Dissertations / Theses on the topic 'Sustained release tablets'

The oral route of drug administration is most extensively used due to the obvious ease of administration. Verapamil hydrochloride is a WHO listed phenylalkylarnine, L-type calcium channel antagonist that is mainly indicated for cardiovascular disorders such as angina pectoris, supraventricular tachycardia and hypertension. Due to its relatively short half-life of approximately 4.0 hours, the formulation of a sustained-release dosage form is useful to improve patient compliance and to achieve predictable and optimized therapeutic plasma concentrations. Direct compression and wet granulation were initially used as methods for tablet manufacture. The direct compression method of manufacture produced tablets that exhibited formulation and manufacturing difficulties. Mini-tablets containing veraparnil hydrochloride were then prepared by wet granulation using Surelease® E-7-19010.and Eudragit® NE 30D as the granulating agents after which the granules were incorporated with an hydrophilic matrix material, Carbopol® 974P NF. Granule and powder blends were evaluated using the angle of repose, loose and tapped bulk density, Can's compressibility index, Hausner's ratio and drug content. Granules with good flow properties and satisfactory compressibility were used for further studies. Tablets were subjected to thickness, diameter and weight variation tests, crushing strength, tensile strength, friability and content uniformity studies. Tablets that showed acceptable pharmaco-technical properties were selected for further analysis. Drug content uniformity and dissolution release rates were determined using a validated isocratic HPLC method. Initially, USP apparatus 1 and 3 dissolution apparatus were used to determine in-vitro drug release rates from the formulations over a 22-hour period. USP apparatus 3 was finally selected as it offers the advantages of mimicking, in part, the changes in the physicochemical environment experienced by products in the gastro-intestinal tract. Differences in release rates between the test formulations and a commercially available product, Isoptin® SR were observed at different pH's using USP apparatus 1. The release of veraparnil hydrochloride from matrix tablets was pH dependent and was markedly reduced at higher pH values. This may be due, in part, to the poor solubility of veraparnil hydrochloride at these pH values and also the possible interaction of verapamil hydrochloride with anionic polymers used in these formulations. Swelling and erosion behaviour of the tablets were evaluated and differences in behaviour were observed which may be attributed to the physico-chemical characteristics of the polymers used in this study. In-vitro dissolution profiles were characterized by the difference (j1) and similarity factor (j2) and also by a new similarity factor, Sct. In addition, the mechanism of drug release from these dosage forms was mainly evaluated using the Korsmeyer-Peppas model and the kinetics of drug release assessed using other models, including Zero order, First order, Higuchi, HixsonCrowell, Weibull and the Baker-Lonsdale model. Dissolution kinetics were best described by application of the Weibull model, and the Korsmeyer-Peppas model. The release exponent, n, confirmed that drug release from these dosage forms was due to the mixed effects of diffusion and swelling and therefore, anomalous release kinetics are predominant. In conclusion, two test batches were found to be comparable to the reference product Isoptin® SR with respect to their in-vitro release profiles.

The use of antiretroviral (ARV) agents in the management of HIV/AIDS has significantly improved the lifestyle and wellbeing of patients. Despite the success that has been achieved with the use of ARV therapy, the occurrence of adverse effects and unpredictable bioavailability associated with most of these drugs remains a major concern. Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is used in combination with other ARV compounds for the treatment of HIV-1 infections. It is also used for the prevention of mother to child transmission of the HIV-1 virus. NVP is a Biopharmaceutics Classification System (BCS) Class II compound. Although NVP exhibits good oral absorption, it induces self-metabolism leading to low and sometimes unpredictable bioavailability. NVP is commercially available as an immediate release and extended release dosage form, viz., Viramune® XR. Formulation of a generic sustained release (SR) dosage form for once daily dosing would result in delivery of constant amount of the drug to the circulation, reduce dose related adverse effects, improve patient compliance to medication and reduce the costs of therapy. A simple RP-HPLC method was developed and optimised using a central composite design approach. The method was validated using ICH guidelines and was found to be linear, precise, specific and accurate for the analysis of NVP both in bulk and dosage forms. Direct compression was used as the method of tablet manufacture. Different polymers were assessed for suitability as rate retarding polymers and included Methocel® K4M, Carbopol® 71G NF and Eudragit® RSPO. Powder blends were assessed for flow properties using the angle of repose, bulk and tapped density, Carr’s Compressibility index and Hausner’s ratio. The traditional approach of changing the amount of polymers and diluents systematically to achieve a desired NVP release profile was used for the development of a preliminary formulation. Response surface methodology was used for the optimisation of the formulation using a Box-Behnken quadratic design. Physical characteristics of the tablets such as thickness, weight, hardness, tensile strength and friability were assessed and the tablets passed Pharmacopoeial testing. NVP assay and content uniformity were assessed using a validated RP-HPLC method. Initially, USP Apparatus 2 was used to study NVP release over a 24 hour period and subsequently dissolution studies were performed using USP Apparatus 3 as it can be used to simulate GIT conditions. The dissolution profiles generated were used to determine the agitation rate for USP Apparatus 3 that would be equivalent to an agitation rate of 50 rpm when using USP Apparatus 2. The effect of the mesh screen pore size, buffer molarity strength and concentration of surfactant on NVP release were also investigated in order to select discriminatory dissolution test conditions for the test formulation. Dissolution profiles were compared to those of the commercially available Viramune® XR using the FDA recommended difference (f1) and similarity (f2) factors. The calculated values for f1 and f2 revealed that the dissolution profile for the optimised formulation that was identified was statistically similar to Viramune® XR. In vitro release data were fitted to different kinetic models to study the release kinetics of NVP. The overall mechanism of NVP release was best described using the Korsmeyer-Peppas diffusion exponent value, n. NVP release was found to be anomalous, implying that the release was influenced by a combination of diffusion, swelling and polymer chain relaxation. The Hixson-Crowell model revealed that there was constant change in surface area of the dosage form suggesting that erosion and swelling were significant factors affecting NVP release from the hydrophilic matrix technology. The release kinetics data were also used to design the optimised formulation. Tablets manufactured using the optimised formulation were subjected to water uptake and erosion studies and the results revealed that swelling and erosion occur simultaneously. The effects of pH and molarity on the swelling and erosion of the tablets were also investigated. The data suggest that increase in pH resulted in a slight increase in swelling while an increase in molarity did not have a significant effect on swelling. The change in pH did not have a significant effect on erosion while an increase in molarity strength resulted in a decrease in matrix erosion. The effect of HPMC grade on swelling, erosion and NVP release revealed that the grade of HPMC used had a significant effect on NVP release, with the release rate decreasing, swelling increasing and erosion decreasing as the viscosity of the HPMC grade increased. The effect of the particle size of MCC on NVP release was also studied by manufacturing tablets containing different grades of MCC and these studies revealed that particle size did not appear to have a significant effect on NVP release. Similarly the use of different types of lactose did not appear to have a significant impact on NVP release. In conclusion a sustained release NVP tablet formulation that has the potential for further development and optimisation has been developed, assessed and manufactured successfully and has been shown to exhibit similar dissolution behaviour to Viramune® XR, a commercially available NVP extended release product.

Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.

<p> The ability of chitosan and tripolyphosphate to form an ionic crosslinked material and its effectiveness in sustained release formulations has been reported. However, key issues commonly observed with these formulations include inefficiencies and inaccuracies in the drug loading as well as an inability to achieve complete release of drug. Acetaminophen, as a model drug, was added to various chitosan-tripolyphosphate crosslinked powders to assess the sustained release characteristics when drug is added extragranularly as opposed to during the crosslinking process, which is the most common procedure for drug addition in prior literature. The influence of various process and formulation variables including chitosan concentration, chitosan:tripolyphosphate ratio, temperature, ionic strength, and pH was assessed. Design of experiments allowed the identification of factors and two factor interactions that have significant effects on particle size and size distribution, yield, zeta potential, true density, and drug release. Statistical model equations were successfully used to manufacture optimized chitosan-tripolyphosphate crosslinked powders with various properties for further evaluation. Analysis of the compressibility of the optimized powders revealed that the crosslinked powders had enhanced compression properties when compared to chitosan powder. Environmental scanning electron microscopy revealed a correlation between the rigidity and density of the powders and corresponding capabilities for enhanced sustained release. Analysis of the moisture sorption and desorption isotherms from dynamic vapor sorption analysis revealed various types and levels of water present and a correlation between the quantity of water internally absorbed during sorption and desorption and sustained release capability. Chitosan-tripolyphosphate crosslinked powder can be manufactured with optimized properties that allow desired sustained drug release profiles while simultaneously serving as the primary diluent for solid oral dosage forms.</p><p>

Parmi toutes les voies d’administration, la voie orale a toujours suscité un grand intérêt. Les formes prises par voie orale présentent une grande facilité d’administration pour le patient, tandis que pour les chercheurs, la physiologie du système gastro-intestinal peut être facilement modélisable. Malheureusement, son importante variabilité, liée principalement au temps de vidange gastrique, peut conduire à une mauvaise reproductibilité des effets thérapeutiques et à une diminution de la biodisponibilité. Ce problème est surtout rencontré dans le cas des principes actifs présentant une fenêtre d’absorption étroite au niveau de l’intestin supérieur [Deshpande et col. 1996]. Une solution a été de développer des formes galéniques à libération prolongée caractérisées par un temps de résidence gastrique accru. Ainsi, le principe actif est libéré progressivement en amont de sa fenêtre d’absorption. Dans cette optique, plusieurs systèmes ont été développés :des formes bioadhésives, expansibles, gonflantes ou à hautes densités [Singh et Kim, 2000]. Mais parmi toutes ces formes, ce sont les systèmes flottants qui semblent offrir la protection la plus efficace contre une vidange gastrique précoce [Moës, 1989]. Seth et Tossounian ont ainsi développé une gélule flottante à libération prolongée, basée sur le gonflement d’un dérivé cellulosique. Etant une forme monolithique, sa vidange gastrique était soumise au phénomène de tout ou rien. De plus, cette forme présentait un inconvénient majeur puisqu’elle était sujette à des fractionnements intra-gastriques, diminuant de ce fait la reproductibilité inter- et intra-individuelle [Seth et Tossounian, 1984]. <p>\<br>Doctorat en Sciences biomédicales et pharmaceutiques<br>info:eu-repo/semantics/nonPublished

