Antimicrobial effect and physical properties of an injectable "active oxygen" gel for the treatment of periodontitis.

PURPOSE: To evaluate an injectable gel, recently proposed for the controlled release of "active oxygen" in periodontal pockets, compared to an antibiotic or an antiseptic gel, respectively. METHODS: The antimicrobial activity, injectability, texture properties, swelling and water uptake of the gels were studied. RESULTS: The "active oxygen" gel showed a bactericidal effect comparable to the two commercially available drug products (containing minocycline or chlorhexidine) on anaerobic periodontal pathogens and did not seem to affect aerobic strains. The gel was easy to inject and stable in an aqueous medium for several days. Texture analysis revealed potential gel fragility. CLINICAL SIGNIFICANCE: The investigated gel for local delivery of oxygen can help to selectively eradicate anaerobic bacteria associated with periodontitis and promote the recovery of a healthy-compatible oral flora.

Poly(D,l-lactide-co-glycolide) particles are metabolised by the gut microbiome and elevate short chain fatty acids.

The production of short chain fatty acids (SCFAs) by the colonic microbiome has numerous benefits for human health, including maintenance of epithelial barrier function, suppression of colitis, and protection against carcinogenesis. Despite the therapeutic potential, there is currently no optimal approach for elevating the colonic microbiome's synthesis of SCFAs. In this study, poly(D,l-lactide-co-glycolide) (PLGA) was investigated for this application, as it was hypothesised that the colonic microbiota would metabolise PLGA to its lactate monomers, which would promote the resident microbiota's synthesis of SCFAs. Two grades of spray dried PLGA, alongside a lactate bolus control, were screened in an advanced model of the human colon, known as the M-SHIME® system. Whilst the high molecular weight (Mw) grade of PLGA was stable in the presence of the microbiota sourced from three healthy humans, the low Mw PLGA (PLGA 2) was found to be metabolised. This microbial degradation led to sustained release of lactate over 48 h and increased concentrations of the SCFAs propionate and butyrate. Further, microbial synthesis of harmful ammonium was significantly reduced compared to untreated controls. Interestingly, both types of PLGA were found to influence the composition of the luminal and mucosal microbiota in a donor-specific manner. An in vitro model of an inflamed colonic epithelium also showed the polymer to affect the expression of pro- and anti-inflammatory markers, such as interleukins 8 and 10. The findings of this study reveal PLGA's sensitivity to enzymatic metabolism in the gut, which could be harnessed for therapeutic elevation of colonic SCFAs.

Thermo-responsive Diels-Alder stabilized hydrogels for ocular drug delivery of a corticosteroid and an anti-VEGF fab fragment.

In the present study, a novel in situ forming thermosensitive hydrogel system was investigated as a versatile drug delivery system for ocular therapy. For this purpose, two thermosensitive ABA triblock copolymers bearing either furan or maleimide moieties were synthesized, named respectively poly(NIPAM-co-HEA/Furan)-PEG6K-P(NIPAM-co-HEA/Furan) (PNF) and poly(NIPAM-co-HEA/Maleimide)-PEG6K-P(NIPAM-co-HEA/-Maleimide) (PNM). Hydrogels were obtained upon mixing aqueous PNF and PNM solutions followed by incubation at 37 °C. The hydrogel undergoes an immediate (<1 min) sol-gel transition at 37 °C. In situ hydrogel formation at 37 °C was also observed after intravitreal injection of the formulation into an ex vivo rabbit eye. The hydrogel network formation was due to physical self-assembly of the PNIPAM blocks and a catalyst-free furan-maleimide Diels-Alder (DA) chemical crosslinking in the hydrophobic domains of the polymer network. Rheological studies demonstrated sol-gel transition at 23 °C, and DA crosslinks were formed in time within 60 min by increasing the temperature from 4 to 37 °C. When incubated at 37 °C, these hydrogels were stable for at least one year in phosphate buffer of pH 7.4. However, the gels degraded at basic pH 10 and 11 after 13 and 3 days, respectively, due to hydrolysis of ester bonds in the crosslinks of the hydrogel network. The hydrogel was loaded with an anti-VEGF antibody fragment (FAB; 48.4 kDa) or with corticosteroid dexamethasone (dex) by dissolving (FAB) or dispersing (DEX) in the hydrogel precursor solution. The FAB fragment in unmodified form was quantitatively released over 13 days after an initial burst release of 46, 45 and 28 % of the loading for the 5, 10 and 20 wt% hydrogel, respectively, due to gel dehydration during formation. The low molecular weight drug dexamethasone was almost quantitively released in 35 days. The slower release of dexamethasone compared to the FAB fragment can likely be explained by the solubilization of this hydrophobic drug in the hydrophobic domains of the gel. The thermosensitive gels showed good cytocompatibility when brought in contact with macrophage-like mural cells (RAW 264.7) and human retinal pigment epithelium-derived (ARPE-19) cells. This study demonstrates that PNF-PNM thermogel may be a suitable formulation for sustained release of bioactive agents into the eye for treating posterior segment eye diseases.

