Mechanisms of chemical and physical transdermal penetration enhancement

The underlying theme of this thesis is one of exploring the processes involved in the enhancement of percutaneous absorption. The development of an attenuated total reflectance Fourier-Transform infrared (ATR-FTIR) spectroscopic method to analyse diffusion of suitable topically applied compounds in membrane is described. Diffusion coefficients (D/h2) and membrane solubility (AO) for topically applied compounds were determined using a solution to Fick's second law of diffusion. This method was employed to determine the diffusional characteristics of a model permeant, 4-cyanophenol (CP), across silicone membrane as a function of formulation applied and permeant physicochemical properties. The formulations applied were able to either affect CP diffusivity and/or its membrane solubility in the membrane; such parameters partially correlated with permeant physicochemical properties in each formulation. The interplay during the diffusion process between drug, enhancer and vehicle in stratum corneum (SC) was examined. When enhancers were added to the applied formulations, CP diffusivity and solubility were significantly enhanced when compared to the neat propylene glycol (PG) application. Enhancers did not affect PG diffusivity in SC but enhancers did affect PG solubility in SC. PG diffusion closely resembled that of CP, implying that the respective transport processes were inter-related. Additionally, a synergistic effect, which increases CP diffusivity and membrane solubility in SC, was found to occur between PG and water. Using 12-azidooleic acid (AOA) as an IR active probe for oleic acid, the simultaneous penetration of CP, AOA and PG into human stratum corneum was determined. It was found that the diffusion profiles for all three permeants were similar. This indicated that the diffusion of each species through SC was closely related and most likely occurred via the same route or SC microenvironment.

Investigation of liquid sodium alginates as mucoadhesive bandages coating the oesophageal mucosa and protecting it from gastric reflux

Gastro-oesophageal Reflux Disease (GORD), is generally caused by excess gastric reflux back to the oesophagus where damage to the mucosa results in injury. GORD is a very common disease in western countries, more than a quarter of western people are suffering from this disease and there is a trend that the percentage population in eastern countries who are diagnosed as GORD is increasing. GORD and its complications damage the quality of life and can lead to serious oesophageal diseases including Barrett’s disease and oesophageal carcinoma. Sodium alginate dissolved in water forms a viscous liquid and can coat on oesophageal mucosa for a period of time. In this study the ability of the liquid alginate to adhere to the oesophageal mucosa was investigated and the factors that affect this retention were examined. The potential of this liquid alginate as a drug delivery vehicle to extend the duration of contact with the oesophageal mucosa was confirmed by this study. The capacity of an alginate coating to retard acid and pepsin diffusion, the two main aggressive factors in gastric reflux, was investigated. A significant reduction in acid and pepsin diffusion by alginate gel layer was demonstrated in this project, indicating that alginate has great potential to protect against damage caused by acidic reflux. A novel method was introduced using an independent score system to assess the protection of oesophageal tissue by a coating of liquid alginate using microscopy as a technique. This technique demonstrated that alginate can protect the oesophageal epithelial tissue from the damage caused by gastric acid and pepsin. Many techniques were used in this study. The experimental results suggested that liquid sodium alginate is a very promising candidate in treating local oesophageal diseases through forming a coating on the oesophageal mucosal surface, retarding the diffusion of components of gastric refluxate and thus reducing the contact of these noxious factors with the epithelium and minimising injury.

