Dissertations / Theses on the topic 'Pharmaceutical emulsions'

INTRODUCCIÓ: Aquesta tesi doctoral està inclosa dins del Pla de Doctorats Industrials de la Generalitat de Catalunya i s’ha realitzat conjuntament entre la Universitat de Barcelona i una empresa veterinària privada: Laboratoris Hipra, S.A. OBJECTIUS: L’objectiu principal d’aquesta tesi ha estat obtenir emulsions estables, amb poder adjuvant i compatibles amb antígens per a la formulació de vacunes veterinàries. MATERIALS I MÈTODES: Com que les emulsions són composicions afectades per múltiples factors, tots els experiments s’han plantejat mitjançant la metodologia del disseny d’experiments. RESULTATS I DISCUSSIÓ: En la formulació d’emulsions o/w, l’objectiu ha estat trobar un substitut de l’Espessant A per evitar diferències de viscositat en l’emulsió resultant causades per la naturalesa de l’espessant en funció del lot utilitzat. S’ha començat substituint l’Espessant A per espessants sintètics sense modificar cap més factor de la formulació de partida, però no ha resultat ser un bon mètode per mantenir l’estabilitat de les emulsions formulades. Seguidament, amb l’assaig de diversos factors alhora, s’han aconseguit les primeres emulsions estables sense Espessant A. A partir d’una d’aquestes emulsions, la qual està composta pels espessants Espessant B i Espessant C, s’han plantejat diversos dissenys per buscar més alternatives d’espessants. Per una banda, s’han buscat més espessants principals per substituir el Espessant B i tenir més alternatives possibles de l’Espessant A. I per altra banda, com que la Espessant C és un espessant d’origen natural i, igual que l’Espessant A, proporciona diferències de viscositat segons el lot utilitzat, també se li han buscat substituts. Així doncs, s’ha aconseguit substituir la Espessant C per Espessant F i el Espessant D' ha resultat ser un bon espessant principal, mantenint en els dos casos l’estabilitat de les emulsions. A partir de tots els resultats d’estabilitat i viscositat obtinguts i de les preferències de l’empresa sobre els components de la formulació, s’ha obtingut una formulació definitiva composta per Espessant D', Espessant F i amb menys concentració de tensioactius i fase antigènica que la formulació de partida. Un cop optimitzades les concentracions dels espessants, s’ha fet un estudi amb diferents lots dels espessants que ha demostrat diferències significatives en la viscositat de l’emulsió en funció del lot de Espessant F utilitzat. S’ha vist que el motiu d’aquestes diferències és que el Espessant F necessita ser sotmès a un procés d’activació prèviament a la formulació per poder actuar correctament. Després de repetir l’optimització amb el Espessant F activat i d’adequar el procés de formulació a nivell de producció industrial, s’ha confirmat que la formulació és robusta i no pateix diferències significatives en funció dels lots utilitzats. Per acabar, s’ha elaborat un estudi d’estabilitat durant 12 mesos que ha corroborat la possible substitució de la formulació de partida per la formulació dissenyada. En la formulació d’emulsions w/o, l’objectiu ha estat substituir una fase oliosa de composició no coneguda per una fase de composició coneguda i senzilla de formular. S’han plantejat nombrosos dissenys per arribar a tenir una emulsió de signe w/o, estable i d’aspecte fluid. El problema ha estat aconseguir el signe d’emulsió desitjat, cosa que s’ha aconseguit disminuint la concentració del tensioactiu hidròfil de les formulacions. Un cop aconseguides algunes emulsions w/o estables, aquestes no han estat robustes ja que la seva repetició no ha donat els mateixos resultats o no s’han pogut formular amb PBS, fet necessari perquè una emulsió sigui compatible també amb antígens. Finalment, s’ha aconseguit una emulsió de signe w/o, aspecte fluid i estable composta per Oli K, Tensioactiu X, Tensioactiu S’ i Estabilitzant M. S’ha elaborat un estudi d’estabilitat durant 6 mesos que ha corroborat la possible substitució de la formulació de partida per la formulació dissenyada. CONCLUSIONS: S’han obtingut dues formulacions noves en forma d’emulsió per a l’administració de vacunes per via parenteral d’ús veterinari que són repetibles, robustes, compatibles amb antígens i estables durant el període d’estabilitat assajat.
