No description available.

No description available.

No description available.

No description available.

The objectives of this project encompass the design and development of a drug delivery system to continuously deliver therapeutic agents from the stomach to the proximal region of the intestine. The delivery system designed would have sufficient gastric residence time together with near zero-order release kinetics. The physicochemical properties pertaining to the formulation development of the model drug (alfuzosin HCl) were evaluated. Excipients were selected based on the studies of their physicochemical properties and compatibility with the active ingredient. Gastro-retentive dosage forms have been the topic of interest in recent years as a practical approach in drug deliveries to the upper GI tract or for release prolongation and absorption. These dosage forms are particularly suitable for drugs that have local effects on the gastric mucosa in the stomach. Other candidates include drugs that are likely to be absorbed in the upper small intestine, or drugs that are unstable in basic environment of distal intestine and colon or those with low solubility at elevated pH conditions (i.e. weak bases). To develop a gastro-retentive delivery system the following steps were taken. First, to investigate the possible incompatibility issues between the model drug and excipients to be used for the delivery system. Stability and physicochemical properties of the active agent and its mixture with excipients were studied using analytical techniques such as Raman spectroscopy and Differential scanning calorimetry (DSC). No incompatibility issues were detected. Second, Kollidon SR as a relatively new release-rate controlling polymer was incorporated in the final formulation. For solid dosage form the ability of the final powder mix to flow well during manufacturing and the intrinsic characteristics that make it compressible are critical. The in-depth compaction study of Kollidon SR was assessed with the help of a compaction simulator. The flowability, swelling and erosion behavior together with release-rate retarding properties of Kollidon SR were also assessed. The final oral delivery system was based on Kollidon SR and Polyethylene Oxide (PEO) 303 as a monolithic matrix system. The noneffervescent monolithic matrix was made by direct compression. In vitro evaluation of the designed system released the active content in a near zero manner. The dosage form was bouyant in pH 2.0 acidic buffer with no floatation lag time which minimizes the possibility of early gastric emptying. / Pharmaceutics

Diabetes is a leading cause of death and disability in the United States. Diabetes requires a lifetime medical treatment. Some diabetes drugs could be taken orally, while others require daily injection or inhalation to maximize bioavailability and minimize toxicity. Parenteral delivery is a group of delivery routes which bypass human gastrointestinal track. Among all the parenteral methods, we chose subcutaneous implant based on its fast act and high patient compliance. When using subcutaneous implant, drug release needs to be strictly controlled. There are three major groups of controlled release methods. Solvent controlled system is already used as osmotic implant. Matrix controlled system is used in Zoladex® implant to treat cancer. Membrane controlled systems is widely used in coating tablets, but not that popular as an implant. Based on the research reported by previous scientists, we decided to build a hybrid system using both matrix and membrane control to delivery human insulin and other small molecule drugs. Subcutaneous environment is different from human GI track. It has less tolerance for external materials so many polymers cannot be used. From the FDA safe excipient database, we selected albumin as our primary polymer and gelatin as secondary choice. In our preliminary insulin diffusion study, we successfully found that insulin mixed with albumin provided a slower diffusion rate compared with control. In addition, we added zinc chloride, a metal salt that can precipitate albumin. The insulin diffusion rate is further reduced. The preliminary study proved that matrix control using albumin is definitely feasible and we might add zinc chloride as another factor. In order to fabricate an implant with appropriate size, we use lyophilisation technology to produce uniformly mixed matrix. Apart from albumin and human insulin, we added sucrose as protectant and plasticizer. The fine powder after freeze-dry was pressed as a form of tablet. The tablets were sealed in Falcon® cell culture insert. Cell culture insert provide a cylinder shape and 0.3 cm2 surface area for drug release. Insulin release study provided a zero order kinetics from prototypes with zinc chloride or 0.4 micron pore size membrane. Caffeine was used as a model drug to investigate the releasing mechanism. Three pore size membranes (0.4, 3 and 8 micron) were tested with same formulation. While 0.4 micron prototypes provided the slowest release, 3 micron ones surprisingly released caffeine faster than 8 micron implants. We calculated the porosity with pore size and concluded that the percentage of open area on a membrane is the key point to control caffeine release. 0.4 micron membranes were used for future research. We increased the percentage of albumin in our excipient, and achieved a slower caffeine release. However, the zero order release could only last for 3 days. After we replaced sucrose with gelatin, a 5 day zero order release of caffeine was achieved. With all the results, we proposed our “Three Phase” drug release mechanism controlled by both membrane and matrix. Seven other small molecule drugs were tested using our prototype. Cloudy suspension was observed with slightly soluble drugs. We updated our “Three Phase” drug release mechanism with the influence of drug solubility. Data shows that releasing rate with same formulation and membrane follows the solubility in pH 7.4. This result proves that our prototype might be used for different drugs based on their solubility. Finally, with all the information of our prototype, we decided to build a “smart insulin implant” with dose adjustment. We proposed an electrical controlled implant with different porosity membranes. Solenoid was used as the mechanical arm to control membrane porosity. 3-D printing technology was used to produce the first real prototype of our implant. Finally, insulin implant with clinically effective insulin release rate was achieved. / Pharmaceutical Sciences

