Characterization of different hydrophilic polymers and their applicability in hot melt extrusion technology

Research in the pharmaceutical field involves investigation of a new drug, delivery route, a delivery system, a technology to design the delivery system, or a combination thereof. Scientists have explored several delivery routes such as oral, pulmonary, nasal, injection/implant, transdermal/dermal, transmucosal etc. for their potential to transport a variety of small and large drug molecules. In the present research work, oral route, a widely accepted route of administration, for the delivery of products with a major market share, has been considered for the delivery of poorly soluble actives. The use of appropriate carrier matrices (polymers) and excipients help in incorporating these drugs and developing a dosage form/drug delivery system with desired properties. The oral delivery systems are most popular, convenient for administration, and mainly include conventional solid dosage forms such as pellets, tablets, and/ or milled material filled in capsules. Since most of the actives studied under current research have low aqueous solubility, it was necessary to utilize a novel technology such as hot melt extrusion (HME) in combination with hydrophilic polymers to obtain tailored drug release. Over recent years HME technology has found widespread application as a viable drug delivery option in the drug development process. Some of the HME applications include taste masking, solid-state stability enhancement, solubility enhancement etc. Solubility enhancement in the HME process occurs through the dispersion of a poorly soluble drug in a polymeric carrier matrix essentially forming a solid dispersion. While this technology can help in producing amorphous or crystalline solid dispersions depending upon several factors, solubility enhancement applications are centered on generating amorphous dispersions, primarily because of the free energy benefits they offer. Amorphous solid dispersions result when melt extruded drug-polymer is cooled at a rate that does not allow the drug to recrystallize, or processed at temperatures where drug melts but remains immiscible with the carrier. Such processing results in kinetic entrapment of the drug in its amorphous state. These dispersions also provide maximum specific surface area and higher saturation solubility, which ultimately increase drug solubility. Although these types of systems exhibit increased rate of dissolution due to high thermodynamic activity, they have a potential to revert to the more stable crystalline form. Thorough understanding of the physicochemical properties of amorphous solid dispersions and their corresponding in vivo behavior is required for the realization of their true potential in the pharmaceutical industry. In the research projects outlined in this dissertation, the focus has been to characterize the different hydrophilic polymeric extrudates produced utilizing HME technology, and emphasize their pharmaceutical applications. HME, in conjunction with suitable polymers, has been demonstrated as a viable approach to develop a novel pellet dosage form with potential abuse deterrent properties. In addition, its application for solubility enhancement aims at generating amorphous solid dispersions utilizing novel hydrophilic polymers, folloby the in-depth characterization of the produced melt extrudates. Moreover, the effect of various formulation variables and process parameters has also been investigated. This underlying research also facilitates the development of a wide-ranging stable solid oral dosage forms with modulated drug release. The key objectives of the chapters in the dissertation are: (1) To develop an abuse-deterrent (AD) platform technology in the formulation development utilizing HME technique; (2) To investigate the effect of process variables and formulation factors on characteristics of hot melt extrudates containing hydrophilic vinylpyrrolidone/vinyl acetate copolymer (Kollidon® VA 64); (3) To investigate the feasibility of producing stable drug-loaded Soluplus® extrudates utilizing HME technology, and to study the influence of formulation and processing parameters such as drug-load and heating duration, respectively, on the drug-polymer miscibility as well as the release from melt extrudates; (4) To explore the feasibility of producing soluble Soluplus®-Curcumin extrudates utilizing HME technology, including the drug-polymer miscibility studies, and the influence of surfactants on dissolution rate of this poorly water-soluble model drug

A Study of the Structure of Shear Turbulence in Free Surface Flows

Turbulence is a familiar phenomenon which gives rise to complicated problems in many branches of engineering. Hinze has set forth the following definition for turbulence: Turbulent fluid motion is an irregular condition of flow in which the various quantities show a random variation in time pnd space coordinates, so that statistically distinct average values can be discerned. Osborne Reynolds (1894) was the first to introduce the notion of statistical mean values into the study of turbulence. He visualized turbulent flow as the sum of mean and eddying motion. By introducing this sum of mean velocity and fluctuating velocity into the Navier-Stokes equations and with the aid of the continuity equation, he derived equations giving relationships between the various components of the fluctuating velocity. It was soon realized that before any further results could be obtained from a theoretical analysis of Reynold;s equations of motion, a mechanism had to be postulated for the ihteraction of fluctuating v~locity components at different points in the turbulent field. Consequently, three decades after Reynold\u27s: work, phenomenological theories of turbulence, such as the momentum-transfer theory of Prandtl (1926), the vorticity transport theory of Taylor (1932) and the similarity theory of Karman (1930) were introduced. Not only are they based on unrealistic physical models, but they do not furnish any information beyond temporal-mean velocity distribution. A complete theory of turbulence should describe the mechanism of production of turbulence, its convection, diffusion, distribution, and eventual dissipation for any given boundary conditions