INTRODUCTION: This thesis is the result of a collaboration between Universitat de Barcelona and a private company called Laboratoris Hipra, S.A. Veterinary companies suffer serious economic losses because of diseases such as swine fever. In order to prevent and treat them, veterinary industry makes use of vaccines, for example, in emulsion form. The development of emulsions is not an easy task because emulsions may present stability problems and incompatibility with the antigens selected therefor. AIM: To obtain stable and robust emulsions, which are compatible with the selected antigens. On the one hand, the first specific aim is to replace the natural thickener thickener A present in a commercial o/w emulsion, to avoid viscosity variability depending on thickener batches. On the other hand, the second specific aim is to replace the oil phase present in a commercial w/o vaccine of an unknown composition by a new oil phase. EXPERIMENTAL METHODS: Since emulsions are multifactorial systems, all the trials were planned using experimental design methodology. RESULTS AND DISCUSSION: Regarding the o/w emulsion aim, the substitution of Thickener A by other thickeners was unsuccessfully tested. After many different tests, a stable emulsion comprising Thickener D' and Thickener F as thickeners was obtained. However, this formulation presented variability depending on the batch of Espessant F. This problem was solved by a previous activation of Thickener F. Finally, the definitive formulation with activated Thickener F passed correctly the toxicity test and stability test up to 12 months. Secondly, to develop a w/o emulsion with low viscosity and stable more than 24 hours was a though process. But finally, as a result of many trials combining different oils and surfactants, a formulation comprising ethyl oleate, Span® 80 and Kolliphor® ELP showed positive results regarding stability and viscosity up to 6 months. CONCLUSIONS: Two new emulsions were developed suitable to replace commercial vaccines keeping substantially their initial features such as viscosity, stability and toxicity.

La piel constituye una de las primeras líneas de defensa de nuestro organismo y, como tal, puede sufrir la agresión de numerosos microorganismos y parásitos. Entre estas patologías cabe mencionar las micosis y la leishmaniosis que pueden tratarse con una variedad de fármacos presentados bajo diferentes formas farmacéuticas diseñadas para las vías de administración correspondientes, siendo las vías más habituales la cutánea, oral y parenteral. Para el tratamiento de afecciones de la piel y sus anejos, la vía cutánea en principio es la de elección, sin embargo, en algunos casos no aporta los resultados terapéuticos esperados, frecuentemente debido a una escasa penetración y/o retención del fármaco a nivel dérmico. Esta falta de eficacia podría paliarse con el uso de vehículos tales como nanoemulsiones e hidrogeles termorreversibles, dando lugar a nuevas formulaciones que podrían usarse como alternativa a los medicamentos de administración oral o parenteral para el tratamiento de patologías cutáneas. La Anfotericina B podría ser un buen candidato, dado su potencial nefrotóxico por vía oral y la ausencia en Europa de medicamentos con este principio activo para su administración cutánea. Si estas nuevas formulaciones fueran viables, supondrían una buena alternativa, dado que en principio se reducirían considerablemente los posibles efectos indeseables del fármaco. Además, comparado con los inyectables, presentarían el beneficio de una administración no invasiva e indolora. Para el desarrollo de la Tesis se ha realizado un amplio estudio bibliográfico preliminar que viene sintetizado en el capítulo 1 de la memoria. Seguidamente, en el capítulo 2, se exponen los objetivos y plan de trabajo establecido. Los demás capítulos tratan de la parte experimental con sus conclusiones finales.
The skin constitutes one of the first lines of defense of our organism and, as such, it can suffer the aggression of many microorganisms and parasites. These pathologies include the mycosis and leishmaniosis that can be treated with a variety of drugs presented under different pharmaceutical forms designed for the corresponding routes of administration, the most common oral, cutaneous and parenteral pathways. For the treatment of skin conditions and their annexes, the skin route in principle is the one of choice, however, in some cases it does not provide the expected therapeutic results, often due to poor penetration and / or retention of the drug at the dermal level. This lack of efficiency could be mitigated by the use of vehicles such as nanoemulsions and thermorreversible hydrogels, giving rise to new formulations that could be used as an alternative to oral or parenteral administration medications for the treatment of cutaneous pathologies. Amphotericin B may be a good candidate, given its oral nephrotoxic potential and the absence in Europe of medications with this active ingredient for its skin administration. If these new formulations were viable, they would be a good alternative, since in principle the potential undesirable effects of the drug would be considerably reduced. In addition, compared with injectables, they would present the benefit of non-invasive and painless administration. For the development of the Thesis, a comprehensive preliminary bibliography study has been carried out which is summarized in Chapter 1 of the report. Next, in Chapter 2, the objectives and established work plan are set out. The other chapters deal with the experimental part with its final conclusions.

