Modified-release oral drug delivery dosage forms are widely used in the pharmaceutical field to overcome all the potential issues imposed by the physiological variabilities of the gastrointestinal tract as well as to maintain drug concentrations within the therapeutic window. In the market, they are available only as solid dosage forms such as capsules or tablets. The development of a liquid oral dosage form with modified-release properties has been keenly awaited. This form could increase the compliance of patients with a swallowing impairment (i.e. paediatric, older or critically ill patients) and, consequently, the efficacy of the therapeutic treatment. In this study, a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup. Omeprazole and budesonide have been employed as model drugs. The coating procedure was optimized to obtain a yield of minimum 90% w/w and a median diameter below 500 µm. Once the final suspension is prepared extemporaneously, it presents sufficient stability to guarantee the administration of multiple doses filled into a syrup bottle and kept for a limited storage time at room temperature (e.g. up to 10 doses to be administered within 10 days). / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

Yes / A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. Results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the environment and PEO molecular weight. / The research was funded by AstraZeneca, Sweden.

PURPOSE: Muscle overuse is characterized by inflammation, reduced strength and muscle damage. It has been proposed that calcium (Ca2+) accumulation during muscle contraction, is responsible for muscle damage. Muscle contractile properties are regulated by calcium regulatory excitation contraction coupling mechanisms. Therefore, the main aim of the present study was to investigate the effects of voluntary repetitive tasks during six weeks on the rate of sarcoplasmic reticulum (SR) Ca2+-uptake, and Ca2+-release, in young female Sprague-Dawley rats. Secondly, this study aims to evaluate the effect of the training on muscular strength and the relationship between SR Ca2+-kinetics and grip strength test performance. METHODS: Six rats were trained (EXP), using a well-established model of reaching and handle pulling with the upper extremities (2 hr/day, 3days/week, 6 weeks), six control rats (KON) were included that were not exposed to the task. Grip strength were evaluated using a grip strength meter for rodents, two weeks prior the training was initiated, and two days after the training period was concluded. Tissue samples were obtained from the supraspinatus and trapezius muscle, and the rate of SR Ca2+-uptake and SR Ca2+-release were analysed using the fluorescent Ca2+ indicator indo 1. RESULTS: The analysis revealed that EXP had a significant higher rate of SR Ca2+-uptake, in both supraspinatus (33%, P < 0,05) and trapezius (14%, P < 0,05), compared to KON. However, no significant differences in SR Ca2+-release rate were found between groups, in neither of the muscles. A decline in grip strength were found in both EXP and KON, with no significant differences between groups. No significant correlation between grip strength and the Ca2+ release uptake variables could be found. CONCLUSION: The present results suggests that repetitive voluntary reaching and handle pulling with the upper extremities during six weeks, induce extant changes in SR Ca2+-uptake rate in rats.