Pulmonary Tuberculosis in a Young Pregnant Female: Challenges in Diagnosis and Management

Background. With the world becoming a global village, tuberculosis is no longer limited to endemic areas. Our case emphasizes the impact of immigration on infectious disease epidemiology and challenges associated with diagnosis and treatment in pregnancy. Case. A 21-year-old Hispanic female presented in preterm labor and was found to be hypoxic. Chest X-ray revealed a paratracheal mass which a CT scan confirmed. PPD test was positive. Bronchoalveolar lavage did not reveal acid-fast bacilli and biopsy revealed caseating granulomas. Diagnosis and treatment were challenging due to constraints in radiological investigations, lack of initial evidence of acid-fast bacilli, and toxic profile of medications. Due to her high risk, she was started on antituberculosis regimen. The diagnosis was confirmed on Day 26 when Mycobacterium tuberculosis was isolated by DNA probe. Conclusion. A high index of suspicion is required to recognize the changing face and disease spectrum of tuberculosis and initiate treatment for better outcomes

Investigation of Particulate Matter Size, Concentration and Mass Emissions from Small Handheld 2-Stroke Spark Ignition Engines

Quality of air, change in the climate and exposure of humans to pollutants have become major concerns globally over the past decade. Particulate matter has been linked to many adverse health effects. Internal combustion engines are major source of PM emissions. Knowing the adverse health effects of particulate matter, the regulatory agencies are in the process of introducing strict regulations to limit the quantity of PM emitted by off-road small handheld gasoline engines. Two-stroke small engines typically emit more smoke as they burn oil-gasoline mixture compared to four-stroke engines running on gasoline only. Current regulations in the United States for these engines regulate only HC+NOx and CO emissions. In spite of their contribution to atmospheric pollution and negative health effects, the PM emissions from handheld, two-stroke engines are yet to be regulated. This led to this study of particulate matter emissions from these engines.;The main objective of this study was to measure particulate matter size, concentration and mass distributions from 2-stroke handheld 25cc weed whacker engine and to evaluate the effect of heat treatment on these emissions in removal of volatile fractions. The exhaust sample was heat treated to different temperatures (200 °C, 150 °C, and 100 °C) before measuring the distributions to better understand what fraction of particulate matter is solid or volatile. Tests were performed in Center for Alternate Fuels, Engines and Emissions Laboratory (CAFEE) at West Virginia University. A Scanning Mobility Particle Sizer (SMPS) Model was used for measuring the particle size distribution and concentrations. The engine was operated at two steady-state modes (wide open throttle) WOT and Idle mode. The WOT mode resulted in a count median diameter (CMD) of 14.1nm when heat treated the sample to 200 ºC compared to 32.1nm for sample in CVS whereas the idle mode resulted in CMD of 5.94nm and 31.1nm respectively. This indicated the existence of volatile particles. These Nano-particles are proved to be harmful to health. Results obtained from the data for the sample in CVS and compared to the data for the heat treated samples, show that the influence of volatile fraction on PM size distribution is reduced with increase in sample conditioning temperatures. The density function used for mass distribution calculations by SMPS does not take diameter of the particle into consideration and so these calculations were compared with the mass distribution calculated by using IPSD method or effective particle density method since previous studies indicated that at ultra-low emission levels this method proved to give more precise results. This comparison resulted in a good correlation in the particle mass distribution given by SMPS

