Academic literature on the topic 'Floating controlled drug delivery system'

The aim of this thesis was to develop biodegradable devices loaded with chemotherapy drug. The system is targeted for advanced ovarian cancer treatment through the intraperitoneal (IP) route of administration. Polylactide-co-glycolide (PLGA) was selected as the model biodegradable polymer to produce drug-loaded microsphere, hollow and solid fibres. Copolymer PLGA with three different lactic:glycolic acids ratios; 50:50, 65:35 and 75:25 were used in order to compare their drug loading capacities and in vitro drug release profiles. Cisplatin, a cytotoxic drug with proven activity against ovarian cancer was selected as the model chemotherapy drug. Intraperitoneal administration is often associated with abdominal pain therefore a local anaesthetic, lidocaine, was selected for the purpose of pain relief.

The aim of this research was to formulate, characterise and assess the feasibility of a novel drug delivery system known as the in situ gelling matrix (ISGM) where a hydrophilic polymer is suspended in a non-aqueous solvent that converts into a gel when injected subcutaneously or intramuscularly thus giving a controlled release matrix for a drug. Although the concept has been patented with claims that this kind of drug delivery is achievable in theory for a wide variety of candidate substances, actual formulation studies for making a commercially viable product for this technology are completely lacking in practice. The research embodied in this thesis addresses this lack. Initial studies involved conducting a biocompatibility study using the HET-CAM (hens egg test - chorioallantoic membrane) test on a range of possible ingredients for the delivery system. The materials deemed biocompatible were then carried through to a screening process where the physical stability of the hydrophilic polymers in non-aqueous solvents was monitored. It was found that the hydrophilic polymers tested sedimented rapidly in the non-aqueous solvents indicating such a system was not physically stable. Consequently, density-inducing or viscosity-inducing agents were added to the non-aqueous solvents to retard the sedimentation rate. The addition of polycarbophil, a viscosity-inducing agent, clearly increased the viscosity of the system. However, undesirable formation of polycarbophil globules occurred during the manufacturing process, which caused batch-to-batch variations in the viscosity of the continuous phase. Various manufacturing methods were tested before arriving at the optimum procedure to prevent globule formation using a high speed dispersion tool. A final physical sedimentation analysis of candidate continuous phases and hydrophilic polymers was conducted for determining the ideal combination of ingredients to use in the system. These investigations finally led to the adoption of an optimum mix of components consisting of 10% (w/w) hydroxypropyl methylcellulose (HPMC) (the hydrophilic polymer) suspended in a continuous phase of propylene glycol (the non-aqueous solvent) containing 0.67% (w/w) polycarbophil (the viscosity inducing agent). Using this mix of components, the in situ gelling matrix system was then subjected to various characterisation studies including infrared (IR), differential scanning calorimetry (DSC), ultraviolet-visible (UV-Vis) spectrophotometry and redispersion studies. The chemical stability of the hydrophilic polymer and the continuous phase (the non-aqueous solvent and polycarbophil) was monitored and were found to be chemically stable over a 9 month period. The feasibility of the in situ gelling matrix technology as a controlled release device was assessed using the drug propranolol. In vitro drug release studies were conducted using a custom-built dissolution apparatus. The effect of various parameters such as the concentration of the hydrophilic gelling agent on the drug release rate was investigated. Increasing the concentration of the gelling agent in the formulation resulted in a slower rate of release. The drug release data were modelled using the Higuchi relationship and a power law relationship to compare the effects of the various parameters on the release rate Stability studies on the drug in the in situ gelling matrix system were carried out by storing samples in accelerated ageing conditions of 40 C / 75% relative humidity for 4 weeks. During this time, the samples were analysed each week by high performance liquid chromatography (HPLC). These demonstrated that no apparent drug degradation had occurred over the 4-week period. This indicates that the drug propranolol in the in situ gelling matrix system is stable under ambient conditions for at least 4 weeks. The results of this study demonstrated that the in situ gelling matrix technology is potentially viable as a drug delivery system and provide a practical methodology for the commercial development of such systems.

