840 resultados para colonic drug delivery
Resumo:
Polymere Nanopartikel sind kleine Teilchen, die vielseitige Einsatzmöglichkeiten für den Transport von Wirkstoffen bieten. Da Nanomaterialien in diesen biomedizinischen Anwendungen oft mit biologischen Systemen in Berührung kommen, erfordert das eine genaue Untersuchung ihrer gegenseitigen Wechselwirkungen. In diesem speziellen Forschungsgebiet, welches sich auf die Interaktionen von Nanomaterialien mit biologischen Komponenten konzentriert, wurde bereits eine Vielzahl verschiedener Nanopartikel-Zell-Interaktionen (z. B. Nanotoxizität, Wirkstofftransport-mechanismen) analysiert. Bezüglich der Untersuchungen zu nanopartikulären Wirkstofftransport-mechanismen ist es im Allgemeinen akzeptiert, dass ein erfolgreicher zellulärer Transport hauptsächlich von der Aufnahme des Nanotransporters abhängt. Deshalb analysieren wir in dieser Arbeit (1) den Wirkstofftransportmechanismus für biologisch-abbaubare eisenhaltige Poly-L-Milchsäure Nanopartikel (PLLA-Fe-PMI) sowie (2) die Aufnahmemechanismen und die intrazellulären Transportwege von nicht-abbaubaren superparamagnetischen Polystyrolnanopartikeln (SPIOPSN). rnIn dieser Arbeit identifizieren wir einen bisher unbekannten und nicht-invasiven Wirkstoff-transportmechanismus. Dabei zeigt diese Studie, dass der subzelluläre Transport der nanopartikulärer Fracht nicht unbedingt von einer Aufnahme der Nanotransporter abhängt. Der identifizierte Arzneimitteltransportmechanismus basiert auf einem einfachen physikochemischen Kontakt des hydrophoben Poly-L-Milchsäure-Nanopartikels mit einer hydrophoben Oberfläche, wodurch die Freisetzung der nanopartikulären Fracht ausgelöst wird. In Zellexperimenten führt die membranvermittelte Freisetzung der nanopartikulären Fracht zu ihrem sofortigen Transport in TIP47+- und ADRP+- Lipidtröpfchen. Der Freisetzungsmechanismus („kiss-and-run") kann durch die kovalente Einbindung des Frachtmoleküls in das Polymer des Nanopartikels blockiert werden.rnWeiterhin wird in Langzeitversuchen gezeigt, dass die Aufnahme der untersuchten polymeren Nanopartikel von einem Makropinozytose-ähnlichen Mechanismus gesteuert wird. Im Laufe dieser Arbeit werden mehrere Faktoren identifiziert, die in diesem Aufnahmemechanismus eine Rolle spielen. Darunter fallen unter anderem die kleinen GTPasen Rac1 und ARF1, die die Aufnahme von SPIOPSN beeinflussen. Darauffolgend werden die intrazellulären Transportwege der Nanopartikel untersucht. Mit Hilfe eines neuartigen Massenspektrometrieansatzes wird der intrazelluläre Transport von nanopartikelhaltigen endozytotischen Vesikeln rekonstruiert. Intensive Untersuchungen identifizieren Marker von frühen Endosomen, späten Endosomen/ multivesikulären Körpern, Rab11+- Endosomen, Flotillin-Vesikeln, Lysosomen und COP-Vesikeln. Schließlich wird der Einfluss des lysosomalen Milieus auf die Proteinhülle der Nanopartikel untersucht. Hier wird gezeigt, dass die adsorbierte Proteinhülle auf den Nanopartikeln in die Zelle transportiert wird und anschließend im Lysosom abgebaut wird. rnInsgesamt verdeutlicht diese Arbeit, dass die klassische Strategie des nanopartikulären und invasiven Wirkstofftransportmechanismuses überdacht werden muss. Weiterhin lässt sich aus den Daten schlussfolgern, dass polymere Nanopartikel einem atypischen Makropinozytose-ähnlichen Aufnahmemechanismus unterliegen. Dies resultiert in einem intrazellulären Transport der Nanopartikel von Makropinosomen über multivesikuläre Körperchen zu Lysosomen.rn
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Solid oral dosage form disintegration in the human stomach is a highly complex process dependent on physicochemical properties of the stomach contents as well as on physical variables such as hydrodynamics and mechanical stress. Understanding the role of hydrodynamics and forces in disintegration of oral solid dosage forms can help to improve in vitro disintegration testing and the predictive power of the in vitro test. The aim of this work was to obtain a deep understanding of the influence of changing hydrodynamic conditions on solid oral dosage form performance. Therefore, the hydrodynamic conditions and forces present in the compendial PhEur/USP disintegration test device were characterized using a computational fluid dynamics (CFD) approach. Furthermore, a modified device was developed and the hydrodynamic conditions present were simulated using CFD. This modified device was applied in two case studies comprising immediate release (IR) tablets and gastroretentive drug delivery systems (GRDDS). Due to the description of movement provided in the PhEur, the movement velocity of the basket-rack assembly follows a sinusoidal profile. Therefore, hydrodynamic conditions are changing continually throughout the movement cycle. CFD simulations revealed that the dosage form is exposed to a wide range of fluid velocities and shear forces during the test. The hydrodynamic conditions in the compendial device are highly variable and cannot be controlled. A new, modified disintegration test device based on computerized numerical control (CNC) technique was developed. The modified device can be moved in all three dimensions and radial movement is also possible. Simple and complex moving profiles can be