Silicone matrices for controlled dexamethasone release: toward a better understanding of the underlying mass transport mechanisms.

Dexamethasone-loaded silicone matrices offer an interesting potential as innovative drug delivery systems, e.g. for the treatment of inner ear diseases or for pacemakers. Generally, very long drug release periods are targeted: several years/decades. This renders the development and optimization of novel drug products cumbersome: experimental feedback on the impact of the device design is obtained very slowly. A better understanding of the underlying mass transport mechanisms can help facilitating research in this field. A variety of silicone films were prepared in this study, loaded with amorphous or crystalline dexamethasone. Different polymorphic drug forms were investigated, the film thickness was altered and the drug optionally partially/completely exchanged by much more water-soluble dexamethasone 'phosphate'. Drug release studies in artificial perilymph, scanning electron microscopy, optical microscopy, differential scanning calorimetry, X-ray diffraction and Raman imaging were used to elucidate the physical states of the drugs and polymer, and of the systems' structure as well as dynamic changes thereof upon exposure to the release medium. Dexamethasone particles were initially homogeneously distributed throughout the systems. The hydrophobicity of the matrix former very much limits the amounts of water penetrating into the system, resulting in only partial drug dissolution. The mobile drug molecules diffuse out into the surrounding environment, due to concentration gradients. Interestingly, Raman imaging revealed that even very thin silicone layers (<20 µm) can effectively trap the drug for prolonged periods of time. The physical state of the drug (amorphous, crystalline) did not affect the resulting drug release kinetics to a noteworthy extent.

Effect of Lactobacillus reuteri on Gingival Inflammation and Composition of the Oral Microbiota in Patients Undergoing Treatment with Fixed Orthodontic Appliances: Study Protocol of a Randomized Control Trial.

The effect of probiotics in improving or maintaining oral health in orthodontic patients is understudied. The aim of this study is to evaluate the effect of probiotic administration in addition to tooth brushing on clinical gingival inflammation, plaque formation, subgingival microbiota composition, and salivary biomarkers of inflammation in adolescents with fixed orthodontic appliances. The present study is a 6-month, double-blind, two-arm, placebo-controlled, single-center trial, in which 116 adolescent volunteers aged 12-16 years will be recruited from the patients of the orthodontics clinic of the University Hospital of Lille, France. Subjects who meet the eligibility criteria will be allocated to one of the following groups: (i) control: two placebo lozenges per day for 90 days together with regular oral hygiene, (ii) test: two probiotic lozenges per day for 90 days together with regular oral hygiene. Clinical assessment and biological sample collection will be performed at baseline, 3 and 6 months. In addition, compliance outcomes and adverse events will be monitored.

Clinical translation of advanced colonic drug delivery technologies.

Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.

In-situforming drug-delivery systems for periodontal treatment: current knowledge and perspectives.

