Carbamazepine (CBZ) is a first-line drug used for the treatment of partial and tonic-clonic seizures. It is also the drug of choice for use during pregnancy and recommended for the treatment of seizure disorders in children. CBZ possesses the ability to induce metabolism of drugs that are transformed in the liver and has the unique ability to induce its own metabolism by a phenomenon known as ‘auto- induction’, where its biological half-life is significantly reduced during chronic administration. Large doses of CBZ are often prescribed as daily divided doses and this often adversely affects patient compliance, with the result that therapy is ineffective. A sustained-release dosage form containing CBZ is currently marketed as Tegretol® CR and the development of a generic product would provide patients with an equivalent product with a similar dosing frequency, at a reduced cost. Therefore, the development of a polymer-based matrix tablet was undertaken to produce a sustained-release dosage form of CBZ, since these dosage forms are relatively simple and cheap to produce when compared to other, more sophisticated forms of sustained-release technology. Preformulation studies were conducted to assess moisture content of excipients and dosage forms and to identify possible incompatibilities between CBZ and potential formulation excipients. Furthermore, studies were conducted to assess the potential for polymorphic transitions to occur during manufacture. Stability testing was conducted to assess the behaviour of the dosage forms under storage conditions that the product may be exposed to. Dissolution testing was undertaken using USP Apparatus 3, which allowed for a more realistic assessment and prediction of in vivo drug release rates. Samples were analysed using a high performance liquid chromatographic method that was developed and validated for the determination of CBZ. Tablets were manufactured by wet granulation and direct compression techniques, and the resultant drug release profiles were evaluated statistically by means of the f1 and f2 difference and similarity factors. The f2 factor was incorporated as an assessment criterion in the design of an artificial neural network that was used to predict drug release profiles and formulation composition. A direct compression tablet formulation was successfully adapted from a prototype wet granulation matrix formulation and a number of formulation variables were assessed to establish their effect(s) on the dissolution rate profile of CBZ that resulted from testing of the dosage forms. The particle size grade of CBZ was also investigated and it was ascertained that fine particle size grade CBZ showed improved drug release profiles when compared to the coarse grade CBZ which was desirable, since CBZ is a highly water insoluble compound. Furthermore, the impact of the viscosity grade and proportion of rate-controlling polymer, viz., hydroxypropyl methylcellulose was also investigated for its effect on drug release rates. The lower viscosity grade was found to be more appropriate for use with CBZ. The type of anti-frictional agent used in the formulations did not appear to affect drug release from the polymeric matrix tablets, however specific compounds may have an effect on the physical characteristics of the polymeric tablets. The resultant formulations did not display zero-order drug release kinetics and a first-order mathematical model was developed to provide an additional resource for athematical analysis of dissolution profiles. An artificial neural network was designed, developed and applied to predict dissolution rate profiles for formulation. Furthermore, the network was used to predict formulation compositions that would produce drug release profiles comparable to the reference product, Tegretol® CR. The formulation composition predicted by the network to match the dissolution profile of the innovator product was manufactured and tested in vitro. The formulation was further manipulated, empirically, so as to match the in vitro dissolution rate profile of Tegretol® CR, more completely. The test tablets that were produced were tested in two health male volunteers using Tegretol® CR 400mg as the reference product. The batch used for this “proof of concept” biostudy was produced in accordance with cGMP guidelines and the protocol in accordance with ICH guidelines. The test matrix tablets revealed in vivo bioavailability profiles for CBZ, however, bioequivalence between the test and reference product could not be established. It can be concluded that the polymeric matrix CBZ tablets have the potential to be used as a twice-daily dosage form for the treatment of relevant seizure disorders.

Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.

Magister Pharmaceuticae - MPharm / 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. / South Africa

In the present study lanolin alcohol films were investigated as potential drug delivery systems for the controlled release of salicylic acid. A series of experiments were conducted in vitro to study the release of salicylic acid from these films. The effect of changes in film composition and stirrer speed on drug release were examined. Seven film compositions with varying proportions of lanolin alcohol and ethyl cellulose were prepared over the ethyl cellulose concentrations of 0-30% w/w, while keeping the drug concentration at 2.5% w/w. The release data obtained in this study were examined by the Q vs 1/2 relationship and the first-order relationship. This was done to probe deeper into the underlying mechanism of drug release. Upon examination of the release data by the Q vs 1/2 treatment, it was observed that the correlation coefficients were quite high and lag times were only slightly negative in agreement with the observed initial release data. In contrast, the first-order treatment of data showed somewhat lower correlation coefficients and very high negative lag times. These data strongly suggest that the unidirectional release of salicylic acid from the lanolin alcoholethyl cellulose films follows Higuchi's diffusion-controlled granular matrix model. The release rate constant showed an initial increase with inclusion of ethyl cellulose followed by a sharp decline as the ethyl cellulose concentration was further increased reaching a minimum value at about 15-20 percent of ethyl cellulose. Further increases in the concentration of ethyl cellulose increased the rate of drug release with a tendency to level off at about 30 percent ethyl cellulose concentration. The effect of stirring rate on the release rate constant showed that the rates of release of salicylic acid increased with increases in the stirring rate.