Since 1970s, ever growing attention has been devoted by worldwide researchers and practitioners to the investigation of job release control. However, the need for control of flow of job/wafer into the wafer fabrication system is identified in the late 1988s. Subsequently, many release policies are developed and presented in the literature for improving its performance with respect to cycle time and throughput. Even though it is pointed out in the literature that there is a need for the development and analysis of policy that control the flow of job/wafer through the manufacturing process, still there is no exhaustive study in view of the previously developed release policies in the literature. Moreover, many new opportunities have evolved in the field of release policy in wafer fabrication industry due to the advancement in technology and computer science. It implies that near real-time decision making for efficient release policy is possible based on the global factory state. However, it appears from the literature that still to date the release policies, which are employed in real wafer fabrication system, are usually based on the static information. Release control/policy is emerging as an important research topic in the wafer fabrication industry given the extremely large capital investment and sales revenue of this industry. Release policy also hold practical significance for manufacturing managers, since neglecting it can lead to wide variations in shop workloads, can cause excessive backlogs, accomplishment of orders will be either too early or too late and there can be frequent need for expediting. All the challenges associated with the performance of the wafer fabrication system discussed here and the puzzle around the release policies and its impact on the wafer fabrication process, this research attempts to investigate existing release policies and proposing a few efficient release policies based on the knowledge gained from the existing release policies strength and weakness. Based on the insights gained from the existing release policies, three new closed loop release policies constant workload (CONSTWL), constant batch machine workload (CONSTBWL) and layer wise control (LWC) are developed by considering the parameters: workload in general, workload in batch machine, and re-entrant characteristics of the wafer fabrication system respectively. The conceptual significance in favour of these proposed closed loop release policies in improving performance of the wafer fabrication system is also outlined in this study. In the literature, few researchers clearly indicate that dispatching rule(s) influence the performance of wafer fabrication system either independently or in integration with release policies. Therefore, to empirically validate this fact, release policy is integrated with dispatching rule particularly applying on bottleneck (discrete processing machine) work station in this study. With these, the aims of proposed release policies are to efficiently improve the system performances in terms of average cycle time, standard deviation of cycle time and throughput. Accordingly, a simulation model is proposed and developed using Arena software for evaluating the performance of release policies in integration with dispatching rule applied on bottleneck work station in wafer fabrication environment. Further, to set the values of parameters in the simulation model, the cause and effect analysis is explored in this study by considering eight critical parameters or factors of the simulated wafer fabrication environment. It includes arrival rate, arrival distribution, processing time, maintenance schedule, operator’s schedule, batch size, dispatching rule and release policy. Simulation based cause and effect analysis not only helps in setting up the values of parameters in the proposed simulation model, but it also helps in strengthening the face validity of the developed simulation model. The verification and validation of the developed simulation model, which is a vital and fundamental aspect of simulation is discussed in detail in this study. Based on the analysis and the results observed from the cause and effect analysis, some modifications are incorporated and subsequently, the parameters values are set in the proposed simulation model for evaluating the performance of release policies integrating with dispatching rules. A series of simulation experiments are conducted using the proposed simulation model with systems conditions such as product mix, complexity of the process, level of machine unreliability, and system congestion level to study the relative effects of each of 18 release policies (one open loop release policy, 14 existing closed loop release policies, and 3 proposed release policies) in integration with dispatching rules (FIFO, LIFO and SRPT), considered in this study, at various throughput levels in the wafer fabrication environment. Particularly, the relative effect of integrating release policies and the dispatching rules are observed and analysed in terms of (a) the effect of dispatching rule on release policy, and (b) the effects of release policies on dispatching rules. It is observed from the overall inferences that dispatching rule: SRPT outperformed both FIFO and LIFO dispatching rule for all the considered release policies, except for the release policy: ‘TOTAL_CT’. Additionally, it is observed that for each of the eighteen release policies integrated with considered, the dispatching rule: SRPT produces less WIP inventory at the bottleneck work station for all throughput levels. The maximum deviation in delay (cycle time) is produced by dispatching rule: LIFO in all the release policies considered except for the release policy: ‘TOTAL_CT’ in which dispatching rule: SRPT produces maximum deviation in delay. Moreover, it is observed that the difference in mean delay with all three dispatching rules (FIFO, LIFO and SRPT) increases with the increase in throughput levels. Furthermore, it is observed that the throughput rate under all release policies (except ‘TOTAL_CT’) is more for dispatching rule: SRPT in comparison with both dispatching rules: FIFO and LIFO for nearly the same threshold values. The experimental results showed that proposed release policy: LWC reliably improves the system performance followed by the proposed release policy: CONSTWL and CONSTBWL with respect to both mean delay and standard deviation for corresponding throughput levels in wafer fabrication system. The characteristics of the proposed release policy: LWC are summarized and the same is presented as follows because this is proven to be best release policy among all the release policies considered in the proposed simulation model. The proposed release policy: LWC is a new measure of the work quantity on the shop floor system, which takes into account the location of jobs/wafers along the production line by employing re-entrant property of wafer fabrication system. As a result, it offers quick response to the stochastic events