Several chemical compounds are considered to be promising as adjuvants in the treatment of periodontitis. Antimicrobials, anti-inflammatory drugs or, more recently, pro-regenerative or antioxidant molecules have shown a very interesting potential to improve the outcomes of mechanical biofilm removal and promote the healing of the damaged tissues. However, their clinical effect is often limited by the challenge of achieving effective and prolonged drug delivery within the periodontal lesion, while limiting the risk of toxicity.In-situforming implants (ISFI) are 'implantable' drug-delivery systems that have gained considerable attention over the last few decades due to their multiple biomedical applications. They are liquids that, when injected at the site to be treated, form a semi-solid or solid dosage form that provides safe and locally controlled drug release. This review discusses current data and future prospects for the use of ISFI in periodontal treatment.

Injection-molded capsule bodies and caps based on polymer blends for controlled drug delivery.

A variety of polymer:polymer blends was used to prepare hot melt extrudates and empty capsules (bodies and caps) by injection-molding using a benchtop extruder (Babyplast). KollidonSR:inulin and Carbothane:inulin blends were investigated. The impact of the blend ratio on the water uptake and dry mass loss kinetics upon exposure to 0.1 MHCl, phosphate buffer pH6.8 and culture medium optionally inoculated with fecal samples from Inflammatory Bowel Disease (IBD) patients were studied. Hot melt extrudates were loaded with up to 60% theophylline, capsules were filled with drug powder. Increasing the inulin content led to increased water uptake and dry mass loss rates, resulting in accelerated drug release from the dosage forms, irrespective of the type of polymer blend. This can be attributed to the higher hydrophilicity/water-solubility of this polymer compared to KollidonSR and Carbothane. Interestingly, the presence of fecal samples in culture medium increased the water uptake and dry mass loss of hot melt extrudates to a certain extent, suggesting partial system degradation by bacterial enzymes. However, these phenomena did not translate into any noteworthy impact of the presence of colonic bacteria on theophylline release from the investigated extrudates or capsules. Hence, drug release can be expected to be independent of the location "small intestine vs. colon" from these dosage forms, which can be advantageous for long term release throughout the entire gastro intestinal tract.

Towards a Better Understanding of Verapamil Release from Kollicoat SR:IR Coated Pellets Using Non-Invasive Analytical Tools.

The aim of this study was to gain deeper insight into the mass transport mechanisms controlling drug release from polymer-coated pellets using non-invasive analytical tools. Pellet starter cores loaded with verapamil HCl (10% loading, 45% lactose, 45% microcrystalline cellulose) were prepared by extrusion/spheronization and coated with 5% Kollicoat SR:IR 95:5 or 10% Kollicoat SR:IR 90:10. Drug release was measured from ensembles of pellets as well as from single pellets upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4. The swelling of single pellets was observed by optical microscopy, while dynamic changes in the pH in the pellet cores were monitored by fluorescence spectroscopy. Also, mathematical modeling using a mechanistically realistic theory as well as SEM and Raman imaging were applied to elucidate whether drug release mainly occurs by diffusion through the intact film coatings or whether crack formation in the film coatings plays a role. Interestingly, fluorescence spectroscopy revealed that the pH within the pellet cores substantially differed upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4, resulting in significant differences in drug solubility (verapamil being a weak base) and faster drug release at lower pH: from ensembles of pellets and single pellets. The monitoring of drug release from and the swelling of single pellets indicated that crack formation in the film coatings likely plays a major role, irrespective of the Kollicoat SR:IR ratio/coating level. This was confirmed by mathematical modeling, SEM and Raman imaging. Importantly, the latter technique allowed also for non-invasive measurements, reducing the risk of artifact creation associated with sample cutting with a scalpel.

Antibiotic Use in Periodontal Therapy among French Dentists and Factors Which Influence Prescribing Practices.

