The influence of plasticization and other formulation factors on the properties of hot-melt extruded dosage forms for the controlled release of water-soluble active compounds was investigated. Citric acid monohydrate was demonstrated to function as a solid-state plasticizer in hot-melt extruded Eudragit® RS PO tablets and in cast films when concentrations below the compatibility limit were employed. Melting of the organic acid and solubilization in the polymer during extrusion were necessary to observe the plasticizing effect. The release rate of diltiazem hydrochloride, used as a high-melting, water-soluble model drug, from melt extruded Eudragit® RS PO matrix tablets increased and became independent of the original drug particle size in the presence of citric acid monohydrate. Thermal analysis of physical mixtures demonstrated that citric acid promoted drug melting during extrusion by interaction and melting point depression. Diltiazem hydrochloride remained amorphous in the final dosage form, and leaching of citric acid monohydrate enhanced drug diffusion by increasing the matrix porosity. Delayed-release matrix pellets with particle sizes below one mm were prepared by hot-melt extrusion, and the influence of the matrix forming polymer and the type and level of plasticizer on the processibility and release properties was investigated. Pellets complied with the USP requirement for delayed release articles to release less than 10% drug at pH 1.2 after 2 hours when plasticized Eudragit® S100 was used as the release-controlling material. High levels of efficient plasticizers had to be employed to decrease the polymeric melt viscosity, increase the process yield and enable extrusion at moderate temperatures to avoid instabilities during processing and storage. The aqueous solubility of the plasticizer further impacted the drug release rate in acid. A novel application of hot-melt extrusion for the preparation of monolithic matrices comprising enteric coated particles was studied. The influence of the mechanical strength of the multiparticulates, pellet loading and nature of the hydrophilic carrier material on the preservation of the delayed-release properties after extrusion was investigated. Soft particles coated with brittle films remained intact when low-melting carriers that did not solubilize the enteric film during extrusion were used, and the dissolution profile was stable over one year. / text

<p>Artemisia Afra, a popular South African traditional herbal medicine is commonly administered as a tea infusion of the leaves. However, clinical trials proving it safety and efficacy are lacking mainly due to the absence of good quality dosage forms and credible placebos for the plant. The objectives of this study were to prepare a standardized preparation of the plant leaves and freeze-dried aqueous extract powder of the leaves, in a tea bag dosage form and to design and prepare credible placebos for these plant materials.</p>

The theoretical part of this diploma work is focused on the polymeric nanoparticles, their properties and advantages connected with them. There are introduced also particular types of organic and inorganic nanoparticles and methods of their preparation. The great attention was directed on biodegradable polymers in particular to poly lactic-co-glycolic acid, which was used in experimental part as carrier for base of terbinafine branched to tripentaerythritol. PLGA is the most suitable copolymer for practice because of good explored its physical, chemical and biological properties, methods of preparation and factors affecting degradation. The aim of this work was to find suitable emulsifier with suitable concentration for preparation of nanoparticles containing the base of terbinafine, suitable solvent for terpolymer and optimal concentration of emulsion to reach the highest yield of terbinafine without any exceptional loss. How it was mentioned, as carrier was used terpolymer of poly lactic-co-glycolic acid with tripentaerythritol. As technique of preparation of nanoparticles was used emulsification by evaporating of organic solvent (solvent evaporation method). During the experimental work we found out some of conclusions, it goes to reduce of polydispersity with increasing concentration of...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Candidate: Karolína Valíková Supervisor: doc. RNDr. Milan Dittrich, CSc. Diploma thesis title: Formulation and study of the antimicrobial agent A literary overview of selected characteristics of silver nanoparticles is presented in the diploma thesis. Size measurement methods are described, while considerable attention is paid to photon correlation spectroscopy (PCS), which was used in the experimental part of this diploma thesis. Various methods of silver nanoparticle synthesis are outlined. Later part of the text is focused on the application of silver nanoparticles in areas concerning human health - mainly for the purposes of medicine, disinfection and as components of cosmetic products. Possible toxic effects of silver nanoparticles on human organism are also discussed. The focus of the thesis is in the experimental part. Stability of microparticles in suspensions used for product formulation was studied, as well as the PCS instrument's capability to distinguish the size distribution of particles in aqueous medium in highly polydisperse systems and in highly diluted systems. It was proven that microparticles have a spontaneous ability to form flocks, nonionic surfactants in 0.1%...

