<p>The preparation of multiple unit tablets was investigated in this thesis with the intention of gaining a deeper understanding of some of the factors that influence the properties of such tablets.</p><p>Initially, three different types of pellets (drug, soft and disintegrant pellets) were combined as a model to investigate the ability of the mixture to form disintegrating tablets. The proportions of the different pellets and the type of disintegrant used were factors that independently influenced the tablet properties. Furthermore, the properties of tablets containing drug pellets barrier-coated with an aqueous polymer dispersion were also found to depend on the coating thickness and the compaction pressure.</p><p>When compacting pellets barrier-coated with a solvent-based polymer solution without incorporating excipient particles in the tablet formulation, a high pellet porosity was advantageous to preserve the original drug release profile, even though highly porous pellets became more densified and deformed than pellets of lower porosity.</p><p>The influence of the properties of excipient particles on the deformation<b> </b>of the reservoir pellets was also studied and, although the amount of flattening of the pellets was only slightly affected, changes in the pellet shape (irregularity) with alterations in the porosity and size of the excipient particles were more substantial. In contrast, the properties of the excipient particles did not affect the pellet densification.</p><p>The solvent-based coating used was able to adapt to the changes in volume and shape that the pellets underwent during compaction. The coating structure appears to be changed by compaction and it is proposed that the final structure of the coating is the net effect of two parallel processes, one reducing and one prolonging the transport time of the drug across the coating. Thus, the drug release could be maintained or even prolonged after compaction, despite extensive structural changes of the reservoir pellets.</p>

<p>The aim of this thesis was to identify some functionality related characteristics of pharmaceutically relevant solid materials and to study the effect of their variation on processing behaviour and product performance. For this purpose, particles with different characteristics were prepared under a variety of conditions by crystal agglomeration, wet granulation and spray drying. The effect of particle size distribution on the evolution of the tablet microstructure during and after compression was investigated. The compression behaviour of particles with different nominal strength and degrees of agglomeration was studied and the influence of the surfactant concentration of amorphous particles on the compression behaviour was examined. The response of the powders to compression was described with the help of various techniques characterising the microstructure and tensile strength of the tablets produced. </p><p>Furthermore, a method suitable for observing drug release from single matrix granules was developed and used to study the effect of granule porosity and compaction pressure on the drug release process. </p><p>The particle size distribution did not influence the evolution of the tablet porosity or the tensile strength during compression, but it could have an effect on the evolution of the tablet microstructure during short-term storage, depending on the instability mechanism. The compression behaviour of particles prepared by crystal agglomeration and wet granulation was dependent on their degree of agglomeration and their failure strength. For particles with similar solid state properties and compression behaviour, the surface energy appears to have an effect on the bonding strength of adsorption bonds acting at interparticulate junctions. Using the method developed to observe the drug release from single matrix granules, reproducible data was obtained enabling the drug release process to be characterised. Depending on the type of matrix and the compaction pressure, the drug release rate could be enhanced or retarded. </p>

The preparation of multiple unit tablets was investigated in this thesis with the intention of gaining a deeper understanding of some of the factors that influence the properties of such tablets. Initially, three different types of pellets (drug, soft and disintegrant pellets) were combined as a model to investigate the ability of the mixture to form disintegrating tablets. The proportions of the different pellets and the type of disintegrant used were factors that independently influenced the tablet properties. Furthermore, the properties of tablets containing drug pellets barrier-coated with an aqueous polymer dispersion were also found to depend on the coating thickness and the compaction pressure. When compacting pellets barrier-coated with a solvent-based polymer solution without incorporating excipient particles in the tablet formulation, a high pellet porosity was advantageous to preserve the original drug release profile, even though highly porous pellets became more densified and deformed than pellets of lower porosity. The influence of the properties of excipient particles on the deformation<b> </b>of the reservoir pellets was also studied and, although the amount of flattening of the pellets was only slightly affected, changes in the pellet shape (irregularity) with alterations in the porosity and size of the excipient particles were more substantial. In contrast, the properties of the excipient particles did not affect the pellet densification. The solvent-based coating used was able to adapt to the changes in volume and shape that the pellets underwent during compaction. The coating structure appears to be changed by compaction and it is proposed that the final structure of the coating is the net effect of two parallel processes, one reducing and one prolonging the transport time of the drug across the coating. Thus, the drug release could be maintained or even prolonged after compaction, despite extensive structural changes of the reservoir pellets.