Thesis (MEng)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: The fracture of ductile materials is currently regarded as a complex and challenging phenomenon to characterise and predict. Recently, a bond-based, non-local theory was formulated called the peridynamic theory, which is able to directly solve solid mechanics problems that include fracture. The failure criterion is governed by a critical stretch relation between bonds. It was found in literature that the critical stretch relates to the popular fracture mechanics parameter called the critical energy release rate for predicting brittle linear-elastic failure. It was also proposed that the non-linear critical energy release rate or J-integral can be used to model ductile failure using peridynamics. The aim of this thesis was to investigate the validity of using the J-integral to determine the critical stretch for predicting ductile failure. Standard ASTM fracture mechanics tests on Compact Tension specimens of Polymethyl methacrylate, stainless steel 304L and aluminium 1200H4 were performed to determine the critical energy release rates and non-linear Resistance-curves. Furthermore, a novel peridynamic-based algorithm was developed that implements a critical energy release rate based failure criterion and Digital Image Correlation (DIC) measured full surface displacement fields of cracked materials. The algorithm is capable of estimating and mapping both the peridynamic damage caused by brittle cracking and damage caused by plastic deformation. This approach was used to validate the use of an energy release rate based failure criterion for predicting linear-elastic brittle failure using peridynamics. Also, it showed a good correlation among the test results for detecting plastic damage in the alloys when incorporating the respective J-integral derived critical stretch values. Additionally, Modified Arcan tests were performed to obtain Mode I, Mode II and mixed Mode fracture load results of brittle materials. Mode I peridynamic models compared closely to test results when using the Mode I critical energy release rate, derived critical stretch and served as validation for the approach. Moreover, it was argued that Mode I failure criteria cannot in principle be used to model shear failure. Therefore, it was proposed to rather use the appropriate Mode II and mixed Mode critical energy release rates to predict the respective failures in peridynamics. Also, for predicting ductile failure loads it was found that using a threshold energy release rate derived from the R-curve yielded considerably more accurate failure load results compared to the usage of the critical energy release rate, i.e. J-integral. In this thesis it was shown that there exists great potential for detecting and characterising cracking and failure by using a peridynamic-based approach through coupling DIC full displacement field measurements and the critical energy release rate of a particular structural material. / AFRIKAANSE OPSOMMING: Duktiele breeking van materiale word tans beskou as 'n kompleks- en uitdagende fenomeen om te voorspel en te karakteriseer. 'n Binding-gebaseerde, nie-lokale teorie is onlangs geformuleer, genaamd die peridinamika teorie. Die laasgenoemde stel ons in staat om soliede meganiese probleme met krake direk op te los. Die falings kriterium word bemagtig deur die kritiese strekfaktor tussen verbindings. Daar was bewys dat die kritiese strekfaktor in verband staan met die popul^ere breek meganika parameter, genaamd die kritiese vrylatings-energie-koers vir die voorspelling van bros line^ere-elastiese faling. 'n Onlangse verklaring meen dat die kritiese strekfaktor vir duktiele falingsgedrag, bereken kan word met die nie-line^ere kritiese vrylatings-energie-koers, beter bekend as die J- integraal. Die doel van hierdie tesis was om te meet hoe geldig die gebruik van die J-integraal is om die kritiese strekfaktor te bereken, om sodoende duktiele breking te ondersoek. Standaard ASTM breukmeganika toetse op Polimetilmetakrilat, vlekvrye staal 304L en aluminium 1200H4 is uitgevoer om die kritiese vrylatings-energie-koers en Weerstandskurwes te bepaal. Verder was 'n nuwe peridinamies-gebaseerde algoritme ontwikkel. Die laasgenoemde implementeer die berekening van 'n kritiese strekfaktor, gebaseer op die kritiese vrylatings-energie-koers, sowel as Digitale Beeld Korrelasie (BDK) vol oppervlaks-verplasings veld metings van gebreekte materiale. Dit is in staat om die peridinamiese skade te bereken, tesame met die beeld wat veroorsaak was van bros krake en plastiese vervorming in duktiele materiale. Hierdie benadering is aangewend om die gebruik van 'n vrylatings-energie-koers gebaseerde falings kriterium vir bros line^ere-elastiese falings in peridinamika te bekragtig. 'n Goeie korrelasie tussen toets resultate is ook gevind vir die opsporing van skade wat veroorsaak is deur plastiese deformasie in die legerings waar die onderskeilike J-integrale gebruik was as falings kriteria. Daarbenewens, was Verandere Arcan toetse uitgevoer om die Modes I, Modes II en gemenge Modes falingsresultate te verkry. Die Modes I peridinamiese model het goed vergelyk met die toetsresultate en het gedien as bekragtiging vir die falingsbenaderings. Verder was dit aangevoer dat Modes I falings kriterium in beginsel nie gebruik kan word om skuiffaling te modelleer nie. Dus was dit voorgestel om eerder die toepaslike Modes II en gemengde Modes kritieke vrylatings-energie-koerse te gebruik om onderskeie falings te voorspel in peridinamiese modelle. Dit was ook gevind dat vir die voorspelling van duktiele falingslaste die drumpel vrylatings-energie-koers, wat verkrygbaar is vanaf die Weerstands-kurwe, aansienlik meer akkurate resultate gee, in vergelyking met die gebruik van die kritiese vrylatings-energie-koers, m.a.w. die J-integraal. In hierdie tesis was dit gewys dat daar groot potensiaal bestaan vir die opsporing en karakterisering van krake en falings met 'n peridinamies-gebaseerde benadering, deur dit te skakel met BDK vol verplasings veld metings en die kritiese vrylatings-energie-koers van 'n bepaalde strukturele materiaal.