Les comprimés matriciels hydrophiles sont fréquemment utilisés pour contrôler la libération d’actif dans les formes galéniques à usage oral. Les amidons représentent un choix intéressant pour cette application. En effet, ce sont des matériaux biocompatibles, biodégradables et disponibles à partir de différentes sources végétales. En plus des amidons natifs, les amidons modifiés (AM) ont été beaucoup étudiés pour la formulation des comprimés matriciels à libération prolongée. Les modifications physico-chimiques peuvent être ajustées de manière à correspondre aux propriétés souhaitées pour une application pharmaceutique spécifique. De nombreux scientifiques ont rapportés l'utilisation de ces amidons pour les comprimés à libération contrôlée. Ils ont obtenu des résultats prometteurs montrant la capacité de ces excipients à retarder la libération d’actif dans. Cependant, la plupart des amidons utilisés dans ces études sont généralement produits à l'échelle laboratoire, et peuvent donc présenter des propriétés différentes des AM produits à l’échelle industrielle. Par conséquent, il pourrait être très difficile de transposer la production de ces amidons à l’échelle industrielle sans altérer leurs propriétés caractéristiques. L'objectif principal de ce travail était d'identifier un nouvel excipient à base d'amidon pour contrôler la libération d’actif à partir de comprimés. Ainsi, dans un premier temps, un grand criblage a permis d'étudier différents types d'amidons pour préparer des comprimés de diprohylline par compression directe. L'impact de l'origine botanique des amidons, de la méthode de pré-gélatinisation, du degré et de la nature de réticulation, ainsi que la substitution chimique ont été étudiées et les cinétiques de libération d’actif ont été mesurées. Pour avoir une meilleure compréhension de ces résultats, l’analyse de texture de l’hydrogel formé au contact du milieu de libération, la microscopie optique et électronique à balayage (MEB) ainsi que l’analyse par diffraction des rayons X ont été réalisées. De plus, un « test rapide » a été mis en place pour évaluer le potentiel d'un d'amidon donné à prolonger libération d’actif. Les résultats obtenus sur l'importance du type d'amidon et leur impact sur les cinétiques de libération d’actif des comprimés matriciels peuvent aider à mieux assimiler et optimiser ces systèmes avancés d'administration de médicaments. Dans une deuxième partie, le potentiel du (PREGEFLO® PI10) a été évalué comme agent matriciel pour les comprimés à libération prolongée. Pour ce faire, différents types de comprimés chargés d’actifs ayant une solubilité différente ont été préparés par compression directe. La robustesse de cette matrice a été étudiée dans des milieux de libération très variés. Plusieurs appareils de dissolution ont été utilisés séparément ou combinés avec d'autres machines pour simuler le stress hydrodynamique subi par les comprimés lors de leur passage à travers le tractus gastro-intestinal. Les résultats obtenus ont montré que les profils de libération d’actif à partir du PREGEFLO® PI10 n'étaient pas affectés par toutes les conditions étudiées. Ainsi, le PREGEFLO® PI10 se positionne comme un bon candidat comme polymère de libération prolongée pour la voie orale. Enfin, pour caractériser la distribution d’actif au sein du système matriciel, en particulier dans les régions «sèches» et gonflés après dissolution du comprimé, et examiner comment les distributions spatiales changent au cours du temps, l'imagerie Raman, la MEB, la spectroscopie de rayons X à dispersion d'énergie (EDX) et la cristallographie aux rayons X ont été utilisées sur des comprimés avant et après exposition au tampon. Les cartographies Raman ont confirmé que l’actif est bien piégé dans le noyau du comprimé «sec». Ces observations ont mis en évidence la différence de morphologie entre la région centrale « sèche » et la région dans laquelle la matrice du comprimé a subi un gonflement important<br>Hydrophilic matrix tablets are frequently used to control the drug release from oral dosage forms. Starch-based polymers are interesting matrix former in this respect, due to their biocompatibility, biodegradability, and availability from different plant sources. In addition to native starches, modified starches have been frequently used with various physiochemical modifications, which could be tailored to provide desired properties for a specific pharmaceutical application. Many scientists have reported the use of modified starches as matrix formers for oral controlled release tablets. Numerous starch-based extended release polymers have successfully retarded drug releases. However, most of the starch batches used in those studies are generally produced at a laboratory scale and may therefore present different properties compared to modified starches obtained with industrial scale. Hence, it could be very difficult to scale up the production of these excipients without changing their key features. The major goal of this work was to identify a new excipient, based on starch to control the drug release from direct compressible matrix tablets. Therefore, in a first instance, a large screening allowed to study different types of starches to prepare diprophylline matrix tablets. The effect of the botanical origin of starches, the type of pre-gelatinization method as well as of the degree and type of cross-linking and chemical substitution have been investigated, and the resulting drug release rates from diprophylline-loaded matrix tablets were measured. For a better understanding of these results, texture analysis of the gel-layer, created upon contact with the release medium, optical and scanning electron microscopy (SEM) as well as X- ray powder diffraction analysis were applied. Moreover, a “quick test” has been proposed to evaluate the potential of a particular type of starch to sustain the drug release rate. The obtained results on the importance of the starch type and their influence on the resulting drug release rates from matrix tablets can help for a better understanding and optimization of this type of advanced drug delivery systems. In a second phase, the potential of (PREGEFLO® PI10), has been evaluated as a matrix former for controlled release tablets. Hence, various types of matrix tablets loaded with drugs having different solubility were prepared by direct compression. The robustness of this cross-linked pregelatinized potato starch matrix was investigated in a variety of release media. In addition to that, several types of experimental USP apparatuses were used separately or combined with other devices to simulate the mechanical stress the tablets are exposed to during transpassage of the gastrointestinal tract. The obtained results showed that the drug release rates from PREGEFLO® PI10 matrix were not impacted by all the conditions studied. Therefore, the explored starch excipient offers an interesting potential as matrix former in controlled release tablets. Finally, to characterize the drug distribution throughout the matrix system, in particular in the “dry” and swollen tablet regions after hydration and the way the spatial distribution patterns change with time, the tablets were investigated using Raman imaging, SEM and Energy Dispersive X-ray Spectroscopy (EDX) before and after exposure to phosphate buffer. The Raman images confirmed that the drug is effectively trapped within the “dry” tablet core. The internal structure of the vacuum-dried tablets was visualized using SEM analysis. These observations highlighted the difference in the morphology between the “dry” core region and the region in which the tablet matrix underwent substantial swelling. The polysaccharide formed a continuous hydrogel in which the drug dissolved. SEM and EDX images have rendered visible the interface “dry “core-swollen gel and the spatial distribution of the drug in both regions. The diprophylline content is predictably much highe

