Browsing by Subject "controlled release"

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  • Paukkonen, Heli (Helsingfors universitet, 2013)
    Casein based formulations are promising materials for controlled drug release. Caseins are the major milk proteins, and their biocompatibility, low toxicity and natural metabolism in physiological systems make caseins extremely suitable materials for pharmaceutical formulations. Polyelectrolyte complex nanoparticles can be prepared under very mild conditions, and they are stable in the gastrointestinal tract, which makes them suitable carrier materials for oral delivery and controlled release of peptide and protein drugs. Aim of this work was to synthesize casein-poly(acrylic acid) polyelectrolyte complex nanoparticles in different mass ratios, and to study the release profile of a model compound rhodamine 6G from these nanoparticles. The casein shell of the nanoparticles was crosslinked with two different crosslinkers, because the objective was to study the effect of surface modification on size of nanoparticles as well as on the release profile of the model compound. The goal was to achieve controlled release of the model compound by modifying the thickness and the density of the casein shell structure. Size and size distribution of nanoparticles was studied by dynamic light scattering. Surface charge was studied by electrophoretic mobility measurements. Morphology was characterized with electron microscopy, and the effect of the casein shell thickness on the release of rhodamine 6G was studied with dialysis method. The synthesized nanoparticles had spherical morphology, but the size distribution was wide. The release of rhodamine 6G was slower from the nanoparticles when compared to the release of reference free rhodamine 6G, but the effect of casein shell thickness on the release of loaded rhodamine 6G remained partially unclear. However, it seems possible to achieve controlled release of encapsulated compounds from casein-poly(acrylic acid) nanoparticles with optimal surface modification in the future.
  • Li, Wei; Zheng, Kai; Petrikaite, Vilma (2021)
  • Mäki-Mikola, Eija (Helsingin yliopisto, 2020)
    Liposomes are nano-sized vesicles, that are composed of a phospholipid bilayer structure. They can be utilized as drug carriers, in which case the drug is incorporated either to their hydrophilic internal cavity, or into their hydrophobic bilayer structure. For anticancer drugs, liposomal formulations have exhibited their capability in reducing adverse effects of anticancer drugs. This is achieved mainly by the enhanced permeability and retention (EPR) effect, in which liposomes accumulate into tumour tissue. However, the conventional liposomes release their drug content passively, and a proportion of drug is distributed to off-target tissues. Therefore, there is a demand to develop liposomes from which the content can be released in a controlled manner, by an external stimulus. The objectives of this master’s thesis project were to determine the potential of light-activated paclitaxel (PTX) liposomes for the treatment of lung cancer, and to optimize a dynamic cell culture system, QuasiVivo® (QV), to study the off-target effects of light-activated PTX liposomes. The hypothesis was that the induction of the light-activated PTX liposomes would increase the efficiency of paclitaxel treatment. For QV experiments, it was expected that the presence of flow would improve the viability of the cells. The encapsulation efficiency of PTX into the liposomes and the effect of the PTX incorporation into the phase transition temperature of the liposomes were determined. The stability of liposomes was determined by monitoring the liposomal size and light sensitizer absorbance during a storage period. The cells of lung cancer cell line A549 were cultured inside QV system, and their viability was monitored with two commercial cell viability assays. Incorporation of PTX decreased the phase transition temperature, but the liposomes remained stable in the studied conditions. The PTX liposome treatments with and without light activation resulted in the similar efficacy as free PTX treatment did. A549 cells failed to display superior viability inside the QV compared to static conditions. Cells cultured under lower flow rate portrayed modestly higher viability. The light-activated PTX liposomes did not improve the efficacy of PTX treatment. Neither of the flow rates were optimal for A549 cells, as the variation between experiments was high. The EPR effect is the main reason for the improved effects of liposomal anticancer drugs, therefore, it is likely that in vivo experiments would elicit the differences between the efficacy of the liposomal and free PTX. The non-existent effects of light activation on the viability are likely caused by the low total concentration of the light sensitizer in the treatment solution.