No description available.

The EPA Lead and Copper Rule set action limits for lead and copper concentrations in drinking water, but accelerated corrosion of lead in distribution systems due to a galvanic connection to copper. Prior research has demonstrated that the effects of galvanic corrosion can be controlled by water chemistry. This study not only investigated the main effects of alkalinity, natural organic matter (NOM), nitrate, disinfectant and inhibitor to galvanic corrosion, but also the interplay between these factors. A 2-level factorial (2v5-1) design was adopted which resulted in 16 testing conditions. Results of bench-scale experiments using static pipes with lead and copper segments demonstrated that alkalinity, disinfectant, inhibitor and alkalinity-inhibitor interaction had a significant impact on galvanic current. The significant factors affecting total lead release were alkalinity, NOM, disinfectant, alkalinity-inhibitor interaction, NOM-nitrate interaction, NOM-disinfectant interaction, NOM-inhibitor interaction, nitrate-disinfectant interaction and disinfectant-inhibitor interaction.

The EPA Lead and Copper Rule set action limits for lead and copper concentrations in drinking water, but accelerated corrosion of lead in distribution systems due to a galvanic connection to copper. Prior research has demonstrated that the effects of galvanic corrosion can be controlled by water chemistry. This study not only investigated the main effects of alkalinity, natural organic matter (NOM), nitrate, disinfectant and inhibitor to galvanic corrosion, but also the interplay between these factors. A 2-level factorial (2v5-1) design was adopted which resulted in 16 testing conditions. Results of bench-scale experiments using static pipes with lead and copper segments demonstrated that alkalinity, disinfectant, inhibitor and alkalinity-inhibitor interaction had a significant impact on galvanic current. The significant factors affecting total lead release were alkalinity, NOM, disinfectant, alkalinity-inhibitor interaction, NOM-nitrate interaction, NOM-disinfectant interaction, NOM-inhibitor interaction, nitrate-disinfectant interaction and disinfectant-inhibitor interaction.

