Made available in DSpace on 2014-06-11T19:32:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-12-21Bitstream added on 2014-06-13T21:03:25Z : No. of bitstreams: 1 andreis_u_dr_botib.pdf: 1982280 bytes, checksum: 3d2499c3ae7d16a4f3593d5077238d10 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A avaliação dos parâmetros motores do trato gastrintestinal é condição necessária para caracterizar o comportamento de formas farmacêuticas sólidas administradas pela via oral. A função motora gastrintestinal pode ser alterada em detrimento de doenças, interações com medicamentos ou intervenções cirúrgicas. Essas alterações, por sua vez, podem influenciar diversos processos farmacêuticos e, consequentemente, a biodisponibilidade dos fármacos. Comprimidos são as formas farmacêuticas mais utilizadas na terapia. Para garantir a eficácia e segurança dessas preparações, são necessários testes in vitro que simulam o trato gastrintestinal. Entretanto, não é possível estimar com precisão a influencia dos parâmetros gastrintestinais na liberação do fármaco. Por essa razão, os ensaios in vivo realizados por técnicas não invasivas e inócuas ao indivíduo são necessários, pois permitem monitorar simultaneamente os parâmetros motores e suas interrelações com os processos de liberação e biodisponibilidade dos fármacos. O objetivo desse trabalho foi empregar a técnica de Biosusceptometria AC associada à farmacocinética para avaliar a influência da motilidade gastrintestinal, bem como das alterações induzidas nessa função pela administração prévia de um procinético (Domperidona) e um antimuscarínico (Butilbrometo de Escopolamina). Além disso, foram avaliadas as influências desses parâmetros no processo de liberação e biodisponibilidade de um fármaco modelo (Diclofenaco Sódico) adicionado a comprimidos revestidos / The evaluation of gastrointestinal motor parameters is necessary towards characterize the behavior of solid dosage forms orally administered. The gastrointestinal motor function may be altered by diseases, drugs or surgery. These alterations may influence a number of pharmaceutical processes and consequently the bioavailability of drugs. Tablets are the dosage forms most commonly used in therapy. To ensure the efficacy and safety of these formulations, in vitro tests in simulated gastrointestinal conditions are needed. However, such conditions as well as the influence of gastrointestinal parameters on drug release cannot be fully predicted. For these reasons, in vivo studies are realized by noninvasive and harmless techniques, since they allows monitoring gastrointestinal motor parameters and the relationships with drug delivery and bioavailability. The aim of this work was to employ the AC Biosusceptometry to evaluate the influence of gastrointestinal motility as well as the induced changes on this function by previous administration of a prokinetic drug (domperidone) and an antimuscarinic agent (scopolamine butilbromide). In addition, it have been evaluated how these alterations influenced the drug release and bioavailability of a model drug (sodium diclofenac) added to coated tablets