developed and the influence of the hydrodynamic conditions on oral solid dosage form performance can be evaluated. Furthermore, a modified basket was designed that allows two-sided fluid flow. CFD simulations of the hydrodynamics and forces in the modified device revealed significant differences in the fluid flow field and forces when compared to the compendial device. Due to the CNC technique moving velocity and direction are arbitrary and hydrodynamics become controllable. The modified disintegration test device was utilized to examine the influence of moving velocity on disintegration times of IR tablets. Insights into the influence of moving speed, medium viscosity and basket design on disintegration times were obtained. An exponential relationship between moving velocity of the modified basket and disintegration times was established in simulated gastric fluid. The same relationship was found between the disintegration times and the CFD predicted average shear stress on the tablet surface. Furthermore, a GRDDS was developed based on the approach of an in situ polyelectrolyte complex (PEC). Different complexes composed of different grades of chitosan and carrageenan and different ratios of those were investigated for their swelling behavior, mechanical stability, and in vitro drug release. With an optimized formulation the influence of changing hydrodynamic conditions on the swelling behavior and the drug release profile was demonstrated using the modified disintegration test device. Both, swelling behavior and drug release, were largely dependent on the hydrodynamic conditions. Concluding, it has been shown within this thesis that the application of the modified disintegration test device allows for detailed insights into the influence of hydrodynamic conditions on solid oral dosage form disintegration and dissolution. By the application of appropriate test conditions, the predictive power of in vitro disintegration testing can be improved using the modified disintegration test device. Furthermore, CFD has proven a powerful tool to examine the hydrodynamics and forces in the compendial as well as in the modified disintegration test device. rn
Resumo:
The pulmonary route is very attractive for drug delivery by inhalation. In this regard, nanoparticulate drug delivery systems, designed as multifunctional engineered nanoparticles, are very promising since they combine several opportunities like a rather uniform distribution of drug dose among all ventilated alveoli allowing for uniform cellular drug internalization. However, although the field of nanomedicine offers multiple opportunities, it still is in its infancy and the research has to proceed in order to obtain a specific targeting of the drug combined with minimum side effects. If inhaled nanoparticulate drug delivery systems are deposited on the pulmonary surfactant, they come into contact with phospholipids and surfactant proteins. It is highly likely that the interaction of nanoparticulate drug delivery systems with surfactant phospholipids and proteins will be able to mediate/modulate the further fate of this specific drug delivery system. In the present comment, we discuss the potential interactions of nanoparticulate drug delivery systems with pulmonary surfactant as well as the potential consequences of this interaction.
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The progress of wet age-related macular degeneration can now be controlled by intravitreal drug injection. This approach requires repeated injections, which could be avoided by delivering the drug to the retina. Intraocular implants are a promising solution for drug delivery near the retina. Currently, their accurate placement is challenging, and they can only be removed after a vitrectomy. In this paper, we introduce an approach for minimally invasive retinal drug delivery using magnetic intraocular inserts. We briefly discuss the electromagnetic-control system for magnetic implants and then focus on evaluating their ability to move in the vitreous humor. The mobility of magnetic intraocular implants is estimated in vitro with synthesized vitreous humors, and ex vivo with experiments on cadaver porcine eyes. Preliminary results show that with such magnetic implants a vitrectomy can be avoided.
Resumo:
To compare the adjunctive clinical effects in the non-surgical treatment of peri-implantitis with either local drug delivery (LDD) or photodynamic therapy (PDT).
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The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions.
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Polyanhydrides have been given much attention in the literature recently because of their desirable properties as controlled drug delivery solutions. Drug therapies could be loaded into a polyanhydride matrix and protected from denaturation and removal from the body while being slowly eluted as the polyanhydride degraded yielding a tailorable concentration profile in the bloodstream at therapeutic levels. To that end, this report discusses the synthesis of a novel monomer for polyanhydride synthesis: 1,1'-(hexane-1,6-diyl)bis(5-oxopyrrolidine-3-carboxylic acid) henceforth known as CPyH monomer for (carboxypyrrolidone)hexane monomer.