  • Kunnari, Mikko (Helsingfors universitet, 2016)
    Crohn's disease is a type of inflammatory bowel disease. There are no treatment procedures that can cure Crohn's disease, but it is usually controllable with medicinal options. However 70 - 80 % of patients will require surgery and most undergo several during their life, due to weak local potency of drugs and disrupted recovery from surgical treatment. A better method of combined treatment, such as a drug releasing surgical suture, could improve the disease recovery process. One approach would be to coat a surgical suture with nanofibrillar cellulose (NFC) hydrogel containing the active drug ingredient within. NFC is biocompatible, biostable and it can be easily chemically modified. It displays pseudoplastic and thixotropic gel-like behavior in aqueous suspension in addition to high shear thinning properties under low and high shear rates. The shear-thinning behavior is particularly useful in a range of different coating applications. Furthermore, recent studies have shown the potential of NFC in controlled drug release. The aim of this Master's thesis was to investigate the suitability of anionic NFC hydrogel for surgical suture coatings and controlled release applications. The structure of NFC hydrogel was modified with crosslinking cations (Fe3+, Al3+, Ca2+) and alginate. The diffusion studies were performed with two antibiotics, metronidazole and rifaximin together with FITC-dextrans (10 and 250 kDa). The surgical suture was coated with each type of hydrogels (n = 16). Furthermore, the suitability of suture drug formulation for controlled drug release was simulated with STELLA® modeling software. It was shown that the NFC hydrogel structure was stiffened with the use of crosslinking cations; however similar results were not observed with the addition of alginate. Release profiles of model compounds were similar before and after NFC hydrogel crosslinking. At 6 days, 50 - 60 % of 10 kDa dextran (6 µg) was released. For 250 kDa dextran (6 µg) the released amount was 25 - 35 %. During the first 3 days of the diffusion study, all of metronidazole (20 µg) was released. Rifaximin samples were not obtained due to high adsorption to the container surfaces. The release profiles of metronidazole and 10 kDa dextran had linear correlation with square-root diffusion process. 250 kDa dextran followed a near zero-order kinetics after a few hours from the start. The coating was performed successfully with NFC hydrogels except for hydrogels with dextrans or without crosslinking. Metronidazole was predicted to release from the surgical suture almost instantly with STELLA® modeling software. NFC hydrogel shows potential as a matrix for controlled drug release and the coating of surgical sutures. However, the manufacturing method of the NFC hydrogel could be improved with surface modifications of nanofibrils or with the choice of a drug or of its derivatives. With pharmacokinetic simulation models it is possible to predict and estimate different factors which affect drug release from the surgical suture. Furthermore, the simulation models can be used to estimate an effect in the treatment of Crohn's disease.
  • Li, Mingwei (Helsingfors universitet, 2016)
    Nanofibrillar cellulose (NFC) can form hydrogels with high water content (> 98 %). It has been studied for drug release, and it has been used as a cell culture matrix, due to its similar structure to extracellular matrix (ECM). In addition it has been found that they has no cytotoxicity. Iontophoresis is the application of an electric current over a defined area for the purpose of enhancing permeation across a membrane for ionized drug species. The aim in the experimental work in this Master's thesis is twofold. First, to find out the suitable drug loading concentrations into NFC hydrogels, which can provide a good release profile, a release study with two model drugs, propranolol and ketoprofen, loaded into three types of NFC hydrogels at three different concentrations, was carried out for this purpose. Second, to see if NFC hydrogels are applicable as a drug reservoir in iontophoretic transdermal drug delivery applications, an iontophoresis study was carried out using porcine ear skin model in vitro for human skin with propranolol loaded into NFC hydrogel of type A. In addition, Stella models were used as an aid to find suitable ways to predict the release and permeation behaviour of models drugs in the abovementioned context. The UPLC results from the release study show for both model drugs, the wt. % released had linear correlation with squareroot of time. At 6 hours, more than 70 wt. % propranolol was released from hydrogel reservoir. For ketoprofen, the release varied between 30 - 87 wt. %, where higher initial loading concentrations produced a decrease in the wt. % released from hydrogel. The iontophoresis study did not show a significant difference between the tested current densities (0.50 mA/cm2; 0.25 mA/cm2) produced on the wt. % of drug released. Simulation models could be run with the mathematical equations for diffusion controlled drug release. In conclusion, the NFC hydrogels show potential as drug reservoir for drug release. Additional experimental data using other types of drug reservoirs should be obtained for a better understanding of the suitability of NFC hydrogels as a drug reservoir in iontophoretic transdermal drug delivery.
  • Rimpelä, Anna-Kaisa; Kiiski, Iiro; Deng, Feng; Kidron, Heidi; Urtti, Arto (2019)
    Biologicals are important ocular drugs that are be delivered using monthly and bimonthly intravitreal injections to treat retinal diseases, such as age-related macular degeneration. Long acting delivery systems are needed for prolongation of their dosing interval. Intravitreal biologicals are eliminated from the eye via the aqueous humor outflow. Thus, the anterior and posterior segments are exposed to the drug. We utilized a kinetic simulation model to estimate protein drug concentrations in the vitreous and aqueous humor after bolus injection and controlled release administration to the vitreous. The simulations predicted accurately the experimental levels of 5 biologicals in the vitreous and aqueous humor. The good match between the simulations and experimental data demonstrated almost complete anterior segment bioavailability, and major dose sparing with ocular controlled release systems. Overall, the model is a useful tool in the design of intraocular delivery of biologicals.