Introduction : La résistance aux antibiotiques est une menace de santé, il est donc urgent de développer de nouveaux antibactériens. CIN-102, est un nouvel antibactérien développé par une industrie pharmaceutique. Il possède un large-spectre d’action et aucune résistance n’a été développée jusqu’à présent. Parmi les possibles applications thérapeutiques du CIN-102, notre recherche s’est focalisée sur les Maladies Inflammatoires Chroniques de l’Intestin (MICIs). Plusieurs facteurs contribuent à l’étiologie des MICIs. Les bactéries intestinales jouent un rôle important dans ces maladies et une augmentation de la charge bactérienne est observée pendant l’inflammation. Les objectifs de ce travail ont été : la caractérisation de l’activité antibactérienne du CIN-102, l’analyse de l’activité antibactérienne des agents anti-inflammatoires et antibiotiques utilisés en cas de MICI et la fabrication des formulations à ciblage colique pour le CIN-102. Le but est de diminuer la charge bactérienne colique par moyen du CIN-102 et améliorer, de cette façon, l’état de l’inflammation.Méthodes: La Concentration Minimale Inhibitrice (CMI), l’Effet Post-Antibiotique (EPA) et le temps de réduction logarithmique du CIN-102 ont été déterminés pour des bactéries aérobies et anaérobies. Les interactions entre le CIN-102 et des antibiotiques sur le marché ont été évaluées. La CMI de l’acide 5-aminosalicylique (5-ASA), GED-0507-34 et antibiotiques ont été déterminées pour des souches anaérobiques. Par rapport aux formulations à libération prolongée : des mini-granules contenant le CIN-102 ont été fabriqués par extrusion-sphéronisation puis pelliculés avec des mélanges de polymères insolubles et polysaccharides. Parallèlement, des mini-comprimés de CIN-102 ont été fabriqués par compression directe. La libération du CIN-102 in vitro, a été mesurée dans des milieux simulant l’estomac et l’intestin grêle. L’efficacité des systèmes à libération prolongée a été évaluée dans un modèle de colite chez la souris. Des prélèvements de selles et tissus coliques ont été soumis à des études bactériologiques. L’expression des cytokines a été mesurée à partir des tissus coliques.Résultats et discussion : Le large-spectre d’action du CIN-102 a été confirmé. Toutes les souches ont été inhibées par le CIN-102. CIN-102 présente un EPA et un temps de réduction logarithmique court. Il présente des interactions synergiques avec plusieurs antibiotiques, notamment la colistine et les aminoglycosides, en les rendant actifs contre des bactéries multirésistantes. Ces résultats in vitro doivent être poursuivis par des études chez l’animal. Des agents anti-inflammatoires utilisés contre les MICIs ne possèdent pas d’activité antibactérienne. Par ailleurs, les antibiotiques testés n’ont pas un large-spectre d’action contre des bactéries anaérobies généralement retrouvées dans l’intestin. Cela confirme le besoin d’un antibiotique à large spectre capable de réduire des charges bactériennes en cas d’inflammation. Dans ce but, des formulations capables de délivrer CIN-102 au niveau du colon ont été étudiées. La libération du CIN-102 des mini-granules pelliculés et mini-comprimés a été réduite dans des milieux simulant l’estomac et l’intestin grêle. Des souris atteintes de colite et traitées avec les formulations du CIN-102 ont eu une diminution des diarrhées et du sang dans les selles. Les concentrations d’entérobactéries adhérentes à la muqueuse colique et dans les selles ont été significativement réduites chez les souris traitées avec le CIN-102. Ces résultats montrent que ces formulations peuvent délivrer CIN-102 dans le tractus gastro-intestinal inferieur, et que la diminution d’entérobactéries semble réduire les symptômes de la colite.Conclusion : CIN-102 est un nouvel antibactérien a large-spectre et des formulations à libération prolongée peuvent délivrer cet agent dans le colon, diminuant la charge d’entérobactéries qui pourrait influencer l’état de l’inflammation<br>Introduction: Antibiotic resistance is a major threat to public health and new antimicrobials are urgently needed. CIN-102, a new antibacterial agent which resembles cinnamon essential oils composition, was developed by a pharmaceutical company. CIN-102 had a broad-spectrum of action and resistance was not developed until now. Between all the possible therapeutic applications for CIN-102, a future utilization against Inflammatory Bowel Diseases (IBD) is aimed. IBD are chronic pathologies with a multifactorial etiology. In this context, enteric bacteria are well-known to have an important role, and higher bacterial concentrations are found in the intestine under inflammatory conditions. The objectives of this work were: to characterize the bacteriological activity of CIN-102, to analyze the bacteriological activity of anti-inflammatory agents and antibiotics used in IBD and to fabricate multiparticulate CIN-102 pharmaceutical forms for colonic targeted drug release. The idea is to use CIN-102 to reduce colonic bacterial loads and improve the state of intestinal inflammation. Methodology: The Minimal Inhibitory Concentration (MIC), the Post-Antibiotic Effect (PAE) and the logarithmic reduction time of CIN-102 were determined against several aerobic and anaerobic bacterial isolates. The interactions between CIN-102 and commercialized antibiotics were evaluated. The MIC of 5-aminosalicilyc acid, GED-0507-34 and antibiotics were determined for anaerobic bacterial isolates. Concerning sustained released formulations: CIN-102 pellet cores were fabricated by extrusion-spheronization and subsequently coated with blends of insoluble polymers and natural biodegradable polysaccharides. CIN-102 mini-tablets were fabricated by direct compression. In vitro drug released was measured in simulated gastric and intestinal fluid. The efficacy of best sustained release formulations was assessed in a murine model of colitis. Samples of luminal contents and sections of the colon were taken to perform a bacteriological analysis. Expression of cytokines was analyzed from colonic tissues.Results and discussion: The broad-spectrum activity of CIN-102 was confirmed. All aerobic and anaerobic strains were susceptible to CIN-102. Furthermore, CIN-102 had an important PAE and exerted a fast logarithmic reduction of bacterial inoculum. It interacts synergistically with several antibiotics, mostly with colistin and aminoglycosides, restoring the antibiotic activity against multi-resistant bacteria. The promising in vitro activity of CIN-102 has to be further confirmed by animal studies. Anti-inflammatory agents used against IBD were not provided of antibacterial activity and neither of the antibiotics tested possessed a broad-spectrum of action against anaerobic isolates commonly found in the intestine. These results confirm the need of a broad-spectrum antibiotic capable of reduced increased bacterial loads during inflammation. Following this aim, oral dosage forms able to deliver CIN-102 into the colon were studied. Concerning the sustained release forms, in vitro CIN-102 release from coated-pellets and mini-tablets was reduced in simulated gastric and intestinal fluids. Colitic mice treated with CIN-102 controlled release formulations had less diarrhea and bloody stools. Furthermore, the concentrations of enterobacteria in colonic tissue and stool were significantly reduced in CIN-102 treated mice. These results show that sustained release formulations can effectively deliver CIN-102 in the lower part of the gastrointestinal tract, where the reduction of enterobacteria seems to ameliorate the course of colitis.Conclusion: CIN-102 is novel broad-spectrum antibacterial and sustained release formulations can effectively deliver this agent into the colon, reducing bacterial loads which might influence the state of intestinal inflammation