Mestrado em Ciência e Engenharia de Materiais<br>A Drug Delivery System (DDS) may provide the precise transportation of the medical drug inside the patient’s body, directly to the pathological area or alternatively it may be also locally administrated. Once at the site of interest, the ideal DDS is expected to release the drug in a sustained manner according to the specific needs of the patient. As compared to other routes of drug administration, an appropriately designed DDS which active components are conveniently targeted should also ensure the desired in situ treatment without harmful effects of the drug over healthy tissues. The inorganic part of the human bone is mainly composed by hydroxyapatite (Ca10(PO4)6(OH)2) (HAP). Chitosan (CH), a natural polymer, is a linear glucose based polysaccharide. These two compounds are non-toxic, biodegradable and highly biocompatible and hence widely used for various biomedical applications (DDS, tissue engineering, implants, etc.). Moreover, some unique features including the amphiphilicity and good mucoadhesive properties of chitosan together with the ability of HAP to adsorb and then release different chemical species make these compounds challenging materials for DDS design. The present work addresses the combination of HAP and CH with a drug model aimed at engineering a DDS with a controlled drug release. Dexamethasone (DEX) is the drug model here selected. DEX is a corticosteroid with anti-inflammatory, antineoplastic and immunosuppressant effects, which is used for the treatment of various diseases like endocrine, dermatologic and neoplastic disorders and cancer among others. In the present research, composite granules with different ratios of HAP and CH components were produced by spray drying aqueous suspension of HAP, chitosan and DEX. To reduce polymer swelling, Glutaraldehyde (GA) was used to cross-link CH. Granules were also produced by a double spray drying technique, which so far has not been yet reported in the literature. The morphology and crystal phase composition of the produced granules were evaluated by scanning electron microscopy (SEM), N2 adsorption using the BET isotherm (BET), and X-ray diffraction (XRD). The obtained results showed that the variation of (HAP/CH) ratio affected the morphology of the granules as when that ratio increases the granules morphology changes from spherical with rough surface to a shape with concavities and smooth surface. Regarding the granules obtained by double spray drying, their morphological characteristics indicated that a core-shell structure was obtained. The drug release experiments were carried out by immersing the DEX loaded granules into phosphate buffer solution (PBS), kept at 37 °C under constant stirring. Aliquots of PBS were withdrawn after different times and their drug content evaluated by UV-Vis spectroscopy at λ= 241,5 nm. The results showed that granules with different composition could display different drug release patterns: HAP/CH granules cross-linked with GA (0,2 wt %) exhibit a more sustained drug release than granules with the same HAP/CH ratio without modification; as for double spray dried granules, a characteristic profile with a double plateau was observed, in line with a core-shell structure. Attempting to elucidate the mechanisms underlying DEX release, different mathematical models were compared with the measured release profiles. It was found that Peppas-Sahlin and Weibull equations are appropriate models for predicting the drug release from the produced granules. In conclusion, the cross-linking and morphology engineering (core-shell structure) via double spray drying allowed improving DEX release profile of HAP/CH DDSs.<br>Um sistema de libertação de fármacos (DDS) pode transportar de forma precisa o fármaco para o sítio alvo,,i.e., directamente para a zona patológica ou ser administrado localmente. Uma vez no local de interesse, o DDS deve libertar o fármaco de forma controlada, de acordo com as necessidades específicas do paciente, garantindo in situ o tratamento desejado, sem efeitos nocivos sobre os tecidos saudáveis. A parte inorgânica do osso humano é composta principalmente por hidroxiapatite (Ca10(PO4)6(OH)2) (HAP). O quitosano (CH), um polímero natural e abundante. Para além de altamente biocompatíveis estes dois compostos são biodegradáveis, podendo ser utilizados em várias aplicações biomédicas (DDS, engenharia de tecidos, implantes, etc.). Além disso, as características de anfifilicidade e as boas propriedades mucoadesivas do quitosano, somadas à capacidade da HAP para absorver diferentes espécies químicas fazem destes compostos materiais desafiantes para um projecto de DDS. O presente trabalho aborda a combinação de HAP com CH para produção de um DDS. A dexametasona (DEX), que é um corticosteróide com acção anti-inflamatória, anti-neoplásica e efeitos imunossupressores, foi o fármaco modelo seleccionado. Neste trabalho produziram-se grânulos compósitos, com diferentes proporções de HAP e CH, por atomização de suspensões aquosas de HAP, quitosano e DEX. Utilizou-se glutaraldeído (GA) para reticular o CH e procedeu-se também à dupla atomização dos grânulos, uma técnica ainda não reportada na literatura. Os ensaios de libertação do fármaco foram efectuados por imersão dos grânulos carregadas com DEX em solução de fosfato tampão mantida a 37 ° C e sob agitação constante. Alíquotas de PBS foram retiradas após diferentes períodos de tempo e a sua concentração de fármaco avaliada por UV-Vis a λ = 241,5 nm. As características morfológicas e a composição de fases cristalinas dos grânulos atomizados foram avaliadas por micróscopia eletrónica de varrimento (SEM), por adsorção de N2 usando a isotérmica de BET e por difração de raios-X (XRD). Os resultados obtidos mostraram que a variação da razão (HAP / CH) afectou a morfologia dos grânulos: quando a razão aumenta a morfologia dos grânulos evolui de esférica e rugosa para lisa e com concavidades. Por outro lado as características morfológicas dos grânulos duplamente atomizados indicam uma estrutura core-shell. No que se refere aos resultados de libertação de DEX, verificou-se que grânulos de composição diferente evidenciam perfis de libertação distintos: os grânulos reticulados com GA (0,2 %) apresentam uma curva de libertação mais lenta do que a observada para os grânulos com igual razão HAP/CH mas não modificados; quanto aos grânulos com dupla atomização, estes apresentam um padrão de libertação característico, com duplo patamar, em linha com a referida estrutura core-shell. Na tentativa de elucidar os mecanismos subjacentes à libertação de DEX, compararam-se os perfis medidos com diferentes modelos matemáticos. Verificou-se que o padrão de libertação da DEX pode ser adequadamente descrito pela equação de Peppas-Sahlin e de Weibull. Em conclusão, a reticulação e a engenharia de morfologia (estrutura core-shell) pela via da dupla atomização permitiram melhorar o perfil de libertação de DEX do DDS à base de grânulos compósitos de HAP/CH.