Comparison of whole blood and PBMC assays for T-cell functional analysis

BACKGROUND: Tuberculosis remains the foremost cause of morbidity and mortality, more than any other single infectious disease in the world. Cell mediated immune response plays a crucial role in the control of tuberculosis. Therefore, measuring cell mediated immune response against the antigens is having a vital role in understanding the pathogenesis of tuberculosis, which will also help in the diagnosis of and vaccination for tuberculosis. FINDINGS: The aim of the present study was to compare and optimize the assay conditions to measure the cell mediated immune response against M. tuberculosis specific antigens. Because the conventional PBMC assays (due to requirement of large volume of blood sample) are unable to screen more number of antigens within the same blood sample. So, here we have compared 6 days culture supernatants of 1:5 and 1:10 diluted blood and PBMCs from healthy laboratory volunteers, to assess the proliferative response of T lymphocytes and secreted IFN-γ levels against purified recombinant antigen of M. tuberculosis (MPT51, Rv3803c), crude antigens of M. tuberculosis (PPD) and mitogen (PHA). CONCLUSIONS: We have observed good correlation between each assay and also the mean difference of these assays did not reach the statistical significance (p > 0.05). From these results, we conclude that 1:10 diluted whole-blood cultures can be well-suited as an alternative assay to measure cytokine production and lymphocyte proliferation in comparison to the conventional PBMC assays. Moreover, 1:10 diluted blood assays require less volume of blood when compared to PBMC assays which will be useful particularly in paediatric and field studies in endemic countries, where blood volume is a limiting factor

Mortality and sexuality after diagnosis of penile cancer: A participative study

Objectives: Survival for penile cancer is high but treatment can have a long-term detrimental effect on urological function and quality of life. Due to its rarity, it is difficult to include men with penile cancer in research about their condition. The aim of this study was to identify aspects of their diagnosis and treatment that they would want explored in penile cancer research.    Design: The study employed a participative, mixed-qualitative-methods design; it utilised focus groups and patient-conducted interviews, combined into a one-day ‘pilot workshop’. The data were analysed using framework analysis.   Results: ‘Early signs and seeking help’, ‘disclosure of a ‘personal’ cancer’ and ‘urological (dys)function’ emerged as three key themes.   Conclusions: Men with penile cancer want research about their condition to explore early signs and helping seeking, disclosure of a ‘personal’ cancer and urological (dys)function. Research could use methodologies that include consideration of the chronological narrative of the experiences of men with penile cancer, which could be applied in clinical practice by integrating opportunities to explore specific aspects of their experiences at appropriate times along the care pathway

Reengineering Standalone C++ Legacy Systems into the J2EE Partition Distributed Environment

ABSTRACT Many enterprise systems are developed in C++ language and most of them are standalone. Because the standalone software can not follow the new market environment, reengineering the standalone legacy systems into distributed environment becomes a critical problem. Some methods have been proposed on related topics such as design recovery, the identification of the component, modeling the interfaces of components and components allocation. Up to now, there does not exist a reengineering process for partition distributed environment, which will offer distinct advantages on horizontal scalability and performance over normal distributed solutions. This paper presents a new process to reengineer C++ legacy systems into the J2EE partition distributed environment. The process consists of four steps: translation from C++ to Java code; extraction of components using the cluster technology; modeling component interfaces and partition of the components in J2EE distribute environment. It has been applied to a large equity-trading legacy system which has proved to be successful

The construction and evaluation of a device for mechanomyography in anaesthetized Göttingen minipigs

OBJECTIVE: To devise a method for assessing evoked muscle strength on nerve stimulation [mechanomyography (MMG)] in the anaesthetized minipig. STUDY DESIGN: Prospective observational. ANIMALS: Sixty male Göttingen minipigs weighing 10.5–26.0 kg. METHODS: After cadaveric studies, a limb fixation device was constructed which allowed the twitch responses of the pelvic limb digital extensor muscles to be measured by force-displacement transduction in response to supramaximal train-of-four (TOF) stimulation of the common peroneal nerve. The device was tested in 60 minipigs weighing 10.5–26.0 kg positioned in dorsal recumbency. RESULTS: The technique recorded the MMG of the common peroneal-pelvic limb digital extensor nerve-muscle unit for up to 12 hours during which twitch height remained constant in 18 animals in which single twitch duration was <300–500 ms. In 42, in which twitch duration was >300–500 ms, 2 Hz nerve stimulation caused progressive baseline elevation (reverse fade) necessitating a modified signal capture method for TOF ratio (TOFR) computation. However, T1 was unaffected. The mean (range) of the TOFR in pigs with reverse fade was 1.2 (1.1–1.3). CONCLUSIONS AND CLINICAL RELEVANCE: The technique allowed MMG recording in unparalysed pigs in response to TOF nerve stimulation and revealed a hitherto unreported complication of MMG monitoring using TOF in animals: reverse fade. This complicated TOFR calculation