A novel concentration dependent amino acid ion pair strategy to mediate drug permeation using indomethacin as a model insoluble drug

Assessment of oral drug bioavailability is an important parameter for new chemical entities (NCEs) in drug development cycle. After evaluating the pharmacological response of these new molecules, the following critical stage is to investigate their in vitro permeability. Despite the great success achieved by prodrugs, covalent linking the drug molecule with a hydrophobic moiety might result in a new entity that might be toxic or ineffective. Therefore, an alternative that would improve the drug uptake without affecting the efficacy of the drug molecule would be advantageous. The aim of the current study is to investigate the effect of ion-pairing on the permeability profile of a model drug: indomethacin (IND) to understand the mechanism behind the permeability improvement across Caco-2 monolayers. Arginine and lysine formed ion-pairs with IND at various molar ratios 1:1, 1:2, 1:4 and 1:8 as reflected by the double reciprocal graphs. The partitioning capacities of the IND were evaluated using octanol/water partitioning studies and the apparent permeabilities (P app) were measured across Caco-2 monolayers for the different formulations. Partitioning studies reflected the high hydrophobicity of IND (Log P = 3) which dropped upon increasing the concentrations of arginine/lysine in the ion pairs. Nevertheless, the prepared ion pairs improved IND permeability especially after 60 min of the start of the experiment. Coupling partitioning and permeability results suggest a decrease in the passive transcellular uptake due to the drop in IND portioning capacities and a possible involvement of active carriers. Future work will investigate which transport gene might be involved in the absorption of the ion paired formulations using molecular biology technologies. © 2014 Elsevier B.V. All rights reserved.

Accounting and the 'insoluble' problem of health care costs

Health service accounting reforms are frequently promoted, explained or justified with reference to ageing populations, expensive medical technologies and their purported implications for the cost of health care. Drawing on Foucault’s genealogical method, we examine the emergence of concerns regarding health expenditure in the wake of the creation of the British National Health Service in 1948, and their relationship with health service accounting practices. We argue that concerns regarding the cost of health care are historically contingent rather than inescapable consequences of demographic and technological change, and that health service accounting practices are both constitutive and reflective of such concerns. We conclude by relating our analysis to current attempts to control costs and increase efficiency in the health services.

Modelling the growth of prion protein aggregates in the brain in variant Creutzfeldt-Jakob disease

Deposition of insoluble prion protein (PrP) in the brain in the form of protein aggregates or deposits is characteristic of the ‘transmissible spongiform encephalopathies’ (TSEs). Understanding the growth and development of these PrP aggregates is important both in attempting to the elucidate of the pathogenesis of prion disease and in the development of treatments designed to prevent or inhibit the spread of prion pathology within the brain. Aggregation and disaggregation of proteins and the diffusion of substances into the developing aggregates (surface diffusion) are important factors in the development of protein aggregates. Mathematical models suggest that if aggregation/disaggregation or surface diffusion is the predominant factor, the size frequency distribution of the resulting protein aggregates in the brain should be described by either a power-law or a log-normal model respectively. This study tested this hypothesis for two different types of PrP deposit, viz., the diffuse and florid-type PrP deposits in patients with variant Creutzfeldt-Jakob disease (vCJD). The size distributions of the florid and diffuse plaques were fitted by a power-law function in 100% and 42% of brain areas studied respectively. By contrast, the size distributions of both types of plaque deviated significantly from a log-normal model in all brain areas. Hence, protein aggregation and disaggregation may be the predominant factor in the development of the florid plaques. A more complex combination of factors appears to be involved in the pathogenesis of the diffuse plaques. These results may be useful in the design of treatments to inhibit the development of protein aggregates in vCJD.