碩士<br>國立暨南國際大學<br>土木工程學系<br>103<br>Persulfate possess oxidation ability, high solubility, long-time presence, good transmission capacity and regulation applicable to a wider range of features. In this study, the biodegradable hydroxypropyl methyl cellulose as a coating material, development of a sustained-release persulfate of green remediation tablets in groundwater. Through batch and column experiment assess release efficiency of persulfate about sustained-release presulfate tablet, with the type of cement persulfate release material were compared. This study aim is as follows: (1) assess release efficiency of persulfate about sustained-release persulfate tablet; (2) to obtain the best proportion of sustained-release persulfate tablet; (3) assess the coating material the impact to in situ environment. The result show, through difference of pressure, hydroxypropyl methyl cellulose proportion, persulfate content on batch release experiment, type of hydropropyl methyl cellulose sustained-release persulfate tablet release time can be accumulated about 10 days. With type of cement persulfate release material were compared, persulfate not only can preserve sustainability release efficiency, but also decrease doubt about secondary pollution in type of hydroxypropyl methyl cellulose sustained-release persulfate tablet. Because hydropropyl methyl cellulose can consume to persulfate that loss of certain degree. When persulfate release from the tablet, that destroy structure of gel. On column release experiment of simulation groundwater environment, mobility of water have obvious effect about persulfate release efficiency, that also decrease degree of consume persulfate with hydropropyl methyl cellulose. These result support hydropropyl methyl cellulose as coating material to sustained-release persulfate tablet was a feasible and apply to remediation on in situ environment.

碩士<br>臺北醫學大學<br>生醫材料暨工程研究所<br>98<br>Huntington''s disease is still an incurable inherited disorder, and currently only symptomatic treatments are available. T1-11, a potential active ingredient for the treatment of Huntington’s disearse, is originally extracted from a traditional Chinese that can now be mass produced by chemical synthesis. Since patients with Huntington''s disease might have difficulties control their movements, thinking, and emotion, frequent drug dosing is not very convenient to the patients. Once per day of drug dosing that can ensure 24 hours of drug release would be very helpful to the patients for their symptom and emotional control. This study is to design and develop the T1-11 orally sustained-release tablet whose main concern is to reduce the dosing frequency and the patient convenience. The formulation development is based on preformulation results. Prefomulation studies including spectral analysis, solubility, stability and excipient compatibility were conducted. Tablets produced by direct compression were composed with selected excipients, and characterization items that were tested including the analytical method validation, tablet hardness, tablet weight, disintegration testing, content uniformity, and dissolution studies. At present, the formula composed of hydroxypropyl cellulose, lactose and microcrystalline cellulose appeared to be the most appropriate for the T1-11 tablet. Under this condition, dissolution of T1-11 revealed a sustained release of 50~60% of the total content up to 6 hours.