Orientadores: Maria Angela de Almeida Meireles Petenate, Diego Tresinari dos Santos
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos
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Resumo: O presente trabalho de doutorado está dividido em dois temas principais, um sobre o uso da tecnologia supercrítica para a formação de partículas e outro sobre o uso do ultrassom para a formulação de emulsões. A revisão da literatura sobre o estado da arte do emprego do CO2 supercrítico para formação de micro e nanopartículas e encapsulação mostrou as potencialidades do uso desta tecnologia. A unidade usada para os experimentos de micronização via tecnologia supercrítica foi desenvolvida pelo grupo de pesquisa e validada utilizando uma substância modelo, o sal de ibuprofeno sódico. Esse fármaco foi selecionado devido às informações sobre o sistema CO2-Ibuprofeno encontradas na literatura. O efeito das condições operacionais (temperatura, pressão, vazão da solução, vazão do CO2, tipo de injetor e concentração de ibuprofeno sódico na solução etanólica) no rendimento de precipitação, teor de solvente residual, morfologia das partículas e consumo energético por unidade de produto processado foi investigado utilizando o método split-plot. Sal de ibuprofeno sódico foi micronizado com sucesso via Antissolvente Supercrítico (SAS) utilizando a unidade construída. A vazão de CO2 influenciou estatisticamente no rendimento de precipitação, enquanto que, não houve influência das condições operacionais no teor de solvente residual das partículas micronizadas. Com a apropriada seleção das condições operacionais, foi possível a obtenção de partículas de ibuprofeno sódico com morfologia de folha, sendo ideal para os processos de compressão do fármaco, com baixo teor de solvente residual e alto rendimento de precipitação. Neste trabalho também foi explorado o uso do ultrassom para a formulação de emulsões, contendo extrato rico em 'delta'-tocotrienol, com o intuito de aumentar o valor agregado deste extrato obtido das sementes de urucum por extração supercrítica com dióxido de carbono. As sementes de urucum já são valiosas pela característica de produzir pigmentos, a bixina e a norbixina. Contudo, essas sementes também vêm adquirindo notoriedade por conter outras substâncias de importância para a saúde do homem, como tocoferóis, tocotrienóis e geranil geraniol. Devido à importância desses compostos bioativos, que apresentam propriedades antioxidade, hidratante e fotoprotetora, este estudo visou o desenvolvimento de métodos para formação de emulsões permitindo a proteção desses compostos instáveis às condições adversas, aumentando assim o valor agregado dos extratos obtidos das sementes de urucum. Extrato de raiz de ginseng brasileiro, rico em saponinas, foi utilizado como biossurfactante. Adicionalmente, emulsões foram obtidas utilizando um homogeneizador tipo dispersor de fase múltipla na mesma densidade energética que foi aplicada no ultrassom. A influência do processo de emulsificação, densidade energética, concentração do biosurfactante, tipo de óleo e de biosurfactante no tamanho de gota e estabilidade da emulsão foi investigada. Os resultados indicaram que o extrato rico em saponinas pode ser uma boa opção para formulação de emulsões para aplicação em produtos alimentícios. Miniemulsões, com tamanho de gota variando entre 0,35 e 0,83 µm, foram obtidas, sendo que os menores tamanhos de gota foram observados empregando o extrato de raiz de ginseng e o ultrassom. O processo de emulsificação influenciou estatisticamente a estabilidade das emulsões
Abstract: The presented doctoral work is divided into two main themes under which one is about the use of supercritical technology for particle formation and the another one about the use of ultrasound for emulsion formulation. A literature review about the state of the art in using supercritical CO2 for micro and nanoparticles formation and encapsulation showed the potential of this technology. A homemade experimental apparatuses constructed by our research group and used for micro and nanoparticles formation has been validated using a model substance, the ibuprofen sodium salt. This drug was selected due to the literature information of the CO2-Ibuprofen system. The effect of operational conditions (temperature, pressure, CO2 flow rate, solution flow rate, injector and concentration of ibuprofen sodium in the ethanol solution) on the precipitation yield, energy consumption per unit of manufactured product, residual solvent content and particle morphology have been investigated using split-plot designs. Ibuprofen sodium salt was successfully micronized by Antisolvent Supercritical (SAS) using the constructed unit. The CO2 flow rate influenced the precipitation yield at statistically significant levels meanwhile none operating parameters did influence the residual solvent content in the micronized particles. Selecting appropriate process conditions, it has been shown to facilitate the production of homogeneous sheet-like microparticles of ibuprofen particles, the best for tableting purposes, with low residual solvent and high precipitation yield. In this work, the use of ultrasound has been also explored for fabricating microemulsion of 'delta'-tocotrienol-rich oil in order to add value to these extracts obtained from annatto seeds using supercritical extraction (SFE). The main pigments of annatto seeds are bixin and norbixin, wich are valuable natural colorants. However, these seeds have acquired notoriety by containing other important substances for human health, such as tocopherols, tocotrienols and geranylgeraniol. Due to the bioactive compounds importance, which have moisturizers, sunscreens and