The aim of this thesis was to identify some functionality related characteristics of pharmaceutically relevant solid materials and to study the effect of their variation on processing behaviour and product performance. For this purpose, particles with different characteristics were prepared under a variety of conditions by crystal agglomeration, wet granulation and spray drying. The effect of particle size distribution on the evolution of the tablet microstructure during and after compression was investigated. The compression behaviour of particles with different nominal strength and degrees of agglomeration was studied and the influence of the surfactant concentration of amorphous particles on the compression behaviour was examined. The response of the powders to compression was described with the help of various techniques characterising the microstructure and tensile strength of the tablets produced. Furthermore, a method suitable for observing drug release from single matrix granules was developed and used to study the effect of granule porosity and compaction pressure on the drug release process. The particle size distribution did not influence the evolution of the tablet porosity or the tensile strength during compression, but it could have an effect on the evolution of the tablet microstructure during short-term storage, depending on the instability mechanism. The compression behaviour of particles prepared by crystal agglomeration and wet granulation was dependent on their degree of agglomeration and their failure strength. For particles with similar solid state properties and compression behaviour, the surface energy appears to have an effect on the bonding strength of adsorption bonds acting at interparticulate junctions. Using the method developed to observe the drug release from single matrix granules, reproducible data was obtained enabling the drug release process to be characterised. Depending on the type of matrix and the compaction pressure, the drug release rate could be enhanced or retarded.

Gold nanoshells are tunable plasmonic nanostructures consisting of spherical silica cores wrapped with thin layer of Au. Based on the size of the Au layer with respect to the silica core, gold nanoshells can resonantly absorb or scatter light at any wavelength on the visible or infrared. On resonance, gold nanoshells interact strongly with light to give rise to collective oscillations of the free electrons against the background of the ionic core, phenomena known as localized surface plasmons. The free electron oscillation creates surface plasmon multimodes of various orders. As a result, the average local near field surrounding the Au nanoshell is enhanced. The local field enhancement has been extensively used in different applications. In this work, the local near-field is used to enhance the Raman spectroscopy of DNA and explore the different modes attributed to the base composition and structure of the DNA sequence. We showed that urface enhanced Raman spectroscopy of DNA is dominated by the adenine modes regardless of the base composition of the DNA sequence, a property that we have used to develop a DNA label-free detection system. As absorbers, plasmon-resonant Au nanoshells can convert absorbed light into heat. As a consequence, the temperature on the Au nanoshell surface increases dramatically. This property is used to light-trigger the release of variety of therapeutic molecules such as single stranded DNA, siRNA and small molecules. We demonstrated that the local heat can be used to dehybridize double stranded DNA attached to the Au surface via a thiol moiety on one of the DNA strands. The complementary sequence (therapeutic sequence) is released at temperature lower than the standard melting temperature of same DNA sequence. Moreover, small molecules (DAPI) which were initially intercalated on the double stranded DNA attached to the Au surface were successfully released due to the heat generated around the nanoshell surface. Finally, siRNA molecules were also released using a different system made of PLL (polylysine) attached to Au nanoshells. The electrostatic interaction between the negatively charged siRNA and the positively charged PLL was overcome by the thermal perturbation causing the siRNA to be released. In vitro experiments successfully showed the release of siRNA, single stranded DNA and small molecules.