The aim of the present survey is to investigate the use of antibiotics during periodontal therapy among French dentists with a focus on exploring potential differences between various groups of practitioners. A self-administered questionnaire was distributed to different groups of practitioners including members of (i) the French Society of Periodontology and Implantology; (ii) the College of University Teachers in Periodontology and, (iii) private practitioners participating in the French general dental practice-based research network. 272 questionnaires were included in the analysis. Prescription patterns were globally in line with the current recommendations. Systemic antibiotics are most frequently used as a first-line therapy in necrotizing periodontitis (92%) and aggressive periodontitis (53.3% to 66.1%). However, malpractice still exists, including in the management of periodontal abscesses. Antibiotics are prescribed (i) less frequently for periodontal abscesses and (ii) more frequently for generalized aggressive periodontitis by members of the periodontal society and University college (p < 0.05). Amoxicillin (59.9%) and the amoxicillin + metronidazole (59.6%) combination were the most frequently prescribed molecules. Providing a high number of periodontal treatments per week, being more recently graduated, having a post-graduate certificate in periodontology and holding or having held an academic position/hospital practice were all factors associated with a better knowledge of and/or more adequate antibiotic use.

How Adding Chlorhexidine or Metallic Nanoparticles Affects the Antimicrobial Performance of Calcium Hydroxide Paste as an Intracanal Medication: An In Vitro Study.

The aim of our study was to explore the potential value of metallic (Ag, Cu, and Zn) salts, polymer/metallic nanoparticles, and chlorhexidine (CHX) for improving the antimicrobial activity of calcium hydroxide (CH) against E. faecalis and C. albicans, associated with persistent endodontic infections. A first screening was performed by determining minimum inhibitory/bactericidal concentrations (MIC/MBC). Antimicrobial activity of the CH paste mixed with metallic salts, chitosan or cyclodextrin polymer metallic nanoparticles was compared to the antimicrobial activity of CH paste alone and CH + CHX using a time-kill kinetics assay. The effect of the antimicrobials on the rheological and the key mechanical properties were also examined. Copper and zinc were discarded because of their MIC/MBC values and silver because of its kill time curve profile. Except for a slower setting time after 24 h and a higher weight loss after 1 week of incubation, the mechanical behavior of the CH paste was unaffected by the addition of CHX. Polymeric/metallic nanoparticles failed to potentiate the antimicrobial effect of CH. By contrast, CHX increased this effect and thus could help eradicate E. faecalis associated with persistent root canal infections without altering the desired key physical properties of the CH paste.

Simulated food effects on drug release from ethylcellulose: PVA-PEG graft copolymer-coated pellets.

BACKGROUND: Food effects might substantially alter drug release from oral controlled release dosage forms in vivo. METHODS: The robustness of a novel type of controlled release film coating was investigated using various types of release media and two types of release apparatii. RESULTS: Importantly, none of the investigated conditions had a noteworthy impact on the release of freely water-soluble diltiazem HCl or slightly water-soluble theophylline from pellets coated with ethylcellulose containing small amounts of PVA-PEG graft copolymer. In particular, the presence of significant amounts of fats, carbohydrates, surfactants, bile salts, and calcium ions in the release medium did not alter drug release. Furthermore, changes in the pH and differences in the mechanical stress the dosage forms were exposed to did not affect drug release from the pellets. CONCLUSION: The investigated film coatings allowing for oral controlled drug delivery are highly robust in vitro and likely to be poorly sensitive to classical food effects in vivo.

Eudragit RL-based film coatings: How to minimize sticking and adjust drug release using MAS.

Polymeric film coatings based on quaternary polymethacrylates (QPMs, e.g. Eudragits®) are frequently used for controlled release applications. However, their considerable sticking tendency is a major drawback in practice. In this study, different amounts of magnesium aluminum silicate (MAS) were added to the film coatings in order to overcome this hurdle. MAS is negatively charged and can electrostatically interact with the positively charged QPM. Different types of tablet cores were coated with aqueous Eudragit® RL 30D dispersions, optionally containing varying amounts of MAS. Dynamic changes in the wet mass of the systems as well as drug release upon exposure to 0.1 M HCl and phosphate buffer pH 6.8 were monitored. Propranolol HCl, acetaminophen, and diclofenac sodium were used as cationic, nonionic and anionic model drugs. The tablets were optionally cured for 12 h at 45 or 60 °C. Importantly, the addition of MAS to aqueous Eudragit® RL 30D dispersion substantially reduced the films' stickiness and led to stable inner coating structures, even without curing. Desired drug release rates can be adjusted by varying the QPM:MAS ratio and coating level.