Aluminium administered in drinking water but not in the diet influences biopterin metabolism in the rodent

To investigate the neurotoxic effects of aluminium (Al) Al was administered: 1) in the diet of the rat (30 mg Al/kg body weight for 6 weeks); 2) as a suspension of aluminium acetate in drinking water of the rat for 3 months and 3) in a long-term study in the mouse in which aluminosilicates were incorporated into a pelleted diet (1035 mg/kg of food over 23 months). In the latter treatment, increased Al was combined with a reduction in calcium and magnesium; a treatment designed to increase absorption of Al into the body. Administration of Al in the drinking water significantly reduced total brain biopterins and BH4 synthesis. However, no significant affect of Al in the diet on total biopterins or BH4 synthesis was found either in the rat or in the long-term study in the mouse. In addition, in the mouse no significant effects of the Al diet on levels of noradrenaline, serotonin, dopamine, 5-HIAA or CAT could be demonstrated. Hence, the occurrence of brain alterations may depend on the Al species present and the method of administration. Al salts in drinking water may increase brain tissue levels compared with the administration of a more insoluble species. Since alterations in biopterin metabolism are also a feature of Alzheimer's disease (AD) these results support the hypothesis that Al in the water supply may be a factor in AD.

The influence of excipients on the diffusion of ibuprofen and paracetamol in gastric mucus

The aim of this study was to examine the diffusion of commonly administered analgesics, ibuprofen and paracetamol, through gastric mucus. As ibuprofen and paracetamol are often formulated with alkalising excipients, or are commonly co-administered with antacids that have been demonstrated to alter their absorption, diffusion was also studied in the presence of a range of soluble and insoluble antacids or buffering agents. The effect of pH, which has been demonstrated to modify the properties of mucus, was also studied. Mucus was a significant barrier to diffusion for both drugs, compared to an unstirred aqueous layer with diffusion rates significantly lower in the presence of a mucus barrier for both drugs; ibuprofen diffusion also demonstrated a significant increase in the lag time. Paracetamol diffusion was not significantly affected by addition of any antacid, whereas ibuprofen rates were affected and the diffusion lag time for ibuprofen was significantly reduced in all cases. Isolated increases in pH increased the rate and reduced the lag time for ibuprofen diffusion. It was shown that mucus acts as a passive barrier in the case of paracetamol diffusion, and an interactive barrier to ibuprofen diffusion. Changes in mucus viscosity at different pH values may be responsible for the observed changes in ibuprofen diffusion rate. © 2004 Elsevier B.V. All rights reserved.

The role of tissue transglutaminase in 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in differentiated human SH-SY5Y neuroblastoma cells

Tissue transglutaminase (TG2) can induce post-translational modification of proteins, resulting in protein cross-linking or incorporation of polyamines into substrates, and can also function as a signal transducing G protein. The role of TG2 in the formation of insoluble cross-links has led to its implication in some neurodegenerative conditions. Exposure of pre-differentiated SH-SY5Y cells to the Parkinsonian neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) resulted in significant dose-dependent reductions in TG2 protein levels, measured by probing Western blots with a TG2-specific antibody. Transglutaminase (TG) transamidating activity, on the other hand, monitored by incorporation of a polyamine pseudo-substrate into cellular proteins, was increased. Inhibitors of TG (putrescine) and TG2 (R283) exacerbated MPP+ toxicity, suggesting that activation of TG2 may promote a survival response in this toxicity paradigm.

Modelling growth of prion protein aggregates in the brain in variant Creutzfeldt-Jakob disease

Deposition of insoluble prion protein (PrP) in the brain in the form of protein aggregates or deposits is characteristic of the ‘transmissible spongiform encephalopathies’ (TSEs). Understanding the growth and development of PrP aggregates is important both in attempting to elucidate the pathogenesis of prion disease and in the development of treatments designed to inhibit the spread of prion pathology within the brain. Aggregation and disaggregation of proteins and the diffusion of substances into the developing aggregates (surface diffusion) are important factors in the development of protein deposits. Mathematical models suggest that if either aggregation/disaggregation or surface diffusion is the predominant factor, then the size frequency distribution of the resulting protein aggregates will be described by either a power-law or a log-normal model respectively. This study tested this hypothesis for two different populations of PrP deposit, viz., the diffuse and florid-type PrP deposits characteristic of patients with variant Creutzfeldt-Jakob disease (vCJD). The size distributions of the florid and diffuse deposits were fitted by a power-law function in 100% and 42% of brain areas studied respectively. By contrast, the size distributions of both types of aggregate deviated significantly from a log-normal model in all areas. Hence, protein aggregation and disaggregation may be the predominant factor in the development of the florid deposits. A more complex combination of factors appears to be involved in the pathogenesis of the diffuse deposits. These results may be useful in the design of treatments to inhibit the development of PrP aggregates in vCJD.