Made available in DSpace on 2014-06-11T19:32:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-09-18Bitstream added on 2014-06-13T20:03:09Z : No. of bitstreams: 1 cora_la_dr_botib.pdf: 5114466 bytes, checksum: ae97ba77c87f4a9ec255be22db0f2b7f (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A administração oral de drogas é uma prática comum na terapia e as formas farmacêuticas sólidas são amplamente utilizadas. A variação no perfil de absorção ao longo do trato gastrintestinal (TGI) humano e a possibilidade de liberar drogas em diferentes regiões são os maiores desafios para o desenvolvimento de novos produtos. Desse modo, avaliar formas farmacêuticas sólidas in vivo fornece um entendimento mais profundo quando um efeito sistêmico ou local é desejado. Geralmente, estes estudos são realizados por meio da cintilografia e técnicas biomagnéticas. A Biosusceptometria de Corrente Alternada (BAC) é uma técnica que merece destaque por suas características, acurácia dos resultados obtidos e versatilidade. A BAC propiciou imagens do processo de desintegração de comprimidos tanto in vitro quanto no estômago humano, introduzindo outra perspectiva na análise desse processo. Os resultados também foram correlacionados com sucesso com aqueles obtidos por metodologias específicas, garantindo uma análise mais acurada dos parâmetros físicos envolvidos com a desintegração de comprimidos. A utilização da BAC permitiu avaliar a motilidade gastrintestinal e o processo de desintegração de cápsulas de hidroxipropilmetilcelulose (HPMC) revestidas no cólon humano. Além disso, também foi possível investigar a influência do estado prandial no esvaziamento gástrico e no trânsito gastrintestinal de um sistema multiparticulado magnético. Todos esses trabalhos fortaleceram a BAC como um método alternativo na pesquisa farmacêutica demonstrando seu potencial para avaliar diferentes processos, apesar das suas limitações. Sintetizando, a BAC é uma ferramenta valiosa, com a vantagem de ser livre de radiação e inócua aos voluntários, e vasta aplicabilidade na pesquisa farmacêutica, farmacológica e fisiológica. / Oral administration is widely accepted route for drug delivery and solid dosage forms are commonly administered. The variation of absorption profiles along the human gastrointestinal tract (GIT) and the ability to target drugs by adequate dosage forms to distinct sites is the challenge in the pharmaceutical development of solid dosage forms. An understanding of the factors involved in drug absorption and how the gastrointestinal variables can interfere with this process is important to develop more reliable drug delivery systems. The performance of pharmaceutical dosage forms must be fully investigated in vivo to provide more reliable information when a local or systemic effect is desirable. Generally, in vivo investigation on the behavior of dosage forms has been made by using gamma‐scintigraphy and biomagnetic techniques. AC Biosusceptometry (ACB) deserves consideration due to its features, accuracy and versatility. By using ACB technique, it was possible to monitor the disintegration process through acquisition of magnetic images in vitro and in human stomach. The results also were successfully correlated with those obtained with standard methods which provided a more reliable analysis on the physical parameters involved in the disintegration process of tablets. ACB allowed evaluating the gastrointestinal motility and the disintegration of hydroxipropylmethylcellulose (HPMC) coated capsules in human colon. Moreover, it was possible to investigate the gastric emptying and gastrointestinal transit of a magnetic multiparticulate system under influence of prandial state. All these studies have contributed to establish the ACB as an alternative method for pharmaceutical research and, despite some limitations, it was feasible to evaluate different pharmaceutical processes. In summary, ACB is a radiation free and non‐invasive technique with wide applicability in pharmaceutical, physiological and pharmacological researches.

Orientador: José Ricardo de Arruda Miranda / Banca: Luciana Aparecida Corá / Banca: Éder Rezende Moraes / Resumo: A administração oral de fármacos é uma prática comum na terapia e as formas farmacêuticas sólidas são amplamente utilizadas. O conhecimento sobre o trânsito de cápsulas e comprimidos no trato gastrointestinal é incompleto. Desse modo, avaliar o trânsito esofágico de farmacêuticas sólidas fornece um entendimento mais profundo sobre os mecanismos que desencadeiam a esofagite induzida por fármacos. Geralmente, os estudos de trânsito esofágico são realizados por meio da cintilografia, manometria e técnicas biomagnéticas, como o SQUID (Dispositivos Supercondutores de Interferência Quântica) e a Biosusceptometria de Corrente Alternada (BAC). A BAC é uma técnica que merece destaque por suas características, acurácia dos resultados obtidos e versatilidade. O objetivo do trabalho foi investigar a influência do tipo e peso da forma farmacêutica no tempo de trânsito esofágico e na velocidade de transporte no esôfago, além de estabelecer parâmetros comparativos entre os métodos cintilográfico e biomagnético empregados, para validar a BAC no estudo de trânsito esofágico de formas farmacêuticas sólidas. Cada um dos seis voluntários que participaram do estudo deglutiu com 50 ml de água cápsulas e comprimidos com 0,5, 0,8 e 1,0 gramas de ferrita, na cintilografia e na BAC. Para o estudo cintilográfico, a radiomarcação das formas farmacêuticas foi feita com 99mTc. Os resultados obtidos mostraram que o tipo e o peso da forma farmacêutica não influenciaram significativamente o tempo de trânsito esofágico e a velocidade de transporte no esôfago, embora os resultados estatísticos apontem para uma variação significativa para um número maior de voluntários. Além disso, uma comparação entre as técnicas permitiu validar a BAC como um método biomagnético para avaliar o trânsito... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Oral administration is a common practice in drug therapy and the solid dosage forms are widely used. Knowledge about esophageal transit of tablets and capsules is incomplete since it have been reported a number of injuries related to drug-induced esophageal damage. Esophageal transit time may be evaluated by employing gammascintigraphy, manometry, and biomagnetic techniques as SQUID and AC Biosusceptometry (ACB). ACB is a non-invasive and radiation free technique which enough versatility for a number of studies related to the gastrointestinal behavior of solid dosage forms. The aim of this work was to investigate the influence of different dosage forms (hard gelatin capsules and tablets) on the esophageal transit time and transport velocity in the esophagus upon to establish a comparison between the Scintigraphy and Biosusceptometry and to validate the ACB as a tool for esophageal transit studies. Six volunteers have participated in the study and they swallowed capsules and tablets with 0.5g, 0.8g and 1.0g of ferrite together 50 ml of water. For scintigraphic study, the dosage forms were labeled with 99mTc. The results showed that the parameters evaluated could not be significantly influenced by the different dosage forms administered. However, it could be observed that the results pointed out to a decrease in the transit time measured for dosage forms with lower weight. We have shown that ACB allowed investigating the influence of dosage forms parameters on the esophageal transit time in healthy volunteers with high spatiotemporal resolution. In summary, this study has allowed introducing the ACB as an alternative technique to investigate the esophageal transit of pharmaceutical dosage forms to understand the factors which could contribute to drug-induced esophageal damages. / Mestre

Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.

The dissolution profiles of eight lots of paracetamol tablets representing seven different tablet brands are determined in a USP rotating basket assembly and a stationary basket-rotating paddle apparatus. The in vitro data are expressed in terms of dissolution parameters and inter-tablet differences are assessed statistically using analysis of variance (ANOVA) and the Scheffe test. Highly significant differences are observed between a number of the tablets at the 95% confidence level. Representative tablets from the dissolution rate study and a control dose of paracetamol dissolved in water are subsequently investigated in a 4 x 4 latin square design bioavailability trial. Serum and urine samples are collected and assayed for paracetamol alone (serum) and together with its metabolites (urine) by means of high pressure liquid chromatography. The in vivo data are expressed in terms of bioavailability parameters and differences between the test doses are assessed by means of ANOVA. No significant differences are observed between the dosage forms at the 95% confidence level.

Numerous experiments in recent years have indicated differences in the bioavailability of corticosteroids from seemingly identical topical dosage forms. The human blanching assay was utilized in this study to assess the comparative blanching activities of various locally manufactured proprietary corticosteroid preparations. The first experiment was performed to assess the relative blanching activities of six semi - solid preparations containing the same concentration of betamethasone 17-valerate. The preparations used were Betnovate cream and ointment, Persivate cream and ointment and Celestoderm-V cream and ointment. This was followed, in the second experiment, by the investigation of the blanching activities of two lotions containing betamethasone 17-valerate (Betnovate and Celestoderm-V) and a lotion containing betamethasone 17,21- dipropionate (Diprosone). The third experiment involved a study of six semi-solid proprietary corticosteroid-containing formulations, viz. Dermovate (clobetasol propionate) cream and ointment, Betnovate (betamethasone 17-valerate) cream and ointment and Eumovate (clobetasone butyrate) cream and ointment. This investigation was prompted by claims in advertisements in the medical media that Dermovate is therapeutically more efficacious than Betnovate which is more efficacious than Eumovate. The penultimate experiment in this study served the purpose of finding a corticosteroid-containing preparation that falls into the moderately potent group of corticosteroid formulations, as described in the United Kingdom MIMS. This preparation was used in the final experiment which was undertaken to ascertain the potency category of Florone (diflorasone diacetate) cream and ointment.