La presente tesis doctoral, titulada "Nanotecnología y química supramolecular en procesos de liberación controlada y reconocimiento molecular para aplicaciones biomédicas", se centra en dos temas importantes: el reconocimiento molecular y los procesos de liberación controlada. Esta tesis doctoral está estructurada en cuatro capítulos. El primer capítulo introduce el concepto de materiales híbridos orgánicos-inorgánicos funcionalizados con puertas moleculares y sus aplicaciones biomédicas como nanomateriales para dirigir y controlar la liberación controlada de fármacos. Además se introduce una breve descripción sobre sensors colorimétricos basados en la base de la quimica supramolecular, particularmente en los procesos de reconocimiento molecular. En particular, el capítulo 2 describe la preparacion de cinco nanodispositivos que responden a enzimas. Estos materiales híbridos se componen de dos unidades principales: un soporte mesoporoso basado en sílice inorgánica, capaz de encapsular moléculas orgánicas y un compuesto orgánico anclado en la superficie externa del soporte mesoporoso inorgánico que actúa como puerta molecular. Todos los sistemas propuestos utilizan puertas moleculares peptídicas que responden a temperatura o enzimas como estímulo. La segunda parte de esta tesis doctoral se centra en el diseño y desarrollo de un nuevo compuesto químico capaz de detectar monóxido de carbono in vivo. En resumen, para todos los resultados antes mencionados podemos decir que esta tesis doctoral constituye una contribución científica original al desarrollo de la química supramolecular. Sus resultados derivados de los estudios presentados dejan rutas abiertas para continuar el estudio y el desarrollo de nuevos materiales híbridos y sensors químicos más eficientes para aplicaciones biomédicas y terapeuticas.<br>This PhD thesis entitled "Nanotechnology and supramolecular chemistry in controlled release and molecular recognition processes for biomedical applications", is focused on two important subjects: molecular recognition and controlled delivery processes. This PhD thesis is structured in four chapters. The first chapter introduces the concept of organic-inorganic hybrid materials containing switchable "gate-like" ensembles and their biomedical applications as nanomaterials for targeting and control drug delivery. Furthermore, is introduced a short review about chromo-fluorogenic chemosensors based on basic principles of supramolecular chemistry, particulary in molecular recognition processes. In particular, in chapter 2 is focus on the development of enzymatic-driven nanodevices. These hybrid materials are composed of two main units: an inorganic silica based mesoporous scaffold, able to store organic molecules and an organic compound anchored on the external surface of the inorganic mesoporous support than acts as molecular gate. All the systems proposed use peptidic gates that respond to temperature or enzimatic stimulis. The second part of this PhD thesis is focused on the design and development of a new chemical compound capable of detecting carbon monoxide in vivo. In summary, for all the results above mentioned we can say that this PhD thesis constitutes an original scientific contribution to the development of supramolecular chemistry. Its results derived from the studies presented leaves open routes to continue the study and development of new hybrid materials and more efficient chemical sensors with biomedical and therapeutic applications.<br>La present tesi doctoral, titulada "Nanotecnologia i química supramolecular en processos d'alliberament controlat i reconeixement molecular per a aplicacions biomèdiques", es centra en dos temes importants de la química: el reconeixement molecular i els processos d'alliberament controlat. Aquesta tesi doctoral està estructurada en quatre capítols. El primer capítol introdueix el concepte de materials híbrids orgànics-inorgànics funcionalitzats amb portes moleculars i les seves aplicacions biomèdiques com nanomaterials per dirigir i controlar l'alliberament controlat de fàrmacs. A més s'introdueix una breu descripció sobre sensors colorimètrics fonamentats en la base de la química supramolecular, particularment en els processos de reconeixement molecular. En particular, el capítol 2 descriu la preparació de cinc nanodispositius que responen a enzims. Aquests materials híbrids es componen de dues unitats principals: un suport mesoporos basat en sílice inorgànica, capaç d'encapsular molècules orgàniques i un compost orgànic ancorat a la superfície externa del suport mesoporós inorgànic que actua com a porta molecular. La segona part d'aquesta tesi doctoral es centra en el disseny i desenvolupaent d'un nou compost químic capaç de detectar monòxid de carboni in vivo. En resum, per a tots els resultats abans mencionats podem dir que esta tesi doctoral constituïx una contribució científica original al desenvolupament de la química supramolecular. Els seus resultats derivats dels estudis presentats deixen rutes obertes per a continuar l'estudi i el desenvolupament de nous materials hibrids i sensors químics més eficients per a aplicacions biomèdiques i terapeutiques.<br>De La Torre Paredes, C. (2017). Nanotechnology and supramolecular chemistry in controlled release and molecular recognition proceses for biomedical applications" [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/94043<br>TESIS