Characterization of ethylcellulose: starch-based film coatings for colon targeting.

BACKGROUND: The site-specific delivery of drugs to the colon can be highly advantageous for various applications, including the local treatment of inflammatory bowel diseases. The aim of this study was to provide efficient tools that can be used to easily adjust the key properties of novel polymeric film coatings allowing for colon targeting. METHODS: Free films based on blends of ethylcellulose and different types of starch derivatives (partially being pregelatinized, acetylated, and/or hydroxypropylated) were prepared and characterized. RESULTS: The key properties of the polymeric systems can effectively be adjusted by varying the polymer blend ratio and type of starch derivative. This includes the water uptake and dry mass loss kinetics as well as the mechanical properties of the films before and upon exposure to aqueous media simulating the contents of the upper GIT. CONCLUSION: Broad ranges of film coating properties can easily be provided, being adapted to the needs of the respective drug treatment.

In-situ forming implants loaded with chlorhexidine and ibuprofen for periodontal treatment: Proof of concept study in vivo.

Control of infection and inflammation is crucial for the success of periodontal treatment. In this study, in-situ forming implants (ISFI) loaded with chlorhexidine dihydrochloride (CHX) and ibuprofen (IBU) were developed and tested to optimize periodontal treatment outcomes. Release profiles were promising. Exposure to 1.5% and 5.3% CHX-IBU loaded ISFI's release media decreased significantly the P. gingivalis growth up to 20-fold and 35-fold, respectively, after 48 h (p < 0.05). The metabolic activity assay of gingival epithelial cells (EC) demonstrated 1.5% CHX-IBU-loaded ISFI to be non-toxic, therefore, it was selected for further experimentation. Furthermore, significant down-regulation of TNF-α release (34% at 6 h and 43% at 24 h, p < 0.05) in P. gingivalis lipopolysaccharide (Pg-LPS) stimulated EC exposed to 1.5% CHX-IBU ISFI release medium was demonstrated by ELISA. In vivo, 1.5% CHX-IBU ISFI was injected into the periodontal pocket in an experimental periodontitis mouse model and the reduction in inflammation and improvement in periodontal wound healing was evaluated through inflammatory cell scoring and histomorphometry at 7- and 15-days post-treatment. The results indicate that CHX-IBU loaded ISFI could be efficient as adjuvant to periodontal therapy for the control of infection and inflammation. Moreover, other (e.g., pro-regenerative) drugs could be incorporated into ISFI to further improve periodontal treatment outcomes.

Lipid implants as drug delivery systems.

The parenteral controlled delivery of acid-labile drugs (e.g., proteins) is difficult, because the standard polymer poly(lactic-co-glycolic acid) used to control drug release upon parenteral administration degrades into shorter chain acids, creating acidic microclimates. Lipid implants do not show this disadvantage. The objective of this article is to give an overview on the present state of the art and to highlight the advantages and drawbacks of the different types of systems reported in the literature. The major preparation techniques for lipid implants, underlying mass transport mechanisms, biocompatibility and in vivo performance of the most interesting systems are described. Lipid implants offer a great potential as parenteral controlled drug delivery systems, especially for protein-based drugs. A broad spectra of release patterns can be provided and acidic microclimates avoided.

Crystalline Polymorphism Emerging From a Milling-Induced Amorphous Form: The Case of Chlorhexidine Dihydrochloride.