Many Active Pharmaceutical Ingredients (API) such as the antiviral agent famciclovir (FCV) are required for paediatric treatment but are not commercially available in age-appropriate dosage forms. It is common practice to prepare oral liquid dosage forms using commercially available tablets, capsules or powdered API and then dispersing or dissolving the crushed and/or powdered materials in a vehicle that the patient can swallow. Vehicles that are commonly used for this purpose include methylcellulose, syrup or combinations of these carriers where possible or commercially available suspending agents such as Ora-Sweet®, if available, can be used. However, several critical factors are overlooked when manufacturing extemporaneous formulations including, but not limited to, physical and chemical properties of the API, excipients, compatibility, stability and bioavailability issues. A stability-indicating High Performance Liquid Chromatography (HPLC) method for the analysis of FCV was developed and validated according to the International Conference on Harmonization (ICH) guidelines. The method is sensitive, selective, precise, accurate and linear over the concentration range 2-120 μg/ml. The stability of 25 mg/ml FCV formulations was assessed in vehicles manufactured from syrup simplex, hydroxypropyl methylcellulose (HPMC), Ora-Sweet® and an aqueous buffer (pH 6) following storage at 25 °C/60% RH and 40 °C/75% RH over six (6) to eight (8) weeks. The shelf life of the products was calculated as the longest period of storage for approximately 90% of the added FCV to be recovered. Formulations were manufactured using syrup simplex or HPMC with methylparaben and propylparaben individually or in combination and with sodium metabisulphite, ascorbic acid or citric acid as antioxidants. The resultant products were subject to quality control analysis for API content, viscosity, pH and appearance and the resultant data were subject to statistical analysis. The degradation rates were calculated for each product and a degradation profile plotted. The degradation rates of FCV in extemporaneous formulations were compared to those of FCV manufactured using a commercially available suspending agent and a buffered vehicle. FCV undergoes major degradation in the presence of sucrose, as observed for formulations in which the vehicle was syrup and Ora-Sweet®. FCV was found to be most stable when dissolved/dispersed in an HPMC vehicle incorporating sodium metabisulphite and a combination of parabens. The formulation that exhibited the maximum stability was manufactured using an aqueous solution buffered to pH 6. Due to the enhanced stability of FCV when added to a buffered vehicle a formulation in which an HPMC vehicle buffered to pH 6 with sodium metabisulphite, methylparaben and propylparaben was selected for optimisation using a Central Composite Design approach (CCD). In this way it was possible to establish a relationship between input variables such as pH, % w/v HPMC, % w/v antioxidant and % w/v preservative and the responses selected for monitoring by means of response surface modelling. A quadratic model was found to be the most appropriate to describe the relationship between input and output variables. Thirty batches of product were randomly manufactured according to the CCD and analysed to establish the stability in respect of viscosity, pH and the amount of FCV remaining following storage and the data were fitted to models using Design-Expert® software. A correlation between input variables and the responses was best described by a quadratic polynomial model. Analysis of Variance indicated that the response surface models were significant (P-value < 0.0001). The pH to which a FCV formulation was buffered was the most significant factor to effect the % drug content and the ultimate pH of the formulation, while the % w/v HPMC had the most significant effect on the viscosity of the product. The optimum composition for the manufacture of an oral liquid FCV formulation was predicted using the optimisation function of the Design-Expert® software. A low % error of prediction was established, indicating that the model is robust and that RSM is an appropriate formulation optimisation tool as it has a high prognostic ability. A liquid FCV formulation was developed, optimised and found to be suitable for its intended purpose. However further optimisation is required in respect of colourants, sweeteners and/or flavourants. The approach followed is useful in ensuring the development of quality products and can be applied in future.

No description available.