Controlled release formulations deliver an active ingredient over an extended period of time. It is an ideal dosage form for an active ingredient with a short elimination half-life. An active ingredient with a short elimination half-life would be released in small portions over an extended period of time and thus less frequent administration is necessary and this improve patient compliance. Other advantages of these formulations include: decreased side effects, constant drug levels in the blood, improvement in treatment efficiency and reduction in cost of administration. Controlled release beads are formulated in such a way that the active ingredient is embedded in a matrix of insoluble substance like chitosan; the dissolving drug then has to find its way through the pores of the matrix into the surrounding medium. The chitosan matrix swells to form a gel, the drug then has to first dissolve in the matrix and diffuse through the outer surface into the surrounding medium. Chitosan is a biocompatible, biodegradable polymer of natural origin. It has mucoadhesive properties as well as the ability to manipulate the tight junctions in the epithelium membrane and these properties have qualified chitosan as an effective drug carrier in controlled release dosage forms. The effect of a modern controlled release polymer namely Kollidon® SR in combination with chitosan on drug release was investigated. Ketoprofen was chosen as model drug. Ketoprofen is an anti-inflammatory drug that causes gastrointestinal side effects in conventional dosage forms. Ketoprofen has a short elimination half-life of 2.05 ± 0.58 h and this characteristic makes it an ideal candidate for use in a controlled release formulation. The aim of this study was to achieve controlled release and minimize gastrointestinal effects of ketoprofen with chitosan particles. Kollidon® SR was used as polymer because it exhibits pH independent release characteristics and previous studies have shown potential for this combination. Chitosan beads and chitosan-Kollidon® SR beads, as well as chitosan granules and chitosan-Kollidon® SR granules, were prepared and investigated as potential controlled release formulations. Chitosan beads were prepared through the inotropic gelation method using tripolyphosphate as a cross linking agent. Granules were prepared through wet granulation using 2% v/v acetic acid as the granulating fluid or by dissolving ketoprofen in ethanol and Kollidon® SR in 2-pyrrolidinone and using the solution as granulating fluid. Kollidon® SR was added in concentrations of 0.25, 0.5 and 1% (w/v) in the bead formulations and concentrations of 1, 5 and 10% (w/w) in the granule formulations. The beads and granules were characterised by evaluating the following properties: morphology, drug loading and drug release. Additionally swelling and friability tests were also conducted on the bead formulations. The cross linking times of the bead formulations were varied to investigate the effect of cross linking time on the characteristics of the beads. Chitosan-Kollidon® SR beads showed promising results for controlled release formulations and ketoprofen were released over an extended period of time. Drug loading of the plain chitosan beads was 74.65 ± 0.71% and it was noted that the inclusion of Kollidon® SR in the beads resulted in an increase in drug loading and the formulation containing 1% (w/v) Kollidon® SR, cross linked for 30 minutes had a drug loading of 77.38 ± 0.01%. Drug loading of the beads that were cross linked for a longer time were slightly lower which is an indication that some of the drug might have leached out during cross linking. The degree of swelling was promising with some beads swelling to a degree of 2.5 in phosphate buffer solution pH 5.6. Granules had a drug loading between 81.73 ± 1.53% and 93.30 ± 0.50%. Ketoprofen release from the beads and the granules in PBS pH 7.40 at 37 °C over a period of 6 hours were investigated. The bead formulations were more effective in achieving controlled release and it was noted that the bead formulations that was cross linked for a longer period was more efficient in achieving controlled release. The granules did not form a matrix and were not effective in achieving controlled release. Controlled release of ketoprofen were achieved and the results show potential for chitosan-Kollidon® SR formulations in the future. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

There has been a significant interest in the estimation of time and effort in fixing defects among both software practitioners and researchers over the past two decades. However, most of the focus has been on prediction of time and effort in resolving bugs, or other low level tasks, without much regard to predicting time needed to complete high-level requirements, a critical step in release planning. In this thesis, we describe a mixed-method empirical study on three large IBM projects in which we developed and evaluated a process of training a predictive model constituting a set of 29 features in nine categories in order to predict if whether or not a requirement will be completed within its planned iteration. We conducted feature engineering through iterative interviews with IBM software practitioners as well as analysis of large development and project management repositories of these three projects. Using machine learning techniques, we were able to make predictions on requirement completion time at four different stages of requirement lifetime. Using our industrial partner’s interest in high precision over recall, we then adopted a cost sensitive learning method and maximized precision of predictions (ranging from 0.8 to 0.97) while maintaining an acceptable recall. We also ranked the features based on their relative importance to the optimized predictive model. We show that although satisfying predictions can be made at early stages, even on the first day of requirement creation, performance of predictions improves over time by taking advantage of requirements’ progress data. Furthermore, feature importance ranking results show that although importance of features are highly dependent on project and prediction stage, there are certain features (e.g. requirement creator, time remained to the end of iteration, time since last requirement summary change and number of times requirement has been replanned for a new iteration) that emerge as important across most projects and stages, implying future worthwhile research directions for both researchers and practitioners. / Graduate

Aim: To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). Methods: Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 mu g). Results: Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse events included nausea (9%) and peripheral edema (9%). Conclusion: FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850