博士<br>國立臺灣大學<br>藥學系<br>85<br>Diclofenac sodium was used as the model drug in this formulation study that hydrophilic matrices were proposed for the sustained-release of the drug. HPC-M, HPC-H, HPMC 2910, and/or HPMC 2208 in different proportions were compared for the matrix material to regulate the sustained release. The matrix type tablets were prepared by adding lactose or wax as the additives and then compressed. The resulting tablets with different formulations were then examined and tested for dissolution. It was found that most dissolution curves resulting from different formulations provided delayed dissolution. Most dissolution curves can be described by the equation (Mt/M∞)= ktn where k represents the dissolution rate constant, and n stands for the diffusion exponential which corresponds to the release mechanism. It was found that the release mechanism varies with the contents of the formulations. In the formulation containing HPC-M the addition of lactose or wax did not change the release mechanism of the drug release. In the formulation containing HPC-H and lactose the release mechanism is close to the case II transport of non- Fickian diffusion whereas the mechanism of the formulation containing HPC-H and wax belongs to the Fickian diffusion. In the formulation containing HPMC 2910 and lactose the drug release mechanism changes with the ratio of HPMC in the formulation. The release mechanism was found to be non- Fickian diffusion for formulation containing HPMC 2910 and wax and to be super case II transport for the formulation containing HPMC 2208 and lactose. For the formulation containing HPMC 2208 and wax the case II transport with zero order release was found. Eight formulations obtained from admixing the model drug with polymers described above were subject to the three month accelerated stability testing at 30℃,, 37℃, and 45℃, and at 75% relative humidity. In these formulations the polymer to lactose or wax ratio was 1:1. All the tested formulations were packaged in HDPE and PTP showed good stability in most cases. The exception was those packed in PTP treated at 45℃. The formulation that gave the dissolution mechanism close to zero order release, say formula M9W05 that contains HPMC 2208 and wax, were compared with conventional enteric coated diclofenac tablets by examining their blood levels resulting from oral administrations in human volunteers. The conventional formulation provided quick absorption and quick decline of the drug blood level. The polymer containing new formulation provided sustained blood levels up to 12 hours after the dosing and the resulting blood levels are comparable to that resulting from some other modified release diclofenac formulations.

碩士<br>國立中興大學<br>食品暨應用生物科技學系所<br>106<br>Rosell calyxes are bright red due to their rich anthocyanin. Many studies have confirmed that anthocyanins have good antioxidant activity. They have many physiological functions such as anti-inflammatory, anti-tumor, anti-cancer, and protection of eyesight. At present, people are eagerly pursuing health foods, and more and more raw materials with physiological effects are used to develop a lot of health foods. Tablet is one of the common types of health foods, with advantages of small size, convenient carrying, low cost, etc. This experiment aims to develop sustained-release tablets by roselle extract powder, and it can be slowly released in the stomach while avoiding damage by the alkaline environment of the intestine to improve the bioavailability. The anthocyanins can be effectively extracted by heating at 75 ℃ for 30 minutes by 30% ethanol. HPLC results showed that the main anthocyanin type of extract was delphinidin, and its content was 126.34 mg/100 g of dried roselle calyces. Also, the DPPH, ABTS free radical scavenging capacity and Fe3+ reducing ability of extract were good. The roselle extract gastro-floating sustained-release tablets prepared with the appropriate proportion of excipients can be quickly floated, and can continuously floating over 12 hours in vitro simulated gastric fluid environment. During the process, the tablets will not disintegrate, keeping the colloidal skeleton slowly releasing the internal index components.With the content of extract powder increased, the cumulative release at 12 hours will increase, and the release of the index components will follow the zero-order kinetics (R2>0.9). The value of R2 with Higuchi kinetic equation was the highest, indicating that the index component in the gastric floating sustained-release tablets prepared in this experiment were released in a diffusion manner, and the release of index components was accumulated. There is a positive relationship between the square root of the time and the cumulative release, and the content of extract powder not change the release behavior. In the Korsmeyer-Peppas release kinetic model showed that the release mechanism of the index component was anomalous transport, representing there was a synergistic effect of diffusion and skeleton erosion. The results of this experiment can lay a theoretical foundation for future development of anthocyanin sustained-release tablets.

碩士<br>大葉大學<br>生物產業科技學系碩士在職專班<br>98<br>In Pharmaceutics, there are two common systems in making the oral Sustained-release tablets,i.e. Matrix system and Reservoir system. The polymers are used as materials in the two systems mostly, such as citosan、xanthan gum and hydroxypropylmethylcellulose (HPMC) etc. In reservoir system,using a fluid-bed spray granulator machine to sprinkle polymers on surface of tablet and forming a membrane. The membrane make drug's effect release slowly. In matrix system, using traditional method to form the tablets with the mixture by mixing the medicine with hydrogel or hydrophobic polymers. That is a cheaper and easier method than others. Many traditional drugs are made by dump system.In order to consider both safety and effect,development of oral slow-release tablets is a good decoration.There are many advantages in slow-release tablets, such as it can maintain the concentration of drugs in the circulation of blood,decrease side effect,decrease the frequency of using drugs and the squander of drugs,and further,it is a more acceptable mode for patients.

Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in Medicine in the branch of Pharmacy<br>A coated doughnut-shaped tablet is evaluated as its ability to release model drugs at a zero-order rate for 8 to 12 hours. The doughnut-shape tablets were compressed using special designed punches.Automated technology is thus feasible for this system. The coating material , 10% w /w gelatin in HPMC K15M was directly compressed and adhered to the tablet core .<br>IT2018

Acetaminophen has been safely used for analgesia for many years. Literature suggests that a plasma acetaminophen level of 5��g/ml is necessary to maintain analgesic relief in humans. Current dosing regiments are inconvenient (every 4-6 hours) and do not maintain this minimum plasma level. Simulations were conducted to examine various doses and input rates for sustained release formulations of acetaminophen. Once parameters were selected from the simulations, sample formulations were prepared and tested using standard dissolution techniques. Investigations into dose/size relationships, hydroxypropylmethylcellulose (HPMC) percentage for erosion matrix tablets, compression force, tablet shape, tablet divisibility, and granulation methods were performed for non-disintegrating hydrophilic matrix tablets. Tablets containing 5% and 7.5% HPMC were selected for pharmacokinetic study in 10 healthy human subjects. Tylenol Extra Strength and Tylenol Extended Relief tablets were administered as control formulations. Pharmacokinetic fitting of the kinetic profiles of all four formulations were performed using Win Nonlin. The formulations were best described by a 1-compartment open model with first order input and first order elimination. The 5% HPMC sustained release acetaminophen formulation was selected for Phase II clinical trials. Patients with osteoarthritis of the knee were recruited for a double blind crossover study of 5% HPMC sustained release acetaminophen formulations and immediate release acetaminophen. Patients received two tablets of study medication, four times a day for 4 weeks. After a seven day wash-out period patients were then crossed over to the other treatment. Patients were evaluated using a twelve question questionnaire and the time to walk 50 feet was measured. Thirty patients were enrolled in the study and seventeen patients completed the study. The sustained release formulations were statistically superior to the baseline treatments in reducing pain level, decreasing disability, and improving the duration of pain relief. Additional, larger scale studies are needed to confirm these findings.<br>Graduation date: 2000