This study considered the use of urea eutectics as fast release solid dosage carrier forms for the acaricide N-methylbis (2,4-xylyliminomethyl) methylamine (AmitrazTM). Wettol D2 and Arkopal N090 were chosen as the wetting agent and dispersants respectively. Their optimum levels were determined as the surfactant concentrations that yielded a minimum in the dispersion viscosity of a concentrated (30% m/m) Amitraz suspension. The optimum dosage levels were found to be ca. 2% Arkopal N090 and ca. 1% Wettol D2. Eutectic phase diagrams were obtained using the melting-cooling method. The components were ground together into a fine powder and heated in a glass tube immersed in a silicon oil bath. The liquid was allowed to cool down and solidify at ambient conditions. The time-dependant temperature change of the sample was tracked with a thermocouple. The data was captured in real time on a personal computer and analysed using an Excel spreadsheet programme. The melt-cast method was used to prepare eutectic mixtures. They were characterised using DSC, DTA, XRD and Light Microscopy. The XRD peaks showed the presence of the two separate crystal structures for the eutectic mixture constituents. The urea – CaBr2.2H2O combination was initially considered as carrier for Amitraz. However, this eutectic system was found to be too hygroscopic. Small additions of PEG 6000 improved the tablet strength but decreased the dissolution rate. Urea and acetamide formed a eutectic at ± 46oC with a composition of ca. 40 % m/m urea. Unfortunately acetamide is a suspected carcinogen. Therefore the urea - 1,3-dimethylurea was selected as Amitraz carrier system instead. The eutectic mixture comprised 40% m/m urea and 60% m/m 1,3-dimethylurea, which melt at ± 56oC. The melt-press method was used to prepare Amitraz containing pellets measuring 5 mm thick and 33 mm ö and weighing about 5,0 g. It was possible to suspend Amitraz powder in the eutectic melt mixture provided it remained in powder form. However, when liquefied (by melting), phase separation occurred. Thus the temperature of the eutectic mixture should be kept below the 80oC melting point of Amitraz. The dissolution tests were performed in a 10-liter Pyrex glass beaker with normal tap water (± 25oC). The time taken for complete dissolution was measured with a stopwatch. These results were confirmed with turbidity tests. Starch-based super disintegrants were used in an attempt to enhance the dissolution rate of the pellets. Explotab® improved the dissolution rate of 30% and 40% m/m Amitraz formulations slightly. The best formulation obtained in this study had the following composition (in m/m): 30% Amitraz; 8% CaCO3; 1 % Wettol D2; 2% Arkopal N090; 10% Explotab® and 49% urea – 1,3-dimethylurea eutectic. Such tablets disintegrated within 6,5 minutes when suspended in water. / Dissertation (MSc (Applied Science))--University of Pretoria, 2007. / Chemical Engineering / MSc / unrestricted

There are many examples in the literature of conventional or traditional drug distribution systems in hospitals which possess many shortcomings with reference to medication errors, the amount of time spent by nursing personnel in medication-related duties, inventory losses, the preparation of intravenous admixtures, and the lack of adequate drug usage records. These deficiencies primarily are due to the pharmacist's minimal influence over the control of the traditional drug distribution systems. An analysis and evaluation of the present pharmacy services at St. Paul's Hospital, Vancouver, B.C., similarly identified a traditional distribution system subject to many of the aforementioned potential problems. Using information based on existing unit dose systems as reviewed in the literature and data collected from a general questionnaire, new pharmacy services based on unit dose drug distribution are projected for St. Paul's Hospital. The required facilities and personnel for a progressive unit dose drug distribution system, an intravenous (I.V.) admixture preparation service and a drug surveillance program are projected accordingly. It would appear that a "centralized" approach to implementing unit dose distribution is most appropriate for St. Paul's Hospital's present requirements. This would involve the preparation and distribution of all drugs to nursing units in single dose packages from a central pharmacy area. A similarly centralized intravenous admixture service and a decentralized drug surveillance program also are described. These services commonly feature a greater responsibility being placed with the pharmacy department for preventing therapy problems such as admixture incompatibilities, drug interactions, adverse drug reactions and inappropriate drug selection. The effect of the above services on the responsibilities and number of pharmacy and nursing personnel is estimated based on results in similar programs. These changes also reflect extended hours of coverage in each area. Finally, a potential phasing plan and time schedule for the implementation of the proposed unit dose drug distribution system, I.V. admixture preparation service and drug surveillance program at St. Paul's Hospital is suggested. / Pharmaceutical Sciences, Faculty of / Graduate