Sixty Four caffeinated chewing gum preparations were formulated by varying the amounts of (i) cinnamaldhyde, (0-0.75%), (ii) docusate (0-0.5%) and (iii) sucrose (40-60%). The gum base consisted of 33.33% yellow beeswax and 66.66% polyisobutylene MH, and was added, adjusting for a final weight of 2 grams per gum. The amount of caffeine was maintained at 100mg. The preparations were subjected to an in vivo release study as well as a hedonic survey with a panel of student volunteers. Data were analyzed by using multiple linear regression on a mainframe computer. The resulting mathematical model was used to predict a theoretically ideal formulation, relating various concentrations of the above constituents to a global rating. The results indicated consistent release (90-100%) of caffeine for most formulations, but considerable variation was observed for the hedonic scores. A positive correlation with cinnamaldehyde and flavor was observed, while increased amounts of sugar appeared to lower the overall rating. The optimum formulation predicted by the model should contain 40% sucrose, 0.5% docusate and 0.75% cinnamaldehyde.

yes / Detailed design of pharmaceutical tablets is essential nowadays in order to produce robust tablets with tailor-made properties. Compressibility and compactibility are the main compaction properties involved in the design and development of solid dosage forms. The data obtained from measured forces and displacements of the punch are normally analysed using the Heckel model to assess the mechanical behaviour of pharmaceutical powders. In this paper, we present a technique for shape modelling of pharmaceutical tablets based on the PDE method. We extended the formulation of the PDE method to a higher dimensional space in order to generate a solid tablet and a cuboid mesh is created to represent the tablet’s components. We also modelled the displacement components of a compressed PDE-based representation of a tablet by utilising the solution of the axisymmetric boundary value problem for a finite cylinder subject to a uniform axial load. The experimental data and the results obtained from the developed model are shown in Heckel plots and a good agreement is found between both. / Available in full text since 5th Feb 2013 following the publisher's embargo period.

PART I: MARKERS OF INFLAMMATION IN DELAYED MUSCLE SORENESS Fifty-five untrained males were assigned to an experimental (E) or a control group (C), to re-examine the concept that DMS represents an acute inflammatory response. Subjects were assigned to receive either Indocin (Id; 100 mg per day) for 2 days prior to the treatment and a placebo (P) for 2 days after (Id-P); or the reverse combination (P-Id); or Id for- 4 days (Id-Id); or placebo (P-P). On the treatment day, to induce DMS, E subjects performed 30 min of bench-stepping with one leg leading throughout; C subjects rested for 30 min. Immediately before and after stepping/resting, all subjects used their right and left leg to perform 19 maximal and 15 submaximal repetitions on the Cybex II. Blood samples were collected -5 min before, immediately after bench stepping (0 h), 2 h after and 24, 48 and 72 h, to evaluate WBC. DMS was also monitored 0, 24, 48 and 72 h. All E subjects experienced a significant amount of DMS (p<.01) which peaked at 48 h after exercise (E=7.58 ± .79 vs 0 for C, X±SEM); however, no significant differences in soreness perception were observed between drug and placebo groups. Total WBC count ( cells/mm³ ) was significantly greater at 0 h (8,340±380) than at -5 min (6,699±365) for both E and C; this increase was most likely a response to Cybex exercise. At 2 h there was a significant increase in total WBC count for E ( 9,603±389) and no change for C ( 8,336±273}. Neutrophils increased significantly at 2 h for E only (6,428±375 vs 4,988±261 for C}. Bench-stepping leads to increases in DMS and increases in WBC count, particularly in neutrophils, 2 h after stepping; this data suggests that inflammation is involved in DMS. PART II: EFFECT OF AN ASPIRIN-LIKE DRUG ON PERCEIVED EXERTION DURING BENCH STEPPING The object of this study was to determine whether perceived exertion (RPE) for the limb performing predominantly positive work was significantly greater than for the limb performing predominantly negative work, during 30 min of bench stepping. A second objective was to determine the effects of indomethacin (Id) on RPE. Thirty-nine males were randomly assigned to a drug (Id) or placebo (P) group and administered 150 mg indomechacin or placebo, beginning 36 h prior to stepping. Results indicated no significant differences between RPE for "concentric" and "eccentric" limbs of the P group inspite of the fact that the metabolic demand of the "concentric" limb was much greater. Indomethacin did not significantly alter RPE during stepping however, when RPE scores were totaled over the entire bench stepping period, the Id condition was associated with a greater (p < .01) psychological cost for the "concentric" leg effort as compared to P; this indicated that indomethacin might alter effort sense related to concentric contractions. / Ph. D.