Acquisition and management of technology in Malaysian companies

This thesis is about the acquisition and diffusion of imported technology. Writers in the field of technology development in developing countries have always recognised that technical progress depends on the diffusion of imported technology and its applications to the provision of products and processes (Rosemberg, 1982). Despite the massive importation of technology by Malaysian companies, little effort has been made to study and understand the diffusion system in local companies. This study analyses: The problems associated with the acquisition of technology, highlighting the technology strategies adopted by the suppliers of technology; the diffusion pattern and key characteristics of the diffusion process; and major factors affecting the diffusion of technology. The policy implications are examined and the framework to manage the diffusion process within the enterprises is suggested. The findings indicated that the diffusion process is not one of passive acceptance but involves systematic efforts to acquire and diffuse the imported technology. A strong system of diffusion in companies had enabled a rapid diffusion of imported technology resulting in higher levels of technical capability. On the other hand, weakness in the company's diffusion system led to limited diffusion and slow technical progress. Characteristics of diffusion system are analysed and discussed extensively. The thesis attempts to develop the idea of `in-house system of diffusion' associated with the acquisition and development of imported technology. It argues for the development ofa stronger theoretical framework on the diffusion and development of technology particularly in countries like Malaysia which relies extensively on the importation of foreign technology.

Steric stabilization and dissolution characteristics of aqueous suspensions of pharmaceutical interest

The adsorption of two qroups of nonionic surface active agents and a series of hiqh molecular weiqht hydrophilic polymer fractions onto a polystyrene latex and a drug substance diloxanide furoate B.P. has been investigated. The presence of pores within the drug surface has been demonstrated and this is shown to increase the adsorption of low molecular weight polymer species. Differences in the maximum amount of polymer adsorbed at both solid-solution interfaces have been ascribed to the different hydrophobicities of the surface as determined by contact angle measurements. Adsorbed layer thicknesses of polymer on polystyrene latex have been determined by three techniques: microelectrophoresis, intensity fluctuation spectroscopy and by viscometric means. These results, in combination with adsorption data, were used to interpret the configuration of the adsorbed polymer molecules at the interface. The type of druq suspension produced on adsorbing the different polymers in the absence of electrostatic stabilization was correlated with theoretical prediuctions of suspension characteristics deduced from potential energy diagrams, The agreement was good for the adsorption of short chain length surfactants, but for the polyvinylalcohols, discrepancies were found between experiment and theory. This was attributed to the inappropriate use of a mean segment density approximation within the adsorbed layer to calculate attractive potentials between particles. A maximum in the redispersibility values for suspensions coated with adsorbed nonylphenylethoxylates was attributed to "partial static stabilization" of the particles in conjunction with the attractive forces operating in the sediment between bare surface patches on neighbouring particles. No significant change in the dissolution of the drug was observed when nonylphenylethoxylates were adsorbed due to desorption upon contact with the dissolution medium. Pluronic F68 and all the polyvinylalcohol fractions caused a reduction in the dissolution rate which is explained by the decreased diffusion of drug' through the adsorbed polymer layer.

Biological barriers to the nasal delivery of peptide drugs

The nasal absorption of larger peptide and protein drugs is generally low. The importance of the mucus layer and enzymic degradation in reducing absorption were investigated. Reversed-phase high-performance liquid chromatographic (HPLC) methods were developed to assay a variety of compounds. Pig gastric mucus (PGM) was selected to investigate the importance of the mucus layer. A method of treating and storing PGM was developed and evaluated which was representative of the gel in vivo. The nature of the mucus barrier was evaluated in vitro with three-compartment diffusion cells and a series of compounds with differing physicochemical properties. Mucus retarded the diffusion of all the compounds with molecular weight and charge exerting a marked effect. Binding to mucus was investigated by a centrifugation method. All of the compounds tested were found to bind to mucus with the exception of the negatively charged molecule benzoic acid. The small peptides did not demonstrate greater binding to mucus than any of the other compounds evaluated. The effect of some absorption enhancers upon the rate of diffusion of tryptophan through mucus was determined in vi tro. At the concentrations employed the enhancers EDTA, N-acetylcysteine and taurodeoxycholic acid exerted no effect, whilst taurocholic acid and cholic acid, were found to slightly reduce the rate of diffusion. The intracellular and luminal proteolytic activity of the nose was investigated in the sheep animal model with a nasal mucosal homogenate and a nasal wash preparation respectively and a series of chemically similar peptides. Hydrolysis was also investigated with the proteolytic enzymes carboxypeptidase A, cytosolic leucine aminopeptidase and microsomal leucine aminopeptidase. Sheep nasal mucosa possesses significant peptide hydrolase activity capable of degrading all the substrates tested. Considerable variation in susceptibility was observed. Degradation occurred excl us i ve ly at the pept ide bond between the aromatic amino ac id and glycine, indicating some specificity for aromatic amino acids. Hydrolysis profiles indicated the presence of both aminopeptidase and carboxypeptidase enzymes. The specific activity of the microsomal fraction was found to be greater than the cytosolic fraction. Hydrolysis in the nasal wash indicated the presence of either luminal or loosely-bound proteases, which can degrade peptide substrates. The same specificity for aromatic amino acids was observed and aminopeptidase activity demonstrated. The specific activity of the nasal wash was smaller than that of the homogenate.

