Application of mesoporous silica for the oral delivery of poorly water-soluble drugs

The objective of this thesis was to improve the dissolution rate of the poorly waters-soluble drug, fenofibrate by processing it with a high surface area carrier, mesoporous silica. The subsequent properties of the drug – silica composite were studied in terms of drug distribution within the silica matrix, solid state and release properties. Prior to commencing any experimental work, the properties of unprocessed mesoporous silica and fenofibrate were characterised (chapter 3), this allowed for comparison with the processed samples studied in later chapters. Fenofibrate was a highly stable, crystalline drug that did not adsorb moisture, even under long term accelerated storage conditions. It maintained its crystallinity even after SC-CO2 processing. Its dissolution rate was limited and dependent on the characteristics of the particular in vitro media studied. Mesoporous silica had a large surface area and mesopore volume and readily picked up moisture when stored under long term accelerated storage conditions (75% RH, 40 oC). It maintained its mesopore character after SC-CO2 processing. A variety of methods were employed to process fenofibrate with mesoporous silica including physical mixing, melt method, solvent impregnation and novel methods such as liquid and supercritical carbon dioxide (SC-CO2) (chapter 4). It was found that it was important to break down the fenofibrate particulate structure to a molecular state to enable drug molecules enter into the silica mesopores. While all processing methods led to some increase in fenofibrate release properties; the impregnation, liquid and SC-CO2 methods produced the most rapid release rates. SC-CO2 processing was further studied with a view to optimising the processing parameters to achieve the highest drug-loading efficiency possible (chapter 5). In this thesis, it was that SC-CO2 processing pressure had a bearing on drug-loading efficiency. Neither pressure, duration or depressurisation rate affected drug solid state or release properties. The amount of drug that could be loaded onto to the mesoporous silica successfully was also investigated at different ratios of drug mass to silica surface area under constant SC-CO2 conditions; as the drug – silica ratio increased, the drug-loading efficiency decreased, while there was no effect on drug solid state or release properties. The influence of the number of drug-loading steps was investigated (chapter 6) with a view to increasing the drug-loading efficiency. This multiple step approach did not yield an increase in drug-loading efficiency compared to the single step approach. It was also an objective in this chapter to understand how much drug could be loaded into silica mesopores; a method based on the known volume of the mesopores and true density of drug was investigated. However, this approach led to serious repercussions in terms of the subsequent solid state nature of the drug and its release performance; there was significant drug crystallinity and reduced release extent. The impact of in vitro release media on fenofibrate release was also studied (chapter 6). Here it was seen that media containing HCl led to reduced drug release over time compared to equivalent media not containing HCl. The key findings of this thesis are discussed in chapter 7 and included: 1. Drug – silica processing method strongly influenced drug distribution within the silica matrix, drug solid state and release. 2. The silica surface area and mesopore volume also influenced how much drug could be loaded. It was shown that SC-CO2 processing variables such as processing pressure (13.79 – 41.37 MPa), duration time (4 – 24 h) and depressurisation rate (rapid or controlled) did not influence the drug distribution within the SBA- 15 matrix, drug solid state form or release. Possible avenues of research to be considered going forward include the development and application of high resolution imaging techniques to visualise drug molecules within the silica mesopores. Also, the issues surrounding SBA-15 usage in a pharmaceutical manufacturing environment should be addressed.

Water exchange rates of water-soluble manganese(III) porphyrins of therapeutical potential.

The activation parameters and the rate constants of the water-exchange reactions of Mn(III)TE-2-PyP(5+) (meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin) as cationic, Mn(III)TnHex-2-PyP(5+) (meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin) as sterically shielded cationic, and Mn(III)TSPP(3-) (meso-tetrakis(4-sulfonatophenyl)porphyrin) as anionic manganese(iii) porphyrins were determined from the temperature dependence of (17)O NMR relaxation rates. The rate constants at 298 K were obtained as 4.12 x 10(6) s(-1), 5.73 x 10(6) s(-1), and 2.74 x 10(7) s(-1), respectively. On the basis of the determined entropies of activation, an interchange-dissociative mechanism (I(d)) was proposed for the cationic complexes (DeltaS(double dagger) = approximately 0 J mol(-1) K(-1)) whereas a limiting dissociative mechanism (D) was proposed for Mn(III)TSPP(3-) complex (DeltaS(double dagger) = +79 J mol(-1) K(-1)). The obtained water exchange rate of Mn(III)TSPP(3-) corresponded well to the previously assumed value used by Koenig et al. (S. H. Koenig, R. D. Brown and M. Spiller, Magn. Reson. Med., 1987, 4, 52-260) to simulate the (1)H NMRD curves, therefore the measured value supports the theory developed for explaining the anomalous relaxivity of Mn(III)TSPP(3-) complex. A magnitude of the obtained water-exchange rate constants further confirms the suggested inner sphere electron transfer mechanism for the reactions of the two positively charged Mn(iii) porphyrins with the various biologically important oxygen and nitrogen reactive species. Due to the high biological and clinical relevance of the reactions that occur at the metal site of the studied Mn(iii) porphyrins, the determination of water exchange rates advanced our insight into their efficacy and mechanism of action, and in turn should impact their further development for both diagnostic (imaging) and therapeutic purposes.