of the manufacturing system and can compensated the system disturbances in time. The proposed release policy: LWC offers more efficient control of flow of job/wafer in the wafer fabrication system with reduced delay (cycle time) and the standard deviation of delay (cycle time) for a given throughput level in comparison with almost all the release policies considered in this study in integration with all three dispatching rules considered and applied on bottleneck work station. For instance, from the analysis of simulation model, the proposed release policy: LWC reduces the average delay up to 98%, 95%, 90%, 89%, 49%, 35%, 21%, 17%, 13%, 12%, 10%, 9%, 9%, 9%, 6% and 4%, and reduces the standard deviation of delay up to 96%, 98%, 94%, 93%, 34%, 22%, 4%, 13%, 11%, 6%, 9%, 14%, 4%, 4%, 10% and 7% for a given throughput level, respectively in relation to other release polices: FRCP, EWIP, TOTAL_CT, PWR, EWC, DRCP, CONLOAD, WIPLCtrl, Droll, DEC, CONWIP, SA, RCONWIP, WR, CONSTBWL and CONSTWL respectively in integration with dispatching rule: SRPT. These improvements can also be understood from another aspect, that is, LWC can increase the system throughput rate for a given cycle time. The improvement is statistically significant according to the two sample t-test for all throughput values with a 95% confidence level. As the improvement of the proposed release policy: LWC is relatively less on the proposed release policies: CONSTWL and CONSTBWL with respect to mean delay, it can be inferred that the performance of CONSTWL and CONSTBWL is relatively better than other existing closed loop release policies for the scenarios considered in the simulation model. However, the best release policy: LWC provides satisfactory performance in comparison with other release policies for almost all scenarios considered in the simulation model. It is important to note that these proposed release policies can be easily applied in real wafer manufacturing systems because it possesses a simple logic and only the reference level need to be prescribed. The performance of four existing closed release policies that are FRCP, EWIP, TOTAL_CT and PWR are relatively worst in comparison with open loop release policy CONST. This is contradicting to the conclusions given in the literature by many authors that closed loop release policies are always better than open loop release policy with respect to cycle time and throughput measures. In fact, a reasonable closed loop release policy can provide better results than open loop release policy, if its objective and the release parameter are designed carefully, so that the release parameter can respond effectively to the dynamics of the manufacturing system. The reason for worst performance of these four existing closed loop release policies in comparison with open loop release policy and other existing policies is described in detail in this study. In order to see the impact of dispatching rules on a particular work station, batch machine work station, which usually has highest processing time in fabrication process, is considered in this study. The entire simulation experiments are replicated in the same manner except the basis that dispatching rules are applied on batch machine work station instead of bottleneck work station. Based on the analysis of the simulation results, the important observations are as follow: It is observed from the overall inferences that the influence of dispatching rules when applied to batch processing machine (diffusion) work station was not much on individual release policies, since the performance of all three dispatching rules provides nearly same performance at higher throughput level in the proposed simulation model. However, the performances of dispatching rule: SRPT in integration with all release policies considered in this study are summarized here because it produces less mean delay at most of the throughput values. In addition, from the analysis of simulation model, the proposed release policy: LWC reduces the average delay up to 97%, 93%, 87%, 85%, 22%, 17%, 15%, 15%, 13%, 11%, 10%, 10%, 9%, 6%, 6% and 2%, and reduces the standard deviation of delay up to 96%, 97%, 92%, 93%, 21%, 5%, 10%, 2%, 16%, 7%, 14%, 4%, 20%, 10%, 10% and 11% for a given throughput level, respectively in relation to FRCP, EWIP, PWR, TOTAL_CT, EWC, DEC, Droll, CONLOAD, SA, RCONWIP, WIPLCtrl, WR, DRCP, CONWIP, CONSTWL and CONSTBWL in integration with dispatching rule: SRPT, when applied on batch processing machine work station. The improvement is statistically significant according to the two sample t-test for most of the throughput values with a 95% confidence level. It is observed from overall inferences that the performance of all the release policies, considered in this study, in integration with dispatching rule: SRPT is better with respect to both mean delay and standard deviation of delay, when the dispatching rule is applied on the bottleneck (discrete machine, lithography) work station in the proposed simulation model. The performance of most of the release policies, considered in this study, in integration with dispatching rule: LIFO is better with respect to standard deviation of delay, when the dispatching rule is applied on the batch (batch machine, diffusion) work station. These results indicate that there is an influence of dispatching rule on the performance of wafer fabrication system if applied on batch machine work station or on bottleneck work station in integration with release policies. In addition, the effects of dispatching rules are highly dependent upon both the type of release policy used and the work station on which it is applied. Overall, the performance of the proposed release policies is proven to be very effective to system variability’s in scenarios considered in the simulation model. The significant impact of the choice of release policies on wafer manufacturing system performance is justified by the simulation experiments. It can be safely concluded that the efficient closed loop release policies that utilizes system information carefully based on the global factory state data can significantly improve the performance of wafer fabrication system. This thesis provides an extensive literature review covering several aspects of wafer fabrication process. Thereafter, a three new efficient closed loop release policies are developed and their workability are conceptually demonstrated with a framework and a flow diagram. The strength and the weakness of the existing release policies are conceptually highlighted and later it is proven to be true through comprehensive simulation study. A simulation model is developed by considering all the real-life fabrication environment for evaluating the performance of release policies in integration with dispatching rules. Cause and effect analysis is explored in proposed simulation model to set the parameters value. A series of simulation experiments are also constructed to empirically justify the conceptual significance of the proposed release policies.