antioxidant properties, this study aimed to develop methods for emulsion formulation enabling the protection of these unstable compounds to adverse conditions, thus increasing the value of extracts from annatto seeds. Saponin-rich extract from Brazilian ginseng roots was used as biosurfactant. Additionally, emulsion was generated through mechanical stirring by dispax Reactor at the same energy density than ultrasound. The influence of the emulsification process, energy density, oil type, biosurfactant type and biosurfactant concentration on the size and stability of the resulting droplets was investigated. The results indicated that saponin-rich extract might be an attractive biosurfactant choice for emulsion formulations for use in food and beverage products. Mini-emulsions were obtained in this work; their droplet sizes ranged from 0.35 to 0.83 µm, saponin-rich extract and ultrasound gave the smallest droplet size. The emulsification process significantly affected the emulsion stability values
Doutorado
Engenharia de Alimentos
Doutora em Engenharia de Alimentos

Para que um produto de aplicação tópica apresente o efeito terapêutico é necessário que o fármaco seja liberado de seu veículo e atravesse a barreira do estrato córneo, atingindo seus sítios de ação nas camadas da pele nas quais o efeito é esperado. Os estudos de penetração cutânea in vitro, utilizando células de difusão de Franz modificadas, podem fornecer resultados úteis quanto à eficácia do produto. As dermatofitoses são micoses superficiais. São manifestações crônicas e resistentes ao tratamento, fato que se explica não só em decorrência da própria natureza destas afecções como também devido à baixa penetração de fármacos antimicóticos na pele. Dentre os antifúngicos disponíveis na terapêutica, ciclopirox olamina é uma substância que tem demonstrado elevada eficácia no tratamento de dermatofitoses. O presente trabalho teve como objetivo desenvolver formulações de uso tópico contendo 0,5% de ciclopirox olamina e avaliar a performance dessas formulações. Foi possível obter formulações estáveis fisicamente, contendo promotores de penetração cutânea. O sistema de amostragem automática utilizado para realização dos experimentos foi qualificado e apresentou-se em condições adequadas.
In order to present the pharmacological effect, a topical product must release the pharmaceutical active ingredient from its vehicle and this active must pass through the stratum corneum barrier, reaching the target layer of the skin, where its effect is desired. In vitro skin penetration studies, using modified diffusion Franz cells, can provide useful results regarding the product efficacy. Dermatophytosis is superficial mycosis resistant to treatment due to the disease nature and also to the low penetration profile of the antifungals into the skin. Among the antifungals available in the therapeutic arsenal, ciclopirox olamine has demonstrated a high efficacy in the treatment of dermatophytosis. The objectives of the present work were to develop topical formulations containing 0,5% of ciclopirox olamine and evaluate their performance. It was possible to obtain physically stable formulae, containing skin penetration enhancers. The automatic sampling system used in the experiments was qualified, showing adequate performance.

The first part of the thesis describes the synthesis and application of functional magnetic polymer beads. The traditional suspension polymerization approach was used to synthesize polystyrene-iron oxide (Fe 3 O 4 ) based magnetic beads. The beads were coupled to different surface functional groups. The Fe 3 O 4 particles were encapsulated into a polystyrene shell. The surface functional groups were generated by graft-polymerization with functional monomers. The average size of the beads was in the range of 100-500 μm. Chemical tests showed that the beads were stable in strong acid, strong base and polar solvent. The beads had a fast response to an external magnetic field. A self-emulsion-polymerization approach was developed to synthesize smaller magnetic beads with the - OH groups on the surface. A modified approach based on traditional suspension-polymerization was developed to synthesize acid-durable beads with more Fe 3 O 4 encapsulated inside the beads. A novel emulsion-suspension polymerization method was successfully developed to synthesize much smaller magnetic beads ( A new peptide synthesis approach was developed using functional magnetic beads as the resin for solid phase synthesis. In this application, synthesized magnetic beads were further modified by a two-step reaction. The amino group was anchored onto the surface of these beads, followed by coupling with the Rink amide linker. The resulting beads were used as the resin to synthesize several model peptides. The peptides were successfully synthesized, and the sequences were confirmed by mass spectrometry analysis. The yields of the peptides were comparable to those obtained from commercial Rink amide resin. The second part of the thesis describes the synthesis and mass spectrometry analysis of two series of model peptides. One series has the linear (non-cyclic) structure, A n K, KA n , P n K, and AcA n K. The other series contains cyclic peptides, c-Ac-DAKAK and c-Ac-DADapAK. All peptides were synthesized using solid phase peptide synthesis. The relative proton affinities of the model peptides were measured using the collision induced dissociation experiments using a triple quadrupole mass spectrometer. It was found that the effective proton affinity of a cyclic peptide was significantly reduced compared to a linear analogue. The reduced proton affinity implies an increased lipophilicity of the peptide.