Compatibilisation of heterogeneous polymer blends by reactive processing

Functionalisation of polystyrene, PS, and ethylene-co-propylene-co-cyclopentadiene terpolymer, EPDM, with acrylic acid, AA, in a melt reactive processing procedure, in the presence of peroxide, trigonox 101, and coagents, Divinyl benzene, DVB (for PS), and trimethylolpropane triacrylate, TRIS (for EPDM), were successfully carried out. The level of grafting of the AA, as determined by infrared analysis, was significantly enhanced by the coagents. The grafting reaction of AA takes place simultaneously with homopolymerisation of the monomers, melt degradation and crosslinking reactions of the polymers. The extent of these competing reactions were inferred from measurements of melt flow index and insoluble gel content. Through a judicious use of both the peroxide and the coagent, particularly TRIS, unwanted side reactions were minimized. Five different processing methods were investigated for both functionalisation experiments; the direct addition of the pre-mixed polymer with peroxide and reactive modifiers was found to give optimum condition for grafting. The functionalised PS, F-PS, and EPDM, F-EPD, and maleinised polypropylene carrying a potential antioxidant, N-(4-anilinophenyl maleimide), F-PP were melt blended in binary mixtures of F-PS/F-EPD and F-PP/F-EPD in the presence (or absence) of organic diamines which act as an interlinking agent, e.g, Ethylene Diamine, EDA, and Hexamethylene Diamine, HEMDA. The presence of an interlinking agent, particularly HEMDA shows significant enhancement in the mechanical properties of the blend, suggesting that the copolymer formed has acted as compatibiliser to the otherwise incompatible polymer pairs. The functionalised and amidised blends, F and A-PSIEPDM (SPOI) and F and A-PPIEPDM (SPD2) were subsequently used as compatibiliser concentrates in the corresponding PSIEPDM and PPIEPDM blends containing various weight propotion of the homopolymers. The SPD1 caused general decreased in tensile strength, albeit increased in drop impact strength particularly in blend containing high PS content (80%). The SPD2 was particularly effective in enhancing impact strength in blends containing low weight ratio of PP (<70%). The SPD2 was also a good thermal antioxidant albeit less effective than commercial antioxidant. In all blends the evidence of compatibility was examined by scanning electron microscopy.

The chemistry of British bituminous coals : an assessment of phase transfer catalysed reactions in the determination of coal structure

Three British bituminous coals, (Gedling, Cresswell, and Cortonwood Silkstone) were selected for study. Procedures were developed, using phase transfer catalysts (PTC's), to degrade the solvent insoluble fractions of the coals. PTC's are of interest because they have the potential to bring about selective high conversion reactions, under mild conditions, (often in the past, severe reaction conditions have had to be used to degrade the coals, this in turn resulted in the loss of much of the structural information). We have applied a variety of physical and chemical techniques to maximise the amount of structural information, these include, elemental analysis, 1H-NMR, 13C-CPMAS-NMR, GPC, GC-MS, FTIR spectroscopy, DRIFT spectroscopy, and gas adsorption measurements. The main conclusions from the work are listed below:- ( 1 ) PTC O-methylation; This reaction removes hydrogen bonds within the coal matrix by 'capping' the phenolic groups. It was found that the polymer-like matrix could be made more flexible, but not significantly more soluble, by O-methylation. I.E. the trapped or 'mobile' phase of the coals could be removed at a faster rate after this reaction had been carried out. ( 2 ) PTC Reductive and Acidic Ether Cleavage; The three coals were found to contain insignificant amounts of dialkyl and alkyl aryl ethers. The number of diaryl ethers could not be estimated, by reductive ether cleavage, (even though a high proportion of all three coals was solublised). The majority of the ethers present in the coals were inert to both cleavage methods, and are therefore assumed to be heterocyclic ethers. ( 3 ) Trif!uoroperacetic Acid Oxidation; This oxidant was used to study the aliphatic portions of the polymer-like macromolecular matrix of the coals. Normally this reagent will only solublise low rank coals, we however have developed a method whereby trifluoroperacetic acid can be used to degrade high rank bituminous coals. ( 4 ) PTC/Permanganate Oxidation; This reagent has been found to be much more selective than the traditional alkaline permanganate oxidation, with a lot more structural information being retained within the various fractions. This degradative method therefore has the potential of yielding new information about the molecular structure of coals.