Fiber-optic interferometric two-dimensional scattering-measurement system.

We present a fiber-optic interferometric system for measuring depth-resolved scattering in two angular dimensions using Fourier-domain low-coherence interferometry. The system is a unique hybrid of the Michelson and Sagnac interferometer topologies. The collection arm of the interferometer is scanned in two dimensions to detect angular scattering from the sample, which can then be analyzed to determine the structure of the scatterers. A key feature of the system is the full control of polarization of both the illumination and the collection fields, allowing for polarization-sensitive detection, which is essential for two-dimensional angular measurements. System performance is demonstrated using a double-layer microsphere phantom. Experimental data from samples with different sizes and acquired with different polarizations show excellent agreement with Mie theory, producing structural measurements with subwavelength accuracy.

Fiber type-specific nitric oxide protects oxidative myofibers against cachectic stimuli.

Oxidative skeletal muscles are more resistant than glycolytic muscles to cachexia caused by chronic heart failure and other chronic diseases. The molecular mechanism for the protection associated with oxidative phenotype remains elusive. We hypothesized that differences in reactive oxygen species (ROS) and nitric oxide (NO) determine the fiber type susceptibility. Here, we show that intraperitoneal injection of endotoxin (lipopolysaccharide, LPS) in mice resulted in higher level of ROS and greater expression of muscle-specific E3 ubiqitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle RING finger-1 (MuRF1), in glycolytic white vastus lateralis muscle than in oxidative soleus muscle. By contrast, NO production, inducible NO synthase (iNos) and antioxidant gene expression were greatly enhanced in oxidative, but not in glycolytic muscles, suggesting that NO mediates protection against muscle wasting. NO donors enhanced iNos and antioxidant gene expression and blocked cytokine/endotoxin-induced MAFbx/atrogin-1 expression in cultured myoblasts and in skeletal muscle in vivo. Our studies reveal a novel protective mechanism in oxidative myofibers mediated by enhanced iNos and antioxidant gene expression and suggest a significant value of enhanced NO signaling as a new therapeutic strategy for cachexia.

FSBS resonances observed in a standard highly nonlinear fiber.

Forward stimulated Brillouin scattering (FSBS) is observed in a standard 2-km-long highly nonlinear fiber. The frequency of FSBS arising from multiple radially guided acoustic resonances is observed up to gigahertz frequencies. The tight confinement of the light and acoustic field enhances the interaction and results in a large gain coefficient of 34.7 W(-1) at a frequency of 933.8 MHz. We also find that the profile on the anti-Stokes side of the pump beam have lineshapes that are asymmetric, which we show is due to the interference between FSBS and the optical Kerr effect. The measured FSBS resonance linewidths are found to increase linearly with the acoustic frequency. Based on this scaling, we conclude that dominant contribution to the linewidth is from surface damping due to the fiber jacket and structural nonuniformities along the fiber.

Portable, Fiber-Based, Diffuse Reflection Spectroscopy (DRS) Systems for Estimating Tissue Optical Properties.

Steady-state diffuse reflection spectroscopy is a well-studied optical technique that can provide a noninvasive and quantitative method for characterizing the absorption and scattering properties of biological tissues. Here, we compare three fiber-based diffuse reflection spectroscopy systems that were assembled to create a light-weight, portable, and robust optical spectrometer that could be easily translated for repeated and reliable use in mobile settings. The three systems were built using a broadband light source and a compact, commercially available spectrograph. We tested two different light sources and two spectrographs (manufactured by two different vendors). The assembled systems were characterized by their signal-to-noise ratios, the source-intensity drifts, and detector linearity. We quantified the performance of these instruments in extracting optical properties from diffuse reflectance spectra in tissue-mimicking liquid phantoms with well-controlled optical absorption and scattering coefficients. We show that all assembled systems were able to extract the optical absorption and scattering properties with errors less than 10%, while providing greater than ten-fold decrease in footprint and cost (relative to a previously well-characterized and widely used commercial system). Finally, we demonstrate the use of these small systems to measure optical biomarkers in vivo in a small-animal model cancer therapy study. We show that optical measurements from the simple portable system provide estimates of tumor oxygen saturation similar to those detected using the commercial system in murine tumor models of head and neck cancer.

Calibrating single-ended fiber-optic Raman spectra distributed temperature sensing data.

Hydrologic research is a very demanding application of fiber-optic distributed temperature sensing (DTS) in terms of precision, accuracy and calibration. The physics behind the most frequently used DTS instruments are considered as they apply to four calibration methods for single-ended DTS installations. The new methods presented are more accurate than the instrument-calibrated data, achieving accuracies on the order of tenths of a degree root mean square error (RMSE) and mean bias. Effects of localized non-uniformities that violate the assumptions of single-ended calibration data are explored and quantified. Experimental design considerations such as selection of integration times or selection of the length of the reference sections are discussed, and the impacts of these considerations on calibrated temperatures are explored in two case studies.