Charles Univerzity in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Candidate: Veronika Müllnerová Consultant: Doc. RNDr. Milan Dittrich, CSc. Title of thesis: Impact of molecular weight and the grade of branching of aliphatic oligoesters on their hydrolytic degradation Theoretical part of the thesis deals with behavior, properties and applications of biodegradable polyesters, mainly copolymers of lactic and glycolic acid (PLGA). This part concerns degradation, erosion and release mechanism. Furthermore, it describes properties that influence the drug release kinetics from systems based on PLGA. The final section of theoretical part is focused on the in situ forming implants, whose carrier of active substance is biodegradable polyester. The experimental part analyzes the influence of different pH of the medium within physiologically common boundaries and also the influence of ionic force on the degree of swelling and polymer erosion. These degradation parameters have been studied on three potential polyester carriers of active substances - PLGA, M3 (terpolymer of lactic and glycolic acid with mannit) and T3 (terpolymer of lactic and glycolic acid with tripentaerythritol). Polymer bodies were kept in temperature of 37řC inside phosphate-citrate buffers with...

Dans le contexte du traitement du kératocône, une formulation contenant de la riboflavine, un principe actif hydrosoluble, deux tensio-actifs (le poloxamère 407 et la monooléine) et de l'eau a été préparée par un processus d'homogénéisation. Un plan factoriel fractionnaire a été utilisé pour estimer les effets principaux et les interactions de cinq paramètres sur deux réponses pertinentes, à savoir la taille des particules et l'efficacité d'encapsulation. Les cinq paramètres étudiés étaient la température des deux phases, la durée de l'émulsification, la présence du chauffage pendant l'homogénéisation, le nombre de cycles et la pression. Il a ainsi été montré que les paramètres les plus influents sont la présence du chauffage pendant l'homogénéisation et la pression qui ont conduit à l'obtention de nanoparticules d'une taille moyenne de 145 nm et une efficacité d'encapsulation moyenne de 46%. La détermination des paramètres optimaux du procédé de fabrication a conduit à l'optimisation de la formulation par le biais de plans d'expériences. L'influence combinée de trois composants a été étudiée dans une partie du diagramme de phase. Ainsi, douze formules décrivant l'espace de conception ont été préparées. Les résultats obtenus par diffraction des rayons X aux petits angles et par cryo-microscopie électronique en transmission ont mis en évidence la présence de nano-objets de structure éponge et/ou hexagonale inverse. Le pourcentage de chacun des composants a été déterminé pour obtenir à la fois une grande efficacité d'encapsulation et une petite taille de particules. Deux formulations très proches dans le diagramme de phase ternaire, ont répondu à ces exigences. / In the context of the keratoconus treatment, a formulation containing riboflavin a water-soluble drug, two surfactants (poloxamer 407 and mono acyl glycerol) and water was optimized and prepared by emulsification and a homogenization process. A fractional factorial design was applied to estimate the main effects and interaction effects of five parameters on two relevant responses, namely particle size and encapsulation efficiency. The five parameters studied were the temperature of the two phases, the duration of emulsification, the presence of heating during homogenization, the number of passes and pressure. It has been shown that the most influent parameters are the presence of heating during the homogenization and the pressure that led to the production of nanoparticles with an average size of 145 nm and an average encapsulation efficiency of 46 %. The determination of the optimal parameters of the process led to an optimization of the formulation by using experimental design. The combined influence of three factor variables (or components) of the formulation that are water, monoolein and poloxamer 407 were, studied. In this way, twelve formulas describing the design space were prepared. Results obtained using SAXS and cryo-TEM evidenced the presence of nano-objects with either sponge or hexagonal inverted structure. In the zone of interest, the percentage of each component was determined to obtain both high encapsulation efficiency and small size of particles. Two formulations are very close in the ternary phase diagram, and have responded to these requirements.