In this paper, solid-state amorphization induced by mechanical milling is shown to be a useful tool to explore the polymorphism of drugs and their mechanism of devitrification. We show in particular how the recrystallization of amorphous chlorhexidine dihydrochloride obtained by milling reveals a complex polymorphism that involves several polymorphic forms. Two new crystalline forms are identified, one of them appearing as a highly disordered precursor state which however clearly differs from the amorphous one. Several interpretations are here proposed to describe the puzzling nature of this phase. In addition, the possibility to amorphize chlorhexidine dihydrochloride by milling allowed to determine the main physical characters of the amorphous state which cannot be obtained through the usual thermal quench of the liquid because of a strong chemical degradation occurring on melting.

When drugs plasticize film coatings: Unusual formulation effects observed with metoprolol and Eudragit RS.

Metoprolol tartrate and metoprolol free base loaded pellet starter cores were coated with Eudragit RS, plasticized with 25% triethyl citrate (TEC). The initial drug loading and coating level were varied from 10 to 40 and 0 to 20%, respectively. Drug release was measured in 0.1 N HCl and phosphate buffer pH 7.4. The water uptake and swelling kinetics, mechanical properties and TEC leaching of/from coated pellets and/or thin, free films of identical composition as the film coatings were monitored. The following unusual tendencies were observed: (i) the relative drug release rate from coated pellets increased with increasing initial drug content, and (ii) drug release from pellets was much faster for metoprolol free base compared to metoprolol tartrate, despite its much lower solubility (factor >70). These phenomena could be explained by plasticizing effects of the drug for the polymeric film coatings. In particular: 1) Metoprolol free base is a much more potent plasticizer for Eudragit RS than the tartrate, leading to higher film permeability and overcompensating the pronounced differences in drug solubility. Also, Raman imaging revealed that substantial amounts of the free base migrated into the film coatings, whereas this was not the case for the tartrate. 2) The plasticizing effects of the drug for the film coating overcompensated potential increasing limited solubility effects when increasing the initial drug loading from 10 to 40%. In summary, this study clearly demonstrates how important the plasticization of polymeric controlled release film coatings by drugs can be, leading to unexpected formulation effects.

Mechanisms controlling protein release from lipidic implants: effects of PEG addition.

Different types of tristearin-based implants for controlled rh-interferon alpha-2a (IFN-alpha) release were prepared by compression and thoroughly characterised in vitro. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was added as a co-lyophilisation agent for protein stabilisation and different amounts of polyethylene glycol (PEG) as efficient protein release modifier. To get deeper insight into the underlying mass transport mechanisms, the release of IFN-alpha, HP-beta-CD and PEG into phosphate buffer pH 7.4 was monitored simultaneously and appropriate analytical solutions of Fick's second law of diffusion were fitted to the experimental results. Importantly, the addition of only 5-20% PEG to the lipidic implants significantly altered the resulting protein release rates and the relative importance of the underlying mass transport mechanisms. The release of IFN-alpha from PEG-free implants was purely diffusion controlled. In contrast, in PEG-containing devices other phenomena were also involved in the control of protein release: the IFN-alpha release rate remained about constant over prolonged periods of time and the total amounts of mobile IFN-alpha increased. Interestingly, the release of PEG itself as well as of HP-beta-CD from the implants remained purely diffusion controlled, irrespective of the amount of added PEG. Thus, different mass transport mechanisms govern the release of the drug, co-lyophilisation agent and release modifier out of the lipidic implants.

[Implants for drug substance delivery]. / Implants pour la délivrance de principes actifs.

Implants for controlled drug delivery can be very helpful to improve the therapeutic efficacy of a medical treatment, and at the same time reduce the risk of toxic side effects. In this article, four different strategies are exemplarily presented: hybrid bone substitutes combining hydroxyapatite and chitosan hydrogels; vascular stents coated with a bio-inspired polymer; cochlear implants for local dexamethasone delivery; and in-situ forming implants for periodontitis treatment. But this is only a restricted selection, and numerous other approaches and applications based on implants releasing a drug (or a combination of drugs) exist. Compared to conventional implants or pharmaceutical dosage forms, they might offer decisive advantages.