A hipertensão arterial é a principal causa da incidência de doenças cardiovasculares no mundo. Os diuréticos anti-hipertensivos como a indapamida são muito utilizados para o tratamento da hipertensão arterial, sendo a formulação de liberação prolongada muito eficaz e bem tolerada para o uso em pacientes idosos. Sistemas multiparticulados de formas farmacêuticas sólidas orais de liberação prolongada apresentam uma série de vantagens tecnológicas e biofarmacotécnicas em relação aos sistemas monolíticos.Assim, o presente trabalho teve como objetivo desenvolver formas farmacêutica sólidas multiparticuladas de indapamida com controle de liberação através de sistema de revestimento utilizando polivinilacetato e sistema matricial de hipromelose. Para avaliação das diferentes formulações de minicomprimidos de indapamida de liberação prolongada, foram empregados os aparatos 1 (cesta) e 3 (Bio-Dis) para, deste modo, identificar aquelas cuja liberação do fármaco estivesse mais próxima do produto referência (Natrilix SR® 1,5mg). Ao final, foi realizada uma busca de patentes relacionadas ao sistema multiparticulado de liberação prolongada de indapamida, para avaliar a possibilidade de uma patente para a formulação proposta. / Hypertension is the main cause of cardiovascular disease around the world. Diuretic antihypertensives, such as indapamide, are widely used for treating hypertension, and, with regards to elderly patients, its extended release formulation is the most effective and well tolerated. Multiparticulate systems of solid oral dosage forms for extended release present a series of technological and biopharmaceutical benefits, when compared to monolithic systems. Thus, the purpose of this study was to develop a multiparticulate solid form of indapamide with controlled release by using a polyvinyl acetate coating system and a hypromelose matrix. For an evaluation of different formulations of indapamide extended release mini-tablets, a 1 (basket) and 3 (Bio-Dis) apparatus was used to identify those with a drug release rate closest to the reference product, Natrilix® SR 1.5mg. Finally, multiparticulate indapamide extended release patents were researched, in order to evaluate the possibility of obtaining a patent for the proposed formulation.