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Biodegradable polymer nanoparticles have the properties necessary to address many of the issues associated with current drug delivery techniques including targeted and controlled delivery. A novel drug delivery vehicle is proposed consisting of a poly(lactic acid) nanoparticle core, with a functionalized, mesoporous silica shell. In this study, the production of PLA nanoparticles is investigated using solvent displacement in both a batch and continuous manner, and the effects of various system parameters are examined. Using Pluronic F-127 as the stabilization agent throughout the study, PLA nanoparticles are produced through solvent displacement with diameters ranging from 200 to 250 nm using two different methods: dropwise addition and in an impinging jet mixer. The impinging jet mixer allows for easy scale-up of particle production. The concentration of surfactant and volume of quench solution is found to have minimal impact on particle diameter; however, the concentration of PLA is found to significantly impact the diameter mean and polydispersity. In addition, the stability of the PLA nanoparticles is observed to increase as residual THF is evaporated. Lastly, the isolated PLA nanoparticles are coated with a silica shell using the Stöber Process. It is found that functionalizing the silica with a phosphonic silane in the presence of excess Pluronic F-127 decreases coalescence of the particles during the coating process. Future work should be conducted to fine-tune the PLA nanoparticle synthesis process by understanding the effect of other system parameters and in synthesizing mesoporous silica shells.
Resumo:
OBJECTIVES: To assess the microbiological outcome of local administration of minocycline hydrochloride microspheres 1 mg (Arestin) in cases with peri-implantitis and with a follow-up period of 12 months. MATERIAL AND METHODS: After debridement, and local administration of chlorhexidine gel, peri-implantitis cases were treated with local administration of minocycline microspheres (Arestin). The DNA-DNA checkerboard hybridization method was used to detect bacterial presence during the first 360 days of therapy. RESULTS: At Day 10, lower bacterial loads for 6/40 individual bacteria including Actinomyces gerensceriae (P<0.1), Actinomyces israelii (P<0.01), Actinomyces naeslundi type 1 (P<0.01) and type 2 (P<0.03), Actinomyces odontolyticus (P<0.01), Porphyromonas gingivalis (P<0.01) and Treponema socranskii (P<0.01) were found. At Day 360 only the levels of Actinobacillus actinomycetemcomitans were lower than at baseline (mean difference: 1x10(5); SE difference: 0.34x10(5), 95% CI: 0.2x10(5) to 1.2x10(5); P<0.03). Six implants were lost between Days 90 and 270. The microbiota was successfully controlled in 48%, and with definitive failures (implant loss and major increase in bacterial levels) in 32% of subjects. CONCLUSIONS: At study endpoint, the impact of Arestin on A. actinomycetemcomitans was greater than the impact on other pathogens. Up to Day 180 reductions in levels of Tannerella forsythia, P. gingivalis, and Treponema denticola were also found. Failures in treatment could not be associated with the presence of specific pathogens or by the total bacterial load at baseline. Statistical power analysis suggested that a case control study would require approximately 200 subjects.
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Site-specific delivery of anticancer agents to tumors represents a promising therapeutic strategy because it increases efficacy and reduces toxicity to normal tissues compared with untargeted drugs. Sterically stabilized immunoliposomes (SIL), guided by antibodies that specifically bind to well internalizing antigens on the tumor cell surface, are effective nanoscale delivery systems capable of accumulating large quantities of anticancer agents at the tumor site. The epithelial cell adhesion molecule (EpCAM) holds major promise as a target for antibody-based cancer therapy due to its abundant expression in many solid tumors and its limited distribution in normal tissues. We generated EpCAM-directed immunoliposomes by covalently coupling the humanized single-chain Fv antibody fragment 4D5MOCB to the surface of sterically stabilized liposomes loaded with the anticancer agent doxorubicin. In vitro, the doxorubicin-loaded immunoliposomes (SIL-Dox) showed efficient cell binding and internalization and were significantly more cytotoxic against EpCAM-positive tumor cells than nontargeted liposomes (SL-Dox). In athymic mice bearing established human tumor xenografts, pharmacokinetic and biodistribution analysis of SIL-Dox revealed long circulation times in the blood with a half-life of 11 h and effective time-dependent tumor localization, resulting in up to 15% injected dose per gram tissue. These favorable pharmacokinetic properties translated into potent antitumor activity, which resulted in significant growth inhibition (compared with control mice), and was more pronounced than that of doxorubicin alone and nontargeted SL-Dox at low, nontoxic doses. Our data show the promise of EpCAM-directed nanovesicular drug delivery for targeted therapy of solid tumors.