  • Kickova, Eva; Salmaso, Stefano; Mastrotto, Francesca; Caliceti, Paolo; Urtti, Arto (2021)
    Posterior segment eye diseases are mostly related to retinal pathologies that require pharmacological treatments by invasive intravitreal injections. Reduction of frequent intravitreal administrations may be accomplished with delivery systems that provide sustained drug release. Pullulan-dexamethasone conjugates were developed to achieve prolonged intravitreal drug release. Accordingly, dexamethasone was conjugated to similar to 67 kDa pullulan through hydrazone bond, which was previously found to be slowly cleavable in the vitreous. Dynamic light scattering and transmission electron microscopy showed that the pullulan-dexamethasone containing 1:20 drug/glucose unit molar ratio (10% w/w dexamethasone) self-assembled into nanoparticles of 461 +/- 30 nm and 402 +/- 66 nm, respectively. The particles were fairly stable over 6 weeks in physiological buffer at 4, 25 and 37 degrees C, while in homogenized vitreous at 37 degrees C, the colloidal assemblies underwent size increase over time. The drug was released slowly in the vitreous and rapidly at pH 5.0 mimicking lysosomal conditions: 50% of the drug was released in about 2 weeks in the vitreous, and in 2 days at pH 5.0. In vitro studies with retinal pigment epithelial cell line (ARPE-19) showed no toxicity of the conjugates in the cells. Flow cytometry and confocal microscopy showed cellular association of the nanoparticles and intracellular endosomal localization. Overall, pullulan conjugates showed interesting features that may enable their successful use in intravitreal drug delivery.
  • Laurén, Patrick (Helsingfors universitet, 2013)
    Cellulose has already been used as an industrial raw material for over a century. However, during recent years the nanostructural features of the naturally occurring biopolymer have been fully investigated and characterized through different processing methods as nanofibrillar cellulose (NFC). This has led to a rapid development of novel cellulose based nanoscale materials and advancements in the field of composite materials. NFC offers interesting specific properties that differ from many other natural and synthetic polymers, such as self-renewable raw materials, semi-crystalline morphology, broad chemical modification capacity, biocompatibility and biodegradability. Biocompatibility and the biomimetic aspects of NFC have enabled the fabrication of nanoporous membranes and scaffolds that can function as medical devices (e.g. tissue engineering, wound healing, novel active implants). In this study, the properties of plant-derived NFC, as potential injectable drug releasing hydrogel "implants" were investigated. Three different sized candidate molecules were selected (123I-NaI, 123I-β-CIT and 99mTc-HSA, from small to large respectively) and investigated with the use of a small animal SPECT/CT molecular imaging device. Study compounds were mixed with the NFC biomaterial and injected into the pelvic region of mice. Drug release was observed for a period of 24 hours and the results were compared to saline/study compound control injections. In addition, 99mTc labeled NFC hydrogels were prepared for dual label tracing to observe the hydrogel positioning during the SPECT/CT acquisitions. For the smaller compounds (123I-NaI, 123I-β-CIT), no differences were found in the drug release or absorption in between the NFC biomaterial and saline injections. However, a clear difference was found with the large compound (99mTc-HSA). In the NFC hydrogel, the rate of release was slower and the distribution of 99mTc-HSA was more concentrated around the area of injection. In addition, the NFC hydrogel did not migrate from, or disintegrate, at the site of injection, suggesting a robust enough structural integrity to withstand normal movement and activity. In conclusion, the labeling of NFC was found to be a reliable and simple method. NFC hydrogels have the potential use as drug releasing medical devices with larger compounds. NFC matrix did not have any controlled release effect on the studied small molecules. Therefore further studies are required for more specific conclusions.
  • Semenyuk, Pavel I.; Kurochkina, Lidia P.; Mäkinen, Lauri; Muronetz, Vladimir I.; Hietala, Sami (2021)
    A prospective technology for reversible enzyme complexation accompanied with its inactivation and protection followed by reactivation after a fast thermocontrolled release has been demonstrated. A thermoresponsive polymer with upper critical solution temperature, poly(N-acryloyl glycinamide) (PNAGA), which is soluble in water at elevated temperatures but phase separates at low temperatures, has been shown to bind lysozyme, chosen as a model enzyme, at a low temperature (10 & DEG;C and lower) but not at room temperature (around 25 & DEG;C). The cooling of the mixture of PNAGA and lysozyme solutions from room temperature resulted in the capturing of the protein and the formation of stable complexes; heating it back up was accompanied by dissolving the complexes and the release of the bound lysozyme. Captured by the polymer, lysozyme was inactive, but a temperature-mediated release from the complexes was accompanied by its reactivation. Complexation also partially protected lysozyme from proteolytic degradation by proteinase K, which is useful for biotechnological applications. The obtained results are relevant for important medicinal tasks associated with drug delivery such as the delivery and controlled release of enzyme-based drugs.