Khadija Schwach-Abdellaoui

Local delivery of antimicrobial agents for the treatment of periodontal diseases

Periodontitis is an inflammatory disease of the supporting tissues of the teeth caused by groups of specific microorganisms. Aggressive forms of periodontitis can be localized or generalized. The concept that localized problem sites may be treated by local drug delivery appears attractive as the antimicrobial agent is delivered within periodontal pockets and the therapy is targeted on specific pathogenic microorganisms. Local delivery of antimicrobial agents using controlled release systems should be considered as adjunctive to mechanical debridement for the treatment of localized forms of periodontal destruction. This article reviews various types of delivery systems evaluated in practical periodontal therapy. Despite the large number of studies showing an enhanced effectiveness of local antibiotherapy, there are insufficient comparative data to support any of the local delivery system.

Release of BSA from poly(ortho ester) extruded thin strands

A solventless procedure was used where powdered polymer and micronized protein were intimately mixed and then extruded into 1 mm strands that were cut to the desired length. The polymers used were poly(ortho esters) specifically designed to allow extrusion in the neighborhood of 70 degrees C. At these temperatures many proteins maintain activity in the dry state. In vitro erosion and BSA release results indicate that after a fairly long lag-time, BSA release and polymer erosion occur concomitantly indicating an erosion-controlled process. The lag-time could be eliminated by the addition to the mixture prior to extrusion between 1 and 5 wt% poly(ethylene glycol) or its methoxy derivatives. The lag-time could also be eliminated by using an AB-block copolymer where A is poly(ortho ester) and B is poly(ethylene glycol).

Therapeutic applications of viscous and injectable poly(ortho esters).

Poly(ortho esters) (POE) are hydrophobic and bioerodible polymers that have been investigated for pharmaceutical use since the early 1970s. Among the four described generations of POE, the third (POE III) and fourth (POE IV) are promising viscous and injectable materials which have been investigated in numerous biomedical applications. POE III has been extensively studied for ophthalmic drug delivery, it presents an excellent biocompatibility and is currently being investigated as a vehicle for sustained drug delivery to treat diseases of the posterior segment of the eye. POE IV is distinguishable by a highly reproducible and controlled synthesis, a higher hydrophobicity, and an excellent biocompatibility. It is currently under development for a variety of applications, such as ocular delivery, periodontal disease treatment and applications in veterinary medicine. This review will also focus on new perspectives for this promising family of polymers, such as guided tissue regeneration, treatment of osteoarthritis, as well as peptide and protein delivery.

Control of Molecular Weight for Auto-Catalyzed Poly(ortho ester) Obtained by Polycondensation Reaction

Polycondensation of auto-catalyzed poly(ortho ester)s (POE x LA y ) containing lactic acid units in the polymer backbone is described. The use of n-decanol during the polymerization as a chain stopper allows good control of polymer molecular weight. POE 70 LA 30 based on 3,9-diet-hylidene-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU), 1,10-decanediol-lactate and 1,10-decanediol and synthesized by using 5, 10 and 15 mol % of n-decanol were characterized by 13 C NMR, 1 H NMR and FT-IR. The thermal and viscoelastic properties of such polymers as well as their molecular weight distribution are also reported.

Poly(ortho esters) : their development and some recent applications

Poly(ortho esters) have been under development since the early 1970s and four families of such polymers have been described. Of most interest are poly(ortho ester) III and poly(ortho ester) IV. Poly(ortho ester) III is a semisolid material that has been shown to be highly biocompatible and is currently being investigated as an adjunct to glaucoma filtering surgery and other ocular applications. However, the polymerization is difficult to control and is not readily scaled up. Poly(ortho ester) IV can be easily prepared in a highly reproducible manner, is very stable provided moisture is rigorously excluded and has also been shown to be highly biocompatible. It is currently under development for a variety of applications, such as ocular delivery, protein release, post-operative pain treatment and post-operative cancer treatment.

Formation of peptide impurities in polyester matrices during implant manufacturing

Most peptides are susceptible, in vivo, to proteolytic degradation, and it is difficult to formulate and to deliver them without loss of biological activity. In addition, it is often desirable to release them continuously and at a controlled rate over a period of weeks or months. For these reasons, a controlled release system is suitable. Poly(lactic acid) (PLA) is a biocompatible and biodegradable material that can be used for many applications, including the design of injectable controlled release systems for pharmaceutical agents. Development of these delivery systems presents challenges in the assessment of stability, specially for peptide drugs. By means of an extrusion method, long-acting poly(lactic acid) implants containing vapreotide, a somatostatin analogue, were prepared. The nature of the main degradation product obtained after implant manufacturing was elucidated. It was found that the main peptide impurity was a lactoyl lactyl-vapreotide conjugate. Because lactide are found in small quantities in most commercially available PLA, the influence of residual lactide in the polymeric matrix, on the formation of peptide impurities during manufacturing, was specially investigated. This work demonstrates that the degree of purity of the carrier is of great importance with regard to the formation of peptide impurities.