The computerisation of community pharmacy

Computers have, over the past 10 to 15 years, become an integral part of many activities carried out by British community pharmacists. This thesis employs quantitative and qualitative research methods to explore the use of computers and other forms of information technology (IT) in a number of these activities. Mail questionnaires were used to estimate the level of IT use among British community pharmacists in 1989 and 1990. Comparison of the results suggests that the percentage of community pharmacists using computers and other forms of IT is increasing, and that the range of applications to which pharmacy computers are put is expanding. The use of an electronic, on-line information service, PINS, by community pharmacists was investigated using mail questionnaires. The majority of community pharmacists who subscribed to the service, and who responded to the questionnaire, claimed to use PINS less than they had expected to. In addition, most did not find it user-friendly. A computer program to aid pharmacists when responding to their patients' symptoms was investigated using interviews and direct observation. The aid was not found to help pharmacists in responding to patients' symptoms because of impracticalities involved in its operation. Use of the same computer program by members of the public without the involvement of a pharmacist was also studied. In this setting, the program was favourably accepted by the majority of those who used it. Provision of computer generated information leaflets from pharmacies was investigated using mail questionnaires and interviews. The leaflets were found to be popular with the majority of recipients interviewed. Since starting to give out the leaflets, 27 out of 55 pharmacists who responded to the questionnaire had experienced an increase in the numbers of prescriptions they dispensed. 46 had experienced an increase in the number of patient enquiries they received.

Computer aided geometric design of form-rolls for NC manufacture

Conventional methods of form-roll design and manufacture for Cold Roll-Forming of thin-walled metal sections have been entirely manual, time consuming and prone to errors, resulting in inefficiency and high production costs. With the use of computers, lead time can be significantly improved, particularly for those aspects involving routine but tedious human decisions and actions. This thesis describes the development of computer aided tools for producing form-roll designs for NC manufacture in the CAD/CAM environment. The work was undertaken to modernise the existing activity of a company manufacturing thin-walled sections. The investigated areas of the activity, including the design and drafting of the finished section, the flower patterns, the 10 to 1 templates, and the rolls complete with pinch-difference surfaces, side-rolls and extension-contours, have been successfully computerised by software development . Data generated by the developed software can be further processed for roll manufacturing using NC lathes. The software has been specially designed for portability to facilitate its implementation on different computers. The Opening-Radii method of forming was introduced as a subsitute to the conventional method for better forming. Most of the essential aspects in roll design have been successfully incorporated in the software. With computerisation, extensive standardisation in existing roll design practices and the use of more reliable and scientifically-based methods have been achieved. Satisfactory and beneficial results have also been obtained by the company in using the software through a terminal linked to the University by a GPO line. Both lead time and productivity in roll design and manufacture have been significantly improved. It is therefore concluded that computerisation in the design of form-rolls for automation by software development is viable. The work also demonstrated the promising nature of the CAD/CAM approach.