Meloksikamas, (4-hidroksi-2-metil-N-(5-metil-2-tiazolil)-2H-1,2-benzotiazin-3-karboksamid-1,1-dioksidas), yra nesteroidinis vaistas nuo uždegimo (NVNU), selektyvus ciklooksigenazės-II (COX-II) inhibitorius ir naudojamas reumatoidiniam artritui, osteoartritui ir kitoms sąnarių ligoms gydyti. Jis yra žymiai efektyvesnis ir sukelia mažiau šalutinių poveikių virškinamąjam traktui lyginant su kitais tradiciniais nesteroidiniais vaistais nuo uždegimo (NVNU). Gydomoji meloksikamo paros dozė (15 mg) yra viena mažiausių lyginant su kitais tradiciniais nesteroidiniais vaistais nuo uždegimo (NVNU). Europoje ir Lietuvoje yra registruotos tik peroralinės ir parenteralinės meloksikamo vaistų formos. Todėl siekiama sukurti transdermalines meloksikamo vaistų formas. Šio darbo tikslas – sukurti meloksikamo išsiskyrimo iš tirpalų pro dializės membraną in vitro metodą ir įvertinti išsiskyrusio meloksikamo kiekį. Tyrimo metu buvo naudojamas 1 proc. meloksikamo propileno glikolio tirpalas. Dializės membrana - regeneruotos celiuliozės. Akceptorinis tirpalas – buferinis tirpalas, kurio pH reikšmė 8,5. Palaikoma temperatūra - 37°C. Bandiniai buvo imami po 15, 30, 60, 120, 180 ir 300 minučių. Išsiskyręs meloksikamo kiekis iš bandinių kiekybiškai buvo vertinamas efektyviosios skysčių chromatografijos (HPLC) metodu. Didžiausias meloksikamo srautas (346, 963 µg/cm²/h) buvo po 15 minučių nuo eksperimento pradžios. Vėliau meloksikamo srautas mažėjo. Mažiausias meloksikamo srautas (67,401 µg/cm²/h)... [toliau žr. visą tekstą] / Meloxicam, (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1, 2-benzothiazine-3-carbox-amide-1, 1-dioxide), a non-steroidal anti-inflammatory drug (NSAID) and selective cyclooxygenase-II (COX-II) inhibitor, is used in the treatment of rheumatoid arthritis, osteoartritis and other joint diseases. It has comparable efficiency and greater gastric tolerability in comparison to conventional non-steroidal anti-inflammatory drugs (NSAIDs). The efficiency dose of meloxicam (15 mg/day) is one of the lowest in the non-steroidal anti-inflammatory drugs (NSAIDs). There are registered only oral and parenteral formulations of meloxicam in Europe and Lithuania. So it is strive to create transdermal formulations of meloxicam. The aim of the present work was to develop in vitro meloxicam release through dialysis membrane method and measure the amount of released meloxicam. On release of meloxicam from 1 % meloxicam propylene glycol solution was used regenerated cellulose dialysis membrane. As acceptor fluid was used buffer pH 8,5. Temperature was controlled at 37°C. Samples 1 ml were withdrawn at intervals of 15, 30, 60, 120, 180 and 300 min. The quantitative determination of meloxicam in samples was performed by high performance liquid chromatography (HPLC). The maximum flux of meloxicam (346,963 µg/cm²/h) was after 15 min from the beginning of the experiment. Later on meloxicam flux was on the decrease. The minimum flux of meloxicam (67,401 µg/cm²/h) was after 300 min from the beginning of... [to full text]

