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ANR funded project

Innovation biomédicale (DS0404)
Edition 2014


Imperio


In-situ forming implants for periodontitis treatment

Customized implants preventing tooth loss
Innovative, in-situ forming implants are developed for the treatment of periodontitis, the leading cause of tooth loss in adults. The innovative drug delivery systems form in-situ, in the periodontal pocket of the patient and release a combination of drugs at pre-programmed rates. Importantly, the systems are free of antibiotic drugs, reliably stay at the site of action and adapt their geometry and dimensions of each individual pocket (personalized medicine).

The main objective of this project is to develop innovative in-situ forming implants, overcoming crucial current hurdles for an efficient drug treatment of periodontitis
Periodontitis is a highly prevalent, chronic inflammatory disease of the periodontium, leading to the destruction of the tooth supporting tissues and finally to 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 >65years). 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 the systems during the treatment and, thus, unreliable drug exposure to the target site. The aim of this project is to overcome these bottlenecks and to develop innovative in-situ forming implants, which: (i) are easy to inject (liquid formulations), (ii) readily spread within the patients’ pockets and adapt their geometry and size to the individuals’ needs, (iii) exhibit reliable residence times, and (iv) control the release of non-antibiotic drugs during optimized periods of time.

In-situ forming implants are formed upon solvent exchange at the site of action. The systems are thoroughly characterized physico-chemically, and the therapeutic effects monitored in mice
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.

Results

In-situ forming implants, loaded with the antiseptic drug chlorhexidine were prepared and characterized. A particular focus was placed on the impact of the drug form (free base versus digluconate versus diHCl versus diacetate) on the key properties of the systems. The drug form strongly impacted the key properties of the in-situ forming implants. Interestingly, there was no simple and straightforward relationship between the drug release kinetics, dynamic mass changes of the implants upon exposure simulated body fluids and the solubility of the drug form. Furthermore, in-situ forming implants combining the antiseptic drug chlorhexidine and the anti-inflammatory drug ibuprofen were investigated. To provide the desired drug release patterns, poly(D,L-lactic-co-glycolic acid) (PLGA)-based implants loaded with chlorhexidine and with polycaprolactone (PCL)-based microparticles containing ibuprofen were prepared. The in-situ forming composite implants were able to control chlorhexidine and ibuprofen release for at least 2 weeks. The presence of ibuprofen PCL microparticles within the PLGA implants significantly reduced the release rate of chlorhexidine. This can be attributed to the significantly reduced implant swelling in presence of ibuprofen loaded PCL-microparticles. The limited implant swelling is of great practical importance, as this significantly reduces the risk of accidental implant expulsion from the periodontal pocket and discomfort for the patient. In addition, the mechanical properties of the novel in-situ forming implants are highly promising: They provide improved textural properties and bioadhesion to human teeth compared to commercial products and can be expected to more easily adapt their geometry to dynamic changes in the shape of the periodontal pockets over time. Hence, they offer an interesting potential to overcome the current shortcomings in local controlled drug delivery for periodontitis treatment.

Outlook

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.

Scientific outputs and patents

Oral presentations 1. Agossa, K; Delcourt-Debruyne, E; Rongthong, T; Siepmann, J; Siepmann, F. 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 Société Française de Parodontologie et d’Implantologie Orale (SFPIO), Lyon, 2016. 2. Morrand, DN; Huck, O; Tennbaum, H; Jessel,N; Davideau, J.-L. Evaluation in vitro d’une membrane de PCL fonctionnalisée par de l’ibuprofène. Congrès national de la Société Française de Parodontologie et d’Implantologie Orale (SFPIO), Lyon, 2016. Posters 1. Rongthong, T; Siepmann, J; Siepmann, F. In-situ forming implants containing drug-loaded microparticles for periodontitis treatment. 10th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Glasgow, UK, Proceedings, 2016. 2. Rongthong, T; Siepmann, J; Siepmann, F. 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, Proceedings, 2016. 3. Agossa, K; Delcourt-Debruyne,E; Rongthong, T; Siepmann, J; Siepmann, F. Propriétés mécaniques d’un implant innovant se formant in-situ pour le traitement parodontal. Congrès du Collège National des Enseignants en Parodontologie (CNEP), Nice, 2016. 4. Agossa, K; Delcourt-Debruyne, E; Rongthong, T; Lizambard, M; Siepmann, J; Siepmann, F. Textural properies and bioadhesion of novel in-situ forming implants for periodontitis treatment. 4th Congress on Innovation in Drug Delivery Site-Specific Drug Delivery, Antibes-Juan-les-Pins, 2016. 5. Rongthong, T; Lizambard, M; Siepmann, J; Siepmann, F. Novel in-situ forming implants loaded with antiseptic and anti-inflammatory drugs for periodontitis treatment. 4th Congress on Innovation in Drug Delivery Site-Specific Drug Delivery, Antibes-Juan-les-Pins, 2016.

Partners

INSERM U 1008 Controlled Drug Delivery Systems and Biomaterials

ImaBiotech ImaBiotech

INSERM U 995 Inflammation : mécanismes de régulation et interactions avec la nutrition et les candidoses

INSERM UMR 1109 Osteoarticular and Dental Regenerative Nanomedicine Laboratory

CNRS UMR 8207 Unité Matériaux et Transformations

ANR grant: 796 993 euros
Beginning and duration: octobre 2014 - 48 mois

Submission abstract

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.

 

ANR Programme: Innovation biomédicale (DS0404) 2014

Project ID: ANR-14-CE16-0025

Project coordinator:
Madame Florence SIEPMANN (Controlled Drug Delivery Systems and Biomaterials)

Project web site: http://u1008.univ-lille2.fr/hosted-websites/anr-imperio.html

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.