Orientador: Anselmo Gomes de Oliveira / Banca: Rosemeire Cristina Linhari Rodrigues Pietro / Banca: Thalita Pedroni Formariz Pilon / Banca: Clovis Augusto Ribeiro / Banca: Francisco Benedito Teixeira Pessine / Resumo: 2-(2-nitrovinil)furano (G-0) apresenta atividade antiprotozoária, antibacteriana e antifúngica frente a elevado número de patógenos porém, a capacidade de sublimação, baixa velocidade de dissolução em meio aquoso, problemas de compatibilidade com excipientes e fotodegradação, tem limitado sua incorporação em formas farmacêuticas para uso humano e/ou veterinário. O propósito do presente trabalho foi avaliar duas alternativas para a estabilização do candidato a fármaco, através da formação de complexos de inclusão liofilizados (FD) com hidroxipropil-β-ciclodextrina e sulfobutiléter-β-ciclodextrina sódica e utilizando a microencapsulação com etilcelulose pelo método de emulsificação/evaporação do solvente. Uma vez formados e previamente caracterizados, os complexos foram submetidos ao ensaio de estabilidade acelerada a 40°C/75 %HR e ensaios de fotoestabilidade acelerada. A câmara de fotoestabilidade também foi utilizada para confirmar o perfil de degradação dos complexos. Os fotoprodutos foram isolados em coluna analítica e o maioritário foi caracterizado por espectroscopia de RMN. Foi avaliada também a volatilidade do G-0 na forma de complexos comparado com misturas físicas equivalentes através de TGA e CG-HS-FID, complementando assim um estudo desenvolvido anteriormente no modo isotérmico. As propriedades biofarmacêuticas da substância livre e na forma complexada foram estudadas em relação ao comportamento de dissolução em Fluido Vaginal Simulado e a permeação/retenção em muco... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: 2-(2-nitrovinyl)furan (G-0) has antiprotozoal, antibacterial and antifungal activity against a large number of pathogens, although the sublimation, low dissolution rate in aqueous medium, low compatibility with excipients and photodegradation, have hindered the incorporation in pharmaceutical dosage forms, to use in human and/or veterinary medicine. The aim of this work was to evaluate two alternatives for the stabilization of the drug candidate through freeze-drying inclusion complex formation (FD) with hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin sodium salt and through microencapsulation with ethylcellulose by mean of emulsion/solvent evaporation method. Once the complexes were prepared and fully characterized previously, they were subjected to an accelerated stability study at 40°C/75 %RH, and a photostability assay under forced irradiation conditions. A photostability chamber was also used in order to confirm the degradation profile for the complexes. Photoproducts were isolated in analytical column and the main degradation product was characterized aided by NMR. Drug volatility was also evaluated when G-0 was complexed, and compared with equivalent physical mixtures through TGA and GC-HS-FID. Biopharmaceutical properties of free drug and in the complexes were studied in terms of dissolution rate in Simulated Vaginal Fluid and permeation/retention in bovine vaginal mucosa. Finally, the influence of both complexes on the "in vitro" antifungal activity a... (Complete abstract click electronic access below) / Doutor

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M. Tech. Polymer Technology / Type II diabetes afflicts more than 300 million people worldwide. The pursuit for improved targeted drug delivery systems has led to the development of highly improved biomaterials with enhanced biocompatibility and biodegradability properties. Hydrogels are of particular interest for drug delivery applications due to their ability to address targeted drug delivery, in addition to their good biocompatibility, tunable network structure needed to control the diffusion of drugs and their ability to imbibe drugs within their mesh network structure. Hydrogels are promising candidates for advanced anti-diabetic applications. They were prepared by application of free-radical polymerization of acrylamide (AAm) in the presence of partially and thermally reduced graphene oxide (rGO) and wheat protein isolate (WPI). The incorporation of two (or more) different drugs onto a single delivery vehicle and the realization of combination therapy is a challenging, just as it is an important aspect for smart drug delivery. Thus, the development of dual drug delivery systems that can control the release behaviours of each drug is highly pertinent. This project aims to develop a dual drug delivery system with smart polymers, exploiting stimuli responses to be utilized as a carrier vehicle to aid in proffering a cure for diabetes. Also, it aims at proffering a solution to the lingering issue of combination therapy; by comparing the effect of the test drugs individually and in combination as anti-diabetic drugs.

Herewith are presented the results of an investigation the statistical power of USP compendial release tests and recommended alternatives. &lt;br&gt;The U.S. drug supply chain, formerly protected by a closed distribution network, is now threatened by the legal and illegal importation of drug products. Whereas quality can never be inspected into final products, compendial release standards may represent the only valid assessment that products of dubious origin would receive. Reliable tests for content uniformity and dissolution are required to protect the safety of the supply chain. A study was designed to test the hypothesis that existing compendial tests for content uniformity and dissolution would protect the supply chain against substandard and counterfeit drugs if basic field tests failed. &lt;br&gt;Compendial tests for content uniformity and dissolution were evaluated for statistical power using simulation studies. The results revealed that the revised content uniformity test, based on tolerance analysis, was subject to an unacceptable level of consumers' risk. The Bergum method proved to be an excellent secondary standard for product assessment and is recommended as an alternative to the USP method. Simulations with the USP dissolution test revealed significant weaknesses and inconsistencies in the test structure. Theoretical models and power assessments confirmed that the coverage specification of the dissolution test was an unacceptably high 50% coverage with 50% confidence. &lt;br&gt;A Bayesian D-optimal design program was used to investigate alternative methods to improve the coverage capability of the USP dissolution test. The result of this program was the identification of two alternatives to the existing USP procedure. The first alternative is based on the addition of attribute coverage tests to stages 2 and 3 of the USP test, whereas the second alternative is based on the concept of tolerance analysis. &lt;br&gt;Validation studies confirmed that both alternatives significantly improved the statistical power of the USP dissolution test without increasing the sample size or modifying the current three-stage procedure. The attribute test is non-parametric and behaves similarly to the existing USP with improved coverage, whereas the continuous alternative is more sensitive and is consistent with the recent revisions to the content uniformity test. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmaceutics / PhD / Dissertation