The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution. The physicochemical properties of multi-component dry powder inhaler (DPI) formulation were characterized by a number of techniques. In addition, the in vitro aerosol dispersion performance, storage stability test, and in vitro drug release of selected spray-dried (SD) multi-component systems were conducted. The physicochemical study revealed that multi-component aerosol particles possessed essential particle properties suitable for deep lung delivery. In general, the multi-component particles (typically 0.5 to 2 µm) indicated that the designed SD aerosol particles could potentially penetrate deep lung regions (such as respiratory bronchiolar and alveolar regions) by sedimentation and diffusion, respectively. The essential particle properties including narrow size distribution, spherical particle and smooth surface morphologies, and low water content (or water vapor sorption) could potentially minimize interparticulate interactions. The study of in vitro aerosol dispersion performance showed that majority of SD multi-component aerosols exhibited low values (less than 5µm) of MMAD, high values (approximately above 30% up to 60.4%) of FPF, and high values (approximately above 90%) of ED, respectively. The storage stability study showed that azithromycin–incorporated multi-component aerosol particles stored at 11 and 40% RH with no partial crystallization were still suitable for deep lung delivery. Compared to SD pure azithromycin particles, the azithromycin-incorporated multi-component particles exhibited an enhanced initial release. The targeted microparticulate and nanoparticulate multi-component dry powder aerosol formulations with essential particle properties for deep lung pulmonary delivery were successfully produced by using spray drying from organic solution. The promising experimental data suggest the multi-component formulations could be further investigated in in vivo studies for the purpose of commercialization.

Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies. A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release data. This method also quantified the effects of topotecan dimerization and surface potential on total amount of drug released from these liposomal formulations. The pH-sensitive release of topotecan from unilamellar vesicles was subsequently evaluated with this method. A mechanistic model identified three permeable species in which the zwitterionic lactone form of topotecan was the most permeable. Ring-closing kinetics of topotecan from its carboxylate to lactone form were found to be rate-limiting for topotecan drug release in the neutral pH region. Models were also developed to non-invasively analyze release kinetics of actively-loaded liposomal formulations of topotecan in vivo. The fluorescence excitation spectra of released topotecan were used to observe release kinetics in aqueous solution and human plasma. Simulations of the intravesicular pH in the various release media indicated accelerated release in plasma was a consequence of increased intravesicular pH due to ammonia levels in the plasma instead of alterations in bilayer integrity. Further studies were performed to understand the roles of dimerization, ion-pairing, and precipitation on loading and release kinetics obtained from actively-loaded topotecan. Extension of this type of modeling for other types of nanoparticles was illustrated with doxorubicin-conjugated polymeric micelles. Mathematical modeling of experimental studies monitoring doxorubicin release identified conjugation stability during storage, hydrazone hydrolysis kinetics, and unconjugated doxorubicin partitioning affected micellar doxorubicin release. This work identifies several of the key parameters governing drug release from these liposomal and micellar nanoparticles and lays the framework for future development of in vivo release models for these formulations.

Several sophisticated techniques to study in vivo GI transit and regional absorption of pharmaceuticals are available and increasingly used. Examples of such methods are Magnetic Marker Monitoring (MMM) and local drug administration with remotely operated capsules. Another approach is the paracetamol and sulfapyridine double marker method which utilizes observed plasma concentrations of the two substances as markers for GI transit. Common for all of these methods is that they generate multiple types of observations e.g. tablet GI position, drug release and plasma concentrations of one or more substances. This thesis is based on the hypothesis that application of mechanistic nonlinear mixed-effect models could facilitate a better understanding of the interrelationship between such variables and result improved predictions of the processes involved in oral absorption. Mechanistic modeling approaches have been developed for application to data from MMM studies, paracetamol and sulfapyridine double marker studies and for linking in vitro and in vivo drug release. Models for integrating information about tablet GI transit, in vivo drug release and drug plasma concentrations measured in MMM studies was outlined and utilized to describe drug release and absorption properties along the GI tract for felodipine and the investigational drug AZD0837. A mechanistic link between in vitro and in vivo drug release was established by estimation of the mechanical stress in different regions of the GI tract in a unit equivalent to rotation speed in the in vitro experimental setup. The effect of atropine and erythromycin on gastric emptying and small intestinal transit was characterized with a semi-mechanistic model applied to double marker studies in fed and fasting dogs. The work with modeling of in vivo drug absorption has highlighted the need for, and led to, further development of mixed-effect modeling methodology with respect to model diagnostics and the handling of censored observations.