by Kenneth Kwing-chin Lee.
Thesis (M.Phil.)--Chinese University of Hong Kong, 1991.
Includes bibliographical references.
ACKNOWLEDGEMENT
ABSTRACT
Chapter CHAPTER I : --- INTRODUCTION AND SOME DISPOSITION PRINCIPLES --- p.1-16
Chapter CHAPTER II: --- DETERMINATION OF EPIRUBICIN IN BIOLOGICAL FLUIDS --- p.17-26
Chapter CHAPTER III : --- DISPOSITION OF EPIRUBICIN IN PATIENTS WITH HEPATIC CARCINOMA --- p.27-44
Chapter CHAPTER IV : --- DESIGN OF THE EMULSION FOR INJECTION --- p.45-85
Chapter CHAPTER V : --- STUDIES ON THE ACUTE TOXICITY OF THE FORMULATED EMULSION --- p.86-113
Chapter CHAPTER VI : --- PHARMACOKINETIC STUDIES OF THE FORMULATED EMULSION IN RABBITS --- p.114-123
REFERENCES --- p.124-130
APPENDICES

PURPOSE: Self-emulsifying systems (SES) emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase. The self-emulsification process plays an important role during formation of emulsion. The objective of current work was to understand and explore the inner structuration of SES through controlled hydration and further to study the influence of additive on the same which ultimately governs performance of final formulation in terms of droplet size. METHODS: Droplet size of final formulations containing structural analogues of ibuprofen was determined. Microstructural properties of intermediate hydrated regimes of SES were investigated using techniques such as small angle X-ray scattering, differential scanning calorimetry and rheology. RESULTS: The current work established inverse relationship between droplet size of the formulations containing structural analogues of ibuprofen and their Log P values. Microstructural analysis of intermediate hydrated regimes of the prepared samples showed formation of local lamellar structure. Structural analogues of ibuprofen significantly altered microstructure of lamellae which was well correlated with the droplet size of final formulations. In vitro drug release study showed increase in dissolution rate of lipophillic drugs when formulated as SES. CONCLUSION: The current work emphasizes the fact that tailor-made formulations can be prepared by controlling the properties of intermediate regimes.

Yes
Microemulsion is a stable, isotropic clear solution consisting of oil based substance, water surfactant and cosurfactant. There are two types of microemulsion which are used as a mobile phase; water in oil (w/o) and oil in water (o/w).Microemulsion has a strong ability to solubilize both hydrophobic and hydrophilic analytes, therefore reducing the pre-treatment of the sample which is needed for the complex sample. Recent reports found that separating the analytes by using microemulsion high performance liquid chromatography can be achieved with superior speed and efficiency compared to conventional HPLC modes. In this work, Oil in water (o/w) microemulsion has been used for the determination of nifedipine in pharmaceutical preparation. The effect of each parameter on the separation process was examined. The samples were injected into C18, analytical columns maintained at 30°C with a flow rate 1 ml/min. The mobile phase was 87.1% aqueous orthophosphate buffer 15 mM (adjusted to pH 3 with orthophosphoric acid), 0.8% of octane as oil, 4.5 SDS, and 7.6% 1-butanol, all w/w. The nifedipine and internal standard peaks were detected by UV detection at λ max 237 nm The calibration curve was linear (r2=0.9995) over nifedipine concentrations ranging from 1 to 60 μg/ml (n=6). The method has good sensitivity with limit of detection (LOD) of 0.33 μg/ml and limit of quantitation (LOQ) of 1.005 μg/ ml. Also it has an excellent accuracy ranging from 99.11 to 101.64%. The intra-day and inter-day precisions (RSD %) were <0.45% and <0.9%, respectively.