Plantar Loading During Cutting While Wearing a Rigid Carbon Fiber Insert.

Context : Stress fractures are one of the most common injuries in sports, accounting for approximately 10% of all overuse injuries. Treatment of fifth metatarsal stress fractures involves both surgical and nonsurgical interventions. Fifth metatarsal stress fractures are difficult to treat because of the risks of delayed union, nonunion, and recurrent injuries. Most of these injuries occur during agility tasks, such as those performed in soccer, basketball, and lacrosse. Objective : To examine the effect of a rigid carbon graphite footplate on plantar loading during 2 agility tasks. Design :  Crossover study. Setting : Laboratory. Patients or Other Participants : A total of 19 recreational male athletes with no history of lower extremity injury in the past 6 months and no previous metatarsal stress fractures were tested. Main Outcome Measure(s) :  Seven 45° side-cut and crossover-cut tasks were completed in a shoe with or without a full-length rigid carbon plate. Testing order between the shoe conditions and the 2 cutting tasks was randomized. Plantar-loading data were recorded using instrumented insoles. Peak pressure, maximum force, force-time integral, and contact area beneath the total foot, the medial and lateral midfoot, and the medial, middle, and lateral forefoot were analyzed. A series of paired t tests was used to examine differences between the footwear conditions (carbon graphite footplate, shod) for both cutting tasks independently (α = .05). Results : During the side-cut task, the footplate increased total foot and lateral midfoot peak pressures while decreasing contact area and lateral midfoot force-time integral. During the crossover-cut task, the footplate increased total foot and lateral midfoot peak pressure and lateral forefoot force-time integral while decreasing total and lateral forefoot contact area. Conclusions : Although a rigid carbon graphite footplate altered some aspects of the plantar- pressure profile during cutting in uninjured participants, it was ineffective in reducing plantar loading beneath the fifth metatarsal.

Un antigène soluble du virus de la mosaïque du tabac

SCOPUS: ar.j

White-Light Supercontinuum Generation with 60-ps Pump Pulses in a Photonic Crystal Fiber

The generation of a spatially single-mode white-light supercontinuum has been observed in a photonic crystal fiber pumped with 60-ps pulses of subkilowatt peak power. The spectral broadening is identified as being due to the combined action of stimulated Raman scattering and parametric four-wave-mixing generation, with a negligible contribution from the self-phase modulation of the pump pulses. The experimental results are in good agreement with detailed numerical simulations. These findings demonstrate that ultrafast femtosecond pulses are not needed for efficient supercontinuum generation in photonic crystal fibers. © 2001 Optical Society of America.

Fundamental limits to few-cycle pulse generation from compression of broadband supercontinua generated in photonic crystal fiber

The compression properties of octave-spanning supercontinuum spectra generated in photonic crystal fibers are studied using stochastic nonlinear Schrödinger equation simulations. The conditions under which sub-5 fs pulses can be obtained after compression are identified. © 2004 Optical Society of America.

Experimental Studies of the Coherence of Microstructure-Fiber Supercontinuum

The phase coherence of supercontinuum generation in microstructure fiber is quantified by performing a Young's type interference experiment between independently generated supercontinua from two separate fiber segments. Analysis of the resulting interferogram yields the wavelength dependence of the magnitude of the mutual degree of coherence, and a comparison of experimental results with numerical simulations suggests that the primary source of coherence degradation is the technical noise-induced fluctuations in the injected peak power. © 2003 Optical Society of America.

Cross-correlation frequency resolved optical gating analysis of broadband continuum generation in photonic crystal fiber: Simulations and experiments

Numerical simulations are used to study the temporal and spectral characteristics of broadband supercontinua generated in photonic crystal fiber. In particular, the simulations are used to follow the evolution with propagation distance of the temporal intensity, the spectrum, and the cross-correlation frequency resolved optical gating (XFROG) trace. The simulations allow several important physical processes responsible for supercontinuum generation to be identified and, moreover, illustrate how the XFROG trace provides an intuitive means of interpreting correlated temporal and spectral features of the supercontinuum. Good qualitative agreement with preliminary XFROG measurements is observed. © 2002 Optical Society of America.

Measurements and simulations of noise imposed on supercontinuum generated in microstructure fiber

We present experimental and theoretical investigations of the highly nonlinear and broadband noise that exists on supercontinuum spectra generated from launching femtosecond Ti:Sapphire pulses into microstructure fiber.

Amplitude noise on supercontinuum generated in microstructure fiber: Measurements and simulations

Supercontinua generated in microstructure fiber can exhibit significant excess amplitude noise. We present experimental and numerical studies of the origins of this excess noise and its dependence on the input laser pulse parameters.