Les nanogels hybrides constitués de polymères thermosensibles et de nanoparticules inorganiques stimulables telles que des nanoparticules magnétiques (NPMs) ou des nanobatônnets d’or (AuNRs) sont extrêmement intéressants pour des applications biomédicales. Leur matrice en polymère permet d’encapsuler et de libérer de grandes quantités de molécules actives, alors que les nanoparticules peuvent générer de la chaleur lorsqu’elles sont exposées à un champ magnétique alternatif (AMF) pour les NPMs, et à une irradiation proche infrarouge (NIR-L) pour les AuNRs. Ce manuscrit de thèse porte sur la synthèse et la caractérisation de nanogels biocompatibles, pH- et thermosensibles, à base de monomères en oligo (éthylène glycol) méthyl éther méthacrylate (OEGMAs), d’acide méthacrylique (MAA) et encapsulant des NPMs et/ou des AuNRs pour déclencher de manière contrôlée, par hyperthermie magnétique ou par photothermie, la libération d’une molécule anticancéreuse, la doxorubicine (DOX). Des nanogels hybrides magnétiques, plasmoniques et magnéto-plasmoniques ont été synthétisés. Ces nanogels ont un diamètre hydrodynamique entre 200 et 500 nm et une température de transition de phase volumique comprise entre 30 et 54 °C. Le comportement de gonflement-dégonflement des nanogels peut être induit par plusieurs stimuli (température, pH, AMF, NIR-L). Ces résultats démontrent que les MagNanoGels sont d’excellents nanovecteurs pour accroître l’internalisation cellulaire en augmentant la cytotoxicité de la DOX et qu’il est possible de déclencher à distance la libération intracellulaire de DOX sous AMF dans des conditions athermiques. Par ailleurs, les PlasMagNanoGels peuvent générer efficacement de la chaleur par photothermie pour une thermothérapie. En outre, les propriétés intrinsèques des NPMs, pour le ciblage magnétique et en tant qu’agents de contraste pour l’imagerie par résonance magnétique (MRI), font de ces nanogels des candidats idéaux pour une nouvelle approche thérapeutique (diagnostique et traitement) contre le cancer. / Hybrid nanogels, composed of thermoresponsive polymers and inorganic responsive nanoparticles, such as magnetic nanoparticles (NPMs) and gold nanorods (AuNRs) are highly interesting for biomedical applications. Their polymeric matrix makes them able to uptake and release high quantities of drugs, whereas nanoparticles can generate heat when exposed to an alternating magnetic field (AMF) for NPMs, and to a near-infrared light for AuNRs. This thesis manuscript focuses on the synthesis and the characterization of biocompatible, pH- and thermoresponsive nanogels, based on oligo(ethylene glycol) monomers (OEGMAs), methacrylic acid (MAA) and encapsulating NPMs and/or AuNR for remotely triggered doxorubicin (DOX, anticancer drug) release, by magnetic hyperthermia or phothothermia. Hybrid magnetic, plasmonic and magneto-plasmonic nanogels were synthesized. Theses nanogels have a hydrodynamic diameter between 200 and 500 nm and a volume phase transition temperature (VPTT) from 30 to 54°C. The nanogels’ swelling-deswelling behavior can be induced by several stimuli (temperature, pH, AMF, NIR-L). These results demonstrate that MagNanoGels are excellent nanocarriers for enhancing cellular internalization enhancing DOX cytotoxicity and that DOX release was significantly enhanced upon exposure to AMF in athermic conditions. In addition, PlasMagNanoGels can efficiently generate heat by photothermy for thermotherapy. Therefore, the intrinsic properties of NPMs for magnetic targeting and as contrast agents for Magnetic Resonance Imaging (MRI), make these nanogels ideal candidates for a new therapeutic approach (diagnosis and treatment) against cancer.