Pretrial release (PTR) is the permanent or temporary freedom from incarceration for criminal defendants awaiting adjudication of their cases in court. From Anglo Saxon times in England, people accused of non-capital crimes were generally permitted to remain free until judicial officials could hear the charges against them. In America, pretrial release has been advocated by the courts since the colonial era. The U. S. Constitution requires that bail not be excessive, but leaves governments free to decide how bail laws are administered. The study briefly traces the historical developments of PTR up to the present time. The study then centers on the PTR process of three Oregon counties (Multnomah, Washington, and Yamhill) and observes the decisions of judges, release assistance officers, and jailers in relation to the release outcomes for a study group (N=619) who were booked into jails of the three counties in 1993. Background data on defendants in the study include gender, race, the crimes for which they were arrested, criminal history, and the disposition of the current charges. Seventy-one percent of the defendants received PTR. Significant factors in the release outcome, as shown by logistic and multiple regression analyses, were probation violation status, felony in the current charge, narcotics offenses in the current charge, and charged with multiple offenses. Gender and race were not strong influences on the release outcome. Hispanic defendants (N = 108) in the study, however, were detained in jail longer than Whites (N=394). Hispanics were less likely than Whites to be released on the same day of arrest and served generally longer jail terms than Whites under similar sentences. Possible explanations are that Hispanics were more frequently charged with distributing narcotics and charged with multiple offenses. Implications suggest further studies on minorities in judicial and corrections settings. The study has applications in judicial and corrections policies on the early release of inmates, an important issue as jails become increasingly overcrowded.

In the pharmaceutical industry, it is always important to have reproducible processes and raw materials of high quality to ensure good quality products. AstraZeneca, that is a leading manufacturer of different pharmaceuticals, works according to GMP to make sure that their processes deliver products of the same quality every time. A problem that has occurred at AstraZeneca is when a raw material is not properly understood and variations in the raw material affects the final product. Variations in drug release in one of AstraZeneca´s products, Product X, has been linked to the cushioning excipient Microcrystalline cellulose (MCC). Variations in drug release has been noticed during change from one batch of MCC to another. The aim of this study was to investigate which material attributes of MCC that contributes to variations in the final product. Particle size and moisture content were identified as critical material attributes (CMA´s) and were therefore chosen to be investigated more thoroughly. By variating particle size and moisture content during manufacturing of Product X, the influence of these attributes could be investigated using Design of Experiment (DoE). An additional experiment that compared two MCC batches from different suppliers was also performed during this study. The results from these experiments showed that the particle size and moisture content of MCC does affect the drug release. Large particles and high moisture content gave rise to a faster drug release compared to small particles and low moisture content that gave rise to a slower drug release. It is however hard to draw conclusions regarding how small differences in particle size and moisture content could affect the drug release.

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