to advanced research, through technological development, up to cutting-edge evaluation in animal models. New types of in-situ forming implants will be prepared and thoroughly characterized in vitro as well as in vivo (periodontitis mouse model). For instance, MS imaging (MALDI) will allow getting deeper insight into the underlying mass transport mechanisms, drug release kinetics and pharmacodynamic efficacy of the systems, mapping for example the spatial distribution of the drug and inflammation markers in the animal tissue. The obtained comprehensive database on the performance and key features of the innovative drug delivery systems will serve as a basis for the conduction of clinical trials, which are envisaged as follow-up studies. With a French SME being part of the consortium, also the economic exploitation of the results is foreseen. Importantly, non-antibiotic drugs will be studied, thus, the project will contribute to the combat against the development of bacterial resistances.