Chloride resistance and durability of cement paste and concrete containing metakaolin

Metakaolin (MK), a calcined clay, was included as a partial cement replacement material, at up to 20% by weight of binder, in cement pastes and concrete, and its influence on the resistance to chloride ingress investigated. Reductions in effective chloride diffusion coefficients through hardened cement paste were obtained for binary blends and by combining OPC, MK and a second cement replacement material of pulverised fuel ash or ground granulated blast furnace slag. Steady state oxygen diffusion measurements through hardened cement pastes measured using an electrochemical cell showed that the interaction between charged species and the pore surfaces is a major factor in determining chloride diffusion rate. Rheology of the binder, particularly at high MK replacement levels, was found to have a dramatic influence on the diffusion performance of cement pastes. It was concluded that plasticising admixtures are essential for adequate dispersion of MK in cement pastes. Chloride concentration profile analysis of the concrete cylinders, exposed to sodium chloride solution for one year, was employed to obtain apparent chloride diffusion coefficients for concrete specimens. MK was found to reduce the depth of chloride penetration into concrete when compared with that of unblended mixes. Corrosion rate and corrosion potential measurements were taken on steel bars embedded in concrete exposed to a saline environment under conditions of cyclic wetting and drying. The initiation time for corrosion was found to be significantly longer for MK blended mixes than for plain OPC systems. The aggregate-paste interfacial zone of MK blended systems was investigated by steady state diffusion of chloride ions through mortar containing glass beads as model aggregate. For the model aggregate specimens tested the work confirmed the hypothesis that properties of the bulk paste are the controlling factors in ionic diffusion through mortar.

Corrosion inhibitors for the rehabilitation of reinforced concrete

Four corrosion inhibitors namely sodium nitrite, sodium monofluorophosphate, ethanolamine and an alkanolamine-based mixture were studied by immersing mild steel bars for 42 days in model electrolytes of varied pH and chloride concentration which were intended to simulate the pore solution phase present within carbonated and/or chloride-contaminated concrete. Site trials were carried out on sodium monofluorophosphate and the alkanolamine-based inhibitor to study their depth of penetration into concrete. The influence of various carbonating atmospheres on the pore solution chemistry and microstructure of hydrated cement paste was investigated. Physical realkalisation of carbonated cement paste and a calcium nitrite-based corrosion rehabilitation system for chloride-contaminated cement paste were investigated by monitoring ionic transport within the pore solution phase of laboratory specimens. The main findings were as follows: 1,Sodium nitrite, sodium monofluorophosphate, ethanolamine and the alkanolamine-based mixture all behaved as passivating anodic inhibitors of steel corrosion in air-saturated aqueous solutions of varied pH and chloride concentration. 2,Sodium monofluorophosphate failed to penetrate significantly into partially carbonated site concrete when applied as recommended by the supplier. Phosphate and fluoride penetrated 5mm into partially carbonated site concrete treated with sodium monofluorophosphate. 3,The ethanolamine component of the alkanolamine-based inhibitor was found to have penetrated significant depths into partially carbonated site concrete. 4,Carbonating hydrated cement paste over saturated solutions of sodium nitrite resulted in significant concentrations of nitrite in the pore solution of the carbonated paste. Saturated solutions of sodium chloride, ammonium nitrate, magnesium nitrate and sodium dichromate were investigated and identified as alternatives for controlling the relative humidity of the carbonating environment. 5,Hardened carbonated cement paste can by physically realkalised to a limited extent due to the diffusion of hydroxyl ions under saturated conditions. A substantial proportion of the hydroxyl ions that diffused into the carbonated cement paste however, became bound into the cement matrix. Hydroxyl ion concentrations remained below 5mmol/l within the pore solution of the realkalised cement paste. 6, Nitrite ions penetrated significant distances by diffusion within the pore solution of saturated uncarbonated hydrated cement paste.