Resumo:
OBJECTIVE: The objective of the study is to compare the clinical, microbiological and host-derived effects in the non-surgical treatment of initial peri-implantitis with either adjunctive local drug delivery (LDD) or adjunctive photodynamic therapy (PDT) after 12 months. MATERIALS AND METHODS: Forty subjects with initial peri-implantitis, that is, pocket probing depths (PPD) 4-6 mm with bleeding on probing (BoP) and radiographic bone loss ≤2 mm, were randomly assigned to two treatment groups. All implants were mechanically debrided with titanium curettes and with a glycine-based powder airpolishing system. Implants in the test group (N = 20) received adjunctive PDT, whereas minocycline microspheres were locally delivered into the peri-implant pockets of control implants (N = 20). At sites with residual BoP, treatment was repeated after 3, 6, 9 and 12 months. The primary outcome variable was the change in the number of peri-implant sites with BoP. Secondary outcome variables included changes in PPD, clinical attachment level (CAL), mucosal recession (REC) and in bacterial counts and crevicular fluid (CF) levels of host-derived biomarkers. RESULTS: After 12 months, the number of BoP-positive sites decreased statistically significantly (P < 0.05) from baseline in both groups (PDT: 4.03 ± 1.66-1.74 ± 1.37, LDD: 4.41 ± 1.47-1.55 ± 1.26). A statistically significant (P < 0.05) decrease in PPD from baseline was observed at PDT-treated sites up to 9 months (4.19 ± 0.55 mm to 3.89 ± 0.68 mm) and up to 12 months at LDD-treated sites (4.39 ± 0.77 mm to 3.83 ± 0.85 mm). Counts of Porphyromonas gingivalis and Tannerella forsythia decreased statistically significantly (P < 0.05) from baseline to 6 months in the PDT and to 12 months in the LDD group, respectively. CF levels of IL-1β decreased statistically significantly (P < 0.05) from baseline to 12 months in both groups. No statistically significant differences (P > 0.05) were observed between groups after 12 months with respect to clinical, microbiological and host-derived parameters. CONCLUSIONS: Non-surgical mechanical debridement with adjunctive PDT was equally effective in the reduction of mucosal inflammation as with adjunctive delivery of minocycline microspheres up to 12 months. Adjunctive PDT may represent an alternative approach to LDD in the non-surgical treatment of initial peri-implantitis.
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The Pulmonary route has been traditionally used to treat diseases of the respiratory tract. However, important research within the last two decades have shown that in addition to treating local diseases, a wide range of systemic diseases can be treated by delivering drugs to the lungs. The recent FDA approval to market Exubera, an inhalable form of insulin developed by Pfizer, to treat Diabetes, may just be the stepping stone that the pharmaceutical industry needs to market other drugs to treat systemic diseases via the lungs. However, this technology still needs repeated drug doses to control glucose levels, as the inhaled drug is cleared rapidly. Technologies have been developed where inhaled particles are capable of controlled release of drug from the lungs. An important feature of these technologies is the large geometric size of the particles that makes it difficult for the lung macrophages to clear these particles, which results in longer residence times for the particles in the lungs. Owing to the porosity, these particles have lower densities making them deliverable to the deep lungs. However, no modulation of drug release can be achieved with these technologies when more drug release may be required. This additional requirement can only be assuaged by additional dosing of the drug formulation, which can have undesirable effects due to excess loading of excipients in the lungs. In an attempt to bring about modulation of release from long residence time particles, a novel concept was developed in our laboratory that has been termed as the Agglomerated Vesicle Technology (AVT). Liposomes with encapsulated drug were agglomerated using well known cross linking chemistries to form agglomerates in the micron sized range. The large particles exhibited aerodynamic sizes in the respirable size range with minimal damage to the particles upon nebulization. By breaking the cross links between the liposomes with a cleaving agent, it was anticipated that triggered release of drug from the AVT particles could be achieved. In vivo studies done in healthy rabbits showed that post-administration modulation of drug release is possible from the AVT particles after the introduction of the cleaving agent. This study has important implications for the future development of this technology, where the AVT particles can be made “sensitive” to the product of disease. It is envisaged that a single dose of AVT containing the appropriate drug when administered to the lungs would maintain drug levels at a controlled rate over an extended period of time. When the need for more drug arises, the product of the disease would trigger the AVT particles to release more drug as needed to control the condition, thus eliminating the need for repeated drug doses and improved compliance amongst patients.