Foram analisados 84 lotes de especialidades fitoterápicas de uso oral, na forma de cápsula, comprimido e pó, contendo 17 drogas vegetais, produzidas por 20 fabricantes e comercializadas em farmácias, drogarias, lojas de produtos naturais e supermercados da cidade de são Paulo. O confronto da apresentação comercial das mesmas em relação à legislação nacional, indicou que a minoria (15/84) atendeu a tais exigências, além de ter demonstrado total falta de padronização de qualidade pelos produtores, inclusive com ausência de definição e conceituação, enquadrando-as indistintamente como medicamentos alopáticos, homeopáticos, produtos dietéticos ou alimentos. Efetuou-se a quantificação de bactérias aeróbias mesófilas (forma vegetativa e esporulada) e de fungos (bolores e leveduras), através da técnica de tubos múltiplos, bem como a pesquisa de Escherichia coli e Salmonella sp. pela metodologia oficial internacional. A contaminação fúngica, predominantemente de bolores, foi inferior em relação à bacteriana aeróbia mesófila, pois o máximo detectado para aquela foi de 4,6 X 105, enquanto que para esta 5,1 X 109/g. A incidência fúngica com carga maior ou igual a 102/g foi de 34,5%, contra 53,6% da carga bacteriana vegetativa com 104/g ou mais e 45,2% da bacteriana esporulada, com o mesmo nível. A determinação do Número Mais Provável de Escherichia coli indicou incidência de 6,0% com a carga maior igual a 1,5 X 102/g. Houve estreita relação entre a carga bacteriana vegetativa total e o número de esporos, assim como a presença de patogênicos específicos em produtos altamente contaminados. Amostras sob a forma de pó foram as mais afetadas, seguidas de cápsulas e comprimidos. Pelo confronto dos dados encontrados, com os diversos padrões microbianos aplicados para medicamentos não estéreis de uso oral, para insumos e produtos fitoterápicos, o índice de aprovação variou de 29,8 a 94,0%. Mesmo frente ao padrão da FIP, a rejeição especialidades fitoterápicas analisadas foi da ordem de 59,5%. Em vista da qualidade sanitária de muitos destes produtos ser imprópria para o consumo, e após análise crítica dos vários padrões microbianos, discutiu-se a necessidade de implantação de especificações nacionais, ainda que a caráter provisório, sugerindo-se limites de tolerância para medicamentos fitoterápicos de uso oral. / 84 samples of phytotherapic products of oral solid dosage forms (capsules, tablets and powders) containing 17 different crude drugs and produced by 20 laboratories, marketed in drugstores, herborist\'s and supermarkets at são Paulo-Brazil were analysed with regard to legal marketing requirements, only 15 samples were in accordance. A complete lack of quality standard was attributed to the manufacturers, including indefinition as to the classification of products among allopathic or homeopathic pharmaceuticals or foods or dietetics. The total aerobic bacterial (vegetative and sporulated forms) and fungal (moulds and yeasts) contents were determined by multiple tube technique; moreover tests were carried out for Escherichia coli and Salmonella sp. by official international methods. The fungal contamination was predominantly of moulds and lower than the aerobic bacterial one. The maximum counts were 4,6 X 105 and 5,1 X 109/g, respectively, for fungi and bacteria. The frequency of samples with or more than 102/g fungi/g was 34,5% that for vegetative and sporulated bacterial counts with or more than 104/g was respectively, 53,6 and 45,2%. The incidence of Escherichia coli was about 6,0% with the highest level at 1,5 X 102/g. There was a tight relation between the vegetative and sporulated bacterial counts as well as the presence of specific pathogenic microorganisms in highly contaminated samples. The highest contamination occured in powders followed by capsules and tablets. Comparing our experimental data with the corresponding microbial standards for oral non sterile pharmaceuticals, crude drugs and phytotherapic products, the index of approval varied between 29,8 and 94,0%. Even by FIP\'s standards 59,5% of the phytotherapic specialties analysed had to be rejected. As many of these products showed innadequate sanitary quality for consumption, coupled to a critical analysis of the different microbial standards, the discution was raised about the necessity of establishing national specifications, even if provisional. Suggestions are made as to the contamination limits of oral phytotherapic pharmaceuticals.

A hipertensão arterial é a principal causa da incidência de doenças cardiovasculares no mundo. Os diuréticos anti-hipertensivos como a indapamida são muito utilizados para o tratamento da hipertensão arterial, sendo a formulação de liberação prolongada muito eficaz e bem tolerada para o uso em pacientes idosos. Sistemas multiparticulados de formas farmacêuticas sólidas orais de liberação prolongada apresentam uma série de vantagens tecnológicas e biofarmacotécnicas em relação aos sistemas monolíticos.Assim, o presente trabalho teve como objetivo desenvolver formas farmacêutica sólidas multiparticuladas de indapamida com controle de liberação através de sistema de revestimento utilizando polivinilacetato e sistema matricial de hipromelose. Para avaliação das diferentes formulações de minicomprimidos de indapamida de liberação prolongada, foram empregados os aparatos 1 (cesta) e 3 (Bio-Dis) para, deste modo, identificar aquelas cuja liberação do fármaco estivesse mais próxima do produto referência (Natrilix SR® 1,5mg). Ao final, foi realizada uma busca de patentes relacionadas ao sistema multiparticulado de liberação prolongada de indapamida, para avaliar a possibilidade de uma patente para a formulação proposta. / Hypertension is the main cause of cardiovascular disease around the world. Diuretic antihypertensives, such as indapamide, are widely used for treating hypertension, and, with regards to elderly patients, its extended release formulation is the most effective and well tolerated. Multiparticulate systems of solid oral dosage forms for extended release present a series of technological and biopharmaceutical benefits, when compared to monolithic systems. Thus, the purpose of this study was to develop a multiparticulate solid form of indapamide with controlled release by using a polyvinyl acetate coating system and a hypromelose matrix. For an evaluation of different formulations of indapamide extended release mini-tablets, a 1 (basket) and 3 (Bio-Dis) apparatus was used to identify those with a drug release rate closest to the reference product, Natrilix® SR 1.5mg. Finally, multiparticulate indapamide extended release patents were researched, in order to evaluate the possibility of obtaining a patent for the proposed formulation.