The pore system and engineering properties of hardened cement paste

The work described in this thesis is an attempt to elucidate the relationships between the pore system and a number of engineering properties of hardened cement paste, particularly tensile strength and resistances to carbonation and ionic penetration. By examining aspects such as the rate of carbonisation, the pore size distribution, the concentration of ions in the pore solution and the phase composition of cement pastes, relationships between the pore system (pores and pore solution) and the resistance to carbonation were investigated. The study was carried out in two parts. First, cement pastes with different pore systems were compared, whilst secondly comparisons were made between the pore systems of cement pastes with different degrees of carbonation. Relationships between the pore structure and ionic penetration were studied by comparing kinetic data relating to the diffusion of various ions in cement pastes with different pore systems. Diffusion coefficients and activation energies for the diffusion process of Cl- and Na+ ions in carbonated and non-carbonated cement pastes were determined by a quasi-steady state technique. The effect of the geometry of pores on ionic diffusion was studied by comparing the mechanisms of ionic diffusion for ions with different radii. In order to investigate the possible relationship between tensile strength and macroporosity, cement paste specimens with cross sectional areas less than 1mm2 were produced so that the chance of a macropore existing within them was low. The tensile strengths of such specimens were then compared with those of larger specimens.

Ionic and molecular diffusion in cementitious materials

The work described in this thesis is an attempt to provide improved understanding of the effects of several factors affecting diffusion in hydrated cement pastes and to aid the prediction of ionic diffusion processes in cement-based materials. Effect of pore structure on diffusion was examined by means of comparative diffusion studies of quaternary ammonium ions with different ionic radii. Diffusivities of these ions in hydrated pastes of ordinary portland cement with or without addition of fly ash were determined by a quasi-steady state technique. The restriction of the pore geometry on diffusion was evaluated from the change of diffusivity in response to the change of ionic radius. The pastes were prepared at three water-cement ratios, 0.35, 0.50 and 0.65. Attempts were made to study the effect of surface charge or the electrochemical double layer at the pore/solution interface on ionic diffusion. An approach was to evaluate the zeta potentials of hydrated cement pastes through streaming potential measurements. Another approach was the comparative studies of the diffusion kinetics of chloride and dissolved oxygen in hydrated pastes of ordinary portland cement with addition of 0 and 20% fly ash. An electrochemical technique for the determination of oxygen diffusivity was also developed. Non-steady state diffusion of sodium potassium, chloride and hydroxyl ions in hydrated ordinary portland cement paste of water-cement ratio 0.5 was studied with the aid of computer-modelling. The kinetics of both diffusion and ionic binding were considered for the characterization of the concentration profiles by Fick's first and second laws. The effect of the electrostatic interactions between ions on the overall diffusion rates was also considered. A general model concerning the prediction of ionic diffusion processes in cement-based materials has been proposed.

Pore structure and diffusional properties of hardened cement pastes

This study has investigated the inclusion of pulverised fuel ash (PFA) and blast furnace slag (BFS) into hardened cement pastes (HCP) in retarding the ingress of chloride ions and oxygen molecules from the external environment. The influence of environmental factors such as drying and carbonation on the pore structure and diffusional properties of OPC, OPC/30%PFA and OPC/65%BFS hardened pastes was investigated. Specimens were desorbed from a saturated surface dry condition to a near constant weight at 65% relative humidity (RH) while others were simultaneously exposed to a 65% RH atmosphere and a carbon dioxide atmosphere of up to 5% by volume until there were fully carbonated. The presence of the interfacial zone at the cement paste-aggregate interface was critically reviewed and identified. The influence of the interfacial zone on porosity and chloride ingress in assumed periodic composites of glass bead mortars was also studied. The investigations have demonstrated the following: (a) The use of fly ash and slag in blended cement pastes has resulted in a marked reduction in capillary porosity and rate of chloride ingress. (b) The ratio of oxygen to chloride diffusion coefficients increased from values close to 1 in permeable pastes, to values of around 15 in low-permeability blended fly ash and slag pastes. This supports the view that the diffusion of chloride ions is retarded by the surface charge of the hydrated cement gel in low-permeability pastes. (c) Compared with plain OPC pastes, the carbonation of blended fly ash and slag pastes resulted in a marked increase in the coarse capillary porosity and a corresponding increase in the oxygen and chloride diffusion rates.