Les amidons non modifiées et modifiés représentent un groupe d’excipients biodégradables et abondants particulièrement intéressant. Ils ont été largement utilisés en tant qu’excipients à des fins diverses dans des formulations de comprimés, tels que liants et/ou agents de délitement. Le carboxyméthylamidon sodique à haute teneur en amylose atomisé (SD HASCA) a été récemment proposé comme un excipient hydrophile à libération prolongée innovant dans les formes posologiques orales solides. Le carboxyméthylamidon sodique à haute teneur en amylose amorphe (HASCA) a d'abord été produit par l'éthérification de l'amidon de maïs à haute teneur en amylose avec le chloroacétate. HASCA a été par la suite séché par atomisation pour obtenir le SD HASCA. Ce nouvel excipient a montré des propriétés présentant certains avantages dans la production de formes galéniques à libération prolongée. Les comprimés matriciels produits à partir de SD HASCA sont peu coûteux, simples à formuler et faciles à produire par compression directe. Le principal objectif de cette recherche était de poursuivre le développement et l'optimisation des comprimés matriciels utilisant SD HASCA comme excipient pour des formulations orales à libération prolongée. A cet effet, des tests de dissolution simulant les conditions physiologiques du tractus gastro-intestinal les plus pertinentes, en tenant compte de la nature du polymère à l’étude, ont été utilisés pour évaluer les caractéristiques à libération prolongée et démontrer la performance des formulations SD HASCA. Une étude clinique exploratoire a également été réalisée pour évaluer les propriétés de libération prolongée de cette nouvelle forme galénique dans le tractus gastro-intestinal. Le premier article présenté dans cette thèse a évalué les propriétés de libération prolongée et l'intégrité physique de formulations contenant un mélange comprimé de principe actif, de chlorure de sodium et de SD HASCA, dans des milieux de dissolution biologiquement pertinentes. L'influence de différentes valeurs de pH acide et de temps de séjour dans le milieu acide a été étudiée. Le profil de libération prolongée du principe actif à partir d'une formulation de SD HASCA optimisée n'a pas été significativement affecté ni par la valeur de pH acide ni par le temps de séjour dans le milieu acide. Ces résultats suggèrent une influence limitée de la variabilité intra et interindividuelle du pH gastrique sur la cinétique de libération à partir de matrices de SD HASCA. De plus, la formulation optimisée a gardé son intégrité pendant toute la durée des tests de dissolution. L’étude in vivo exploratoire a démontré une absorption prolongée du principe actif après administration orale des comprimés matriciels de SD HASCA et a montré que les comprimés ne se sont pas désintégrés en passant par l'estomac et qu’ils ont résisté à l’hydrolyse par les α-amylases dans l'intestin. Le deuxième article présente le développement de comprimés SD HASCA pour une administration orale une fois par jour et deux fois par jour contenant du chlorhydrate de tramadol (100 mg et 200 mg). Ces formulations à libération prolongée ont présenté des valeurs de dureté élevées sans nécessiter l'ajout de liants, ce qui facilite la production et la manipulation des comprimés au niveau industriel. La force de compression appliquée pour produire les comprimés n'a pas d'incidence significative sur les profils de libération du principe actif. Le temps de libération totale à partir de comprimés SD HASCA a augmenté de manière significative avec le poids du comprimé et peut, de ce fait, être utilisé pour moduler le temps de libération à partir de ces formulations. Lorsque les comprimés ont été exposés à un gradient de pH et à un milieu à 40% d'éthanol, un gel très rigide s’est formé progressivement sur leur surface amenant à la libération prolongée du principe actif. Ces propriétés ont indiqué que SD HASCA est un excipient robuste pour la production de formes galéniques orales à libération prolongée, pouvant réduire la probabilité d’une libération massive de principe actif et, en conséquence, des effets secondaires, même dans le cas de co-administration avec une forte dose d'alcool. Le troisième article a étudié l'effet de α-amylase sur la libération de principe actif à partir de comprimés SD HASCA contenant de l’acétaminophène et du chlorhydrate de tramadol qui ont été développés dans les premières étapes de cette recherche (Acetaminophen SR et Tramadol SR). La modélisation mathématique a montré qu'une augmentation de la concentration d’α-amylase a entraîné une augmentation de l'érosion de polymère par rapport à la diffusion de principe actif comme étant le principal mécanisme contrôlant la libération de principe actif, pour les deux formulations et les deux temps de résidence en milieu acide. Cependant, même si le mécanisme de libération peut être affecté, des concentrations d’α-amylase allant de 0 UI/L à 20000 UI/L n'ont pas eu d'incidence significative sur les profils de libération prolongée à partir de comprimés SD HASCA, indépendamment de la durée de séjour en milieu acide, le principe actif utilisé, la teneur en polymère et la différente composition de chaque formulation. Le travail présenté dans cette thèse démontre clairement l'utilité de SD HASCA en tant qu'un excipient à libération prolongée efficace.<br>Unmodified and modified starches represent a particularly interesting group of biodegradable and abundant excipients. They have been widely used as excipients for various purposes in tablet formulations, such as binders and/or disintegrants. Spray-dried high-amylose sodium carboxymethyl starch (SD HASCA) was recently proposed as an innovating hydrophilic excipient for sustained-release (SR) in solid oral dosage forms. Amorphous high-amylose sodium carboxymethyl starch (HASCA) was first produced by the etherification of high-amylose corn starch with chloroacetate. HASCA was then spray dried to obtain SD HASCA. This new excipient has shown advantageous and effective properties in the production of SR delivery systems. SR matrix tablets prepared from SD HASCA are inexpensive, simple to formulate and easy to produce by direct compression. The main objective of the present research was to continue the development and optimization of matrix tablets using SD HASCA as the retarding excipient in view of their ultimate application as sustained drug-release delivery systems for oral administration. For this purpose, dissolution tests simulating some of the most relevant physiological conditions of the gastrointestinal tract, taking into account the nature of the polymer under investigation, were employed to evaluate the drug-release characteristics and demonstrate the performance of SD HASCA SR formulations. An exploratory clinical study was also carried out to evaluate the SR properties of this new drug delivery system in the gastrointestinal tract. The first article presented in this thesis evaluated the drug-release characteristics and the physical integrity of formulations containing a compressed blend of drug, sodium chloride and SD HASCA in biorelevant media. The influence of different acidic pH values and residence times was investigated. The SR profile from an optimized SD HASCA formulation was not significantly affected by both the acidic pH value and the residence time in the acidic medium. These results suggest a limited influence of intra- and inter-subject variability of gastric pH on the release kinetics from SD HASCA matrices. In addition, the optimized formulation maintained its integrity throughout the duration of the dissolution tests. The exploratory in vivo study demonstrated extended drug absorption after oral administration of SD HASCA matrix tablets and that the matrix tablets did not disintegrate while passing through the stomach and resisted hydrolysis by α-amylase in the intestine. The second article reports the development of once-daily and twice-daily SD HASCA tablets containing tramadol hydrochloride (100 mg and 200 mg). These SR formulations presented high crushing strengths without requiring the addition of binders, which facilitates tablet processing and handling. The compression force (CF) applied to produce the tablets did not significantly affect the drug-release profiles. The total release time from SD HASCA tablets increased significantly in function of the tablet weight and can be used to modulate the total release time from theses formulations. When exposed to a pH gradient and to a 40% ethanol medium, a very rigid gel formed progressively on the surface of the tablets providing controlled drug-release properties. These properties indicated that SD HASCA is a robust excipient for oral, sustained drug-release, likely to minimize the possibility of dose dumping and consequent adverse effects, even when co-administered with high doses of alcohol. The third article investigated the effect of α-amylase on drug-release from previously developed SD HASCA tablets containing acetaminophen and tramadol hydrochloride (Acetaminophen SR and Tramadol SR). Mathematical modeling showed that an increase in α-amylase concentration resulted in an increase of polymer erosion over drug diffusion as the main mechanism controlling drug-release, for both formulations and both residence times in acidic medium. However, even if the mechanism of release was affected, α-amylase concentrations ranging from 0 IU/L to 20000 IU/L did not significantly affect the drug-release profiles from SD HASCA SR tablets, regardless of the residence time in acidic medium, the drug used, the polymer content and the different composition of each formulation. The work presented in this thesis clearly demonstrates the value of SD HASCA as an efficient SR excipient.