Optimization of a novel bioerodible device based on auto-catalyzed poly(ortho esters) for controlled delivery of tetracycline to periodontal pocket

Local delivery of antimicrobial agents in inflamed periodontal pocket has been shown to be effective in reducing periodontopathic microorganisms. This research focuses on developing and characterizing bioerodible formulations based on auto-catalyzed poly(ortho esters) (POExLAy) for modulated release of tetracycline over 2 weeks. POExLAy are a new versatile family of POE-containing lactoyl lactyl dimers in the polymer backbone. By modifying the proportion of lactic acid in the polymer, viscous or solid materials having different degradation rate can be produced. The formulations can be either injected or placed as a solid device directly into the periodontal pocket. Tetracycline-free base incorporated into these materials was released within 10-14 days depending on polymer structure. Increase in lactic acid content in the polymer tended to increase the drug release rate and to reduce the initial lag time. Tetracycline release from such bioerodible delivery system occurs predominantly by surface erosion of the polymeric matrix, leading to kinetics which can be zero order. This periodontal drug delivery system is designed to be used as an adjunct in the treatment of periodontal diseases. Clinical studies are currently in progress.

Influence of irradiation sterilization on a semi-solid poly(ortho ester)

Viscous poly(ortho ester) (POE), a promising polymer for controlled release is being investigated as an injectable drug delivery system for peptides, for antiproliferative agents after glaucoma filtering surgery and for antibiotics in the treatment of periodontitis. Due to the chemical lability of POE, the strategies for obtaining a sterile product are limited to aseptic processing and terminal sterilization using high energy radiation. In the first part of the present investigation, we used electron-paramagnetic-resonance (EPR) spectroscopy to evaluate radical formation and radical-induced polymer degradation after irradiation treatment. Due to the viscous nature of POE, radicals were only found at low temperatures or by using the method of ‘spin-trapping’. Several radical species could be distinguished by a variation of the microwave power and the differences of the thermal stability of the radicals. The incorporation of 5-fluorouracil accelerates the degradation of the polymer. In the second part, we have compared the effects of the two commonly applied methods for irradiation sterilization (i.e. gamma and beta rays) on POE and on POE with incorporated 5-fluorouracil and compared these methods to aseptically prepared devices. In addition, we have checked the possibility of preventing radical-induced degradation using two different protecting agents: α-tocopherol at a concentration of 0.1% (w/w) and sterilization under nitrogen monoxide. The weight and number average molecular weight of POE decreased drastically after irradiation treatment and subsequent to irradiation, an accelerated degradation was observed. Generally it was found that higher molecular weight polymers are more affected and that gamma irradiation leads to more degradation than beta treatment. Also, the addition of protecting agents did not significantly prevent polymer degradation. Therefore, we have concluded that irradiation sterilization of POE is not a viable process and aseptic preparation is preferred. Without sterilization POE is stable for about 1 year when kept as monodoses at low temperatures.

Development and applications of injectable poly(ortho esters) for pain control and periodontal treatment.

Poly(ortho esters) with a low glass transition temperature are semi-solid materials so that therapeutic agents can be incorporated at room temperature, without the use of solvents, by a simple mixing procedure. When molecular weights are limited to < 5 kDa, such materials are directly injectable using a needle size no larger than 22 gauge. Somewhat hydrophilic polymers can be produced by using the diketene acetal 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane and triethylene glycol (TEG), while hydrophobic materials can be produced by using the diketene acetal and 1,10-decanediol. Molecular weight can be reproducibly controlled by using an excess of the diol, or by use of an alcohol that acts as a chain-stopper. Erosion rates can be controlled by varying the amount of latent acid incorporated into the polymer backbone. Toxicology studies using the TEG polymer have been completed and have shown that the polymer is non-toxic. Toxicology studies using the decanediol polymer are underway. Development studies using the TEG polymer aimed at providing a sustained delivery of an analgesic agent to control post-surgical pain are under development and human clinical trials using the decanediol polymer for the treatment of periodontitis are also underway.

Bioerodible Injectable Poly(ortho ester) for Tetracycline Controlled Delivery to Periodontal Pockets: Preliminary Trial in Humans

The semisolid consistency of poly(ortho esters) (POEs) containing tetracycline free base allows direct injection in the periodontal pocket and shows sustained and almost constant in vitro release in phosphate buffer, pH 7.4 at 37°C, for up to 14 days. Total polymer degradation concomitant with drug release was obtained. Formulations containing 10% or 20% (wt/wt) tetracycline were evaluated in a panel of 12 patients suffering from severe and recurrent periodontitis. In the first trial including 6 patients, single-rooted teeth and molar teeth with furcations were treated immediately after scaling and root planing. Patients tolerated both formulations well, experienced no pain during application, and showed no signs of irritation or discomfort during the observation period. However, retention of the formulation was minimal in this first study. An improved clinical protocol followed in the second study (stopping bleeding after scaling and root planning) prolonged the retention of the formulations in the inflamed periodontal pockets. For up to 11 days, tetracycline concentrations in the gingival crevicular fluid were higher than the minimum inhibitory concentration of tetracycline against most periodontal pathogens.