Properties and performance of polymer modified cements and mortars

Polymer modified cements and mortars have become popular for use as patch repair materials. General evidence suggests that these materials offer considerable improvements compared to traditional mortars although the mechanisms for this are not fully understood. This work elucidates the factors which govern some properties and performance of different polymer systems. In view of the wide range of commercial systems available, investigations concentrated on the use of three of the most commonly available groups of polymers. These were: (1) Styrene Butadiene Rubber (SBR), (2) Acrylics and, (3) Ethylene Vinyl Acetates (EVA). The later two were in the form of both emulsions and redispersible powders. Experiments concentrated on: (1) Rheological behaviour of polymer modified cement pastes; (2) Workability of polymer modified mortars; (3) Influence of curing conditions on the pore size distribution and diffusion of chloride ions; (4) Bond strength of polymer modified cement and mortar patches; and (5) Microscopic examination and semi-quantitative analyses of the bulk and interfacial microstructures. The following main conclusions were reached: (1) The addition of polymer emulsions have a considerable influence on the workability of fresh cement pastes, the extent of this depending on the type of system used. (2) The rheological parameters of fresh polymer modified mortars can be established using a two-point workability test which may be used when comparing the properties of different systems at constant workability. (3) Curing conditions affect the properties of polymer modified systems and a wet/dry curing regime was essential for good adhesion of these materials to mortar substrates. (4) In contrast, the wet/dry curing regime resulted in a curing affected zone at the surface of patch materials. This can result in a much coarser pore structure and enhanced diffusion of e.g. chloride ions. (5) The microstructure of polymer modified systems was very different compared with the unmodified cement/mortar and varied depending on curing conditions.

Corrosion and passivation of steel in concrete

A study of several chemical and electrochemical factors which affect the behaviour of embedded steel in cement pastes and concrete has been made. The effects of internal and external sources of chloride ions on the pore solution chemistry of Portland cement pastes, with and without additions of anodic corrosion inhibitors, have been studied using a pore solution expression device which has enabled samples of pore solution to be expressed from hardened cement pastes and analysed for various ionic species. Samples of pure alite and tricalcium aluminate have been prepared and characterised with respect to morphology, free lime content and fineness. Kinetics of diffusion of chloride ions in hardened pastes of alite and alite blended with tricalcium aluminate have been investigated and an activation energy obtained for the diffusion process in alite. The pore structures of the hardened pastes and the chloride ion binding capacity of alite have also been determined. Concrete cylinders containing embedded steel with four different surface conditions were exposed to various environments. The electrochemical behaviour of the steel was monitored during the period of exposure by means of rest potential measurements and the steel corrosion products analysed before and after being embedded. An examination was made of the nature of the interfacial zones produced between the embedded steel and cement. Rest potential measurements were monitored for steel embedded in alite paste in the presence of chloride ions and cement paste containing various levels of inhibitors in combination with chloride ions. In the latter case the results were supported by polarisation resistance determinations.

Surfactant-free purification of membrane proteins with intact native membrane environment

In order to study the structure and function of a protein, it is generally required that the protein in question is purified away from all others. For soluble proteins, this process is greatly aided by the lack of any restriction on the free and independent diffusion of individual protein particles in three dimensions. This is not the case for membrane proteins, as the membrane itself forms a continuum that joins the proteins within the membrane with one another. It is therefore essential that the membrane is disrupted in order to allow separation and hence purification of membrane proteins. In the present review, we examine recent advances in the methods employed to separate membrane proteins before purification. These approaches move away from solubilization methods based on the use of small surfactants, which have been shown to suffer from significant practical problems. Instead, the present review focuses on methods that stem from the field of nanotechnology and use a range of reagents that fragment the membrane into nanometre-scale particles containing the protein complete with the local membrane environment. In particular, we examine a method employing the amphipathic polymer poly(styrene-co-maleic acid), which is able to reversibly encapsulate the membrane protein in a 10 nm disc-like structure ideally suited to purification and further biochemical study.