Lipoidal species in ocular spoilation processes

Tear component deposition onto contact lenses is termed `spoilation' and occurs due to the interaction of synthetic polymers with their biological fluid environment. Spoilation phenomena alter the physico-chemical properties of hydrophilic contact lenses, diminishing the optical properties of the lens; causing discomfort and complications for the wearer. Eventually these alterations render the lens unwearable. The primary aim of this interdisciplinary study was to develop analytical techniques capable of analysing the minute quantities of biological deposition involved, in particular the lipid fraction. Prior to this work such techniques were unavailable for single contact lenses. It is envisaged that these investigations will further the understanding of this biological interfacial conversion. Two main analytical techniques were developed: a high performance liquid chromatography (HPLC) technique and fluorescence spectrofluorimetry. The HPLC method allows analysis of a single contact lens and provided previously unavailable valuable information about variations in the lipid profiles of deposited contact lenses and patient tear films. Fluorescence spectrophotofluorimetry is a sensitive non-destructive technique for observing changes in the fluorescence intensity of biological components on contact lenses. The progression and deposition of tear materials can be monitored and assessed for both in vivo and in vitro spoiled lenses using this technique. An improved in vitro model which is comparable to tears and chemically mimics ocular spoilation was also developed. This model allows the controlled study of extrinsic factors and hydrogel compositions. These studies show that unsaturated tear lipids, probably unsaturated fatty acids, are involved in the interfacial conversion of hydrogel lenses, rendering them incompatible with the ocular microenvironment. Lipid interaction with the lens surface then facilitates secondary deposition of other tear components. Interaction, exchange and immobilisation (by polymerisation) of the lipid layer appears to occur before the final and rapid growth of more complex, insoluble discrete deposits, sometimes called `white spots'.

Solubility enhancement of poorly water soluble drugs using liposome technology

The aim of this work is to investigate the various parameters that could control the encapsulation of lipophilic drugs and investigate the influence of the physical properties of poorly water-soluble drugs on bilayer loading. Initial work investigated on the solubilisation of ibuprofen, a model insoluble drug. Drug loading was assessed using HPLC and UV spectrophotometric analysis. Preliminary studies focused on the influence of bilayer composition on drug loading to obtain an optimum cholesterol concentration. This was followed up by studies investigating the effect of longer alkyl chain lipids, unsaturated alkyl chain lipids and charged lipids. The studies also focused on the effects of pH of the hydration medium and addition of the single chain surfactant a-tocopherol. The work was followed up by investigation of a range of insoluble drugs including flurbiprofen, indomethacin, sulindac, mefenamic acid, lignocaine and progesterone to investigate the influence of drugs properties and functional group on liposomal loading. The results show that no defined trend could be obtained linking the drug loading to the different drug properties including molecular weight, log P and other drug specific characteristics. However, the presence of the oppositely charged lipids improved the encapsulation of all the drugs investigated with a similar effect obtained with the substitution of the longer chain lipids. The addition of the single chain surfactant a-tocopherol resulted in enhancement of drug loading and possibly is governed by the log P of the drug candidate. Environmental scanning-electron microscopy (ESEM) was used to dynamically follow the changes in liposome morphology in real time during dehydration thereby providing a alternative assay of liposome formulation and stability. The ESEM analysis clearly demonstrated ibuprofen incorporation enhanced the stability of PC:Chol liposomes.

Polymer film formulations for the preparation of enteric pharmaceutical capsules

Objectives. Standard pharmaceutical capsules are designed to dissolve in the acidic environment of the stomach releasing the encapsulated contents for absorption. When release is required further along the gastrointestinal tract capsules can be coated with acid insoluble polymers to enable passage through the stomach and dissolution in the intestine. This paper describes formulations that have the potential to be used to produce two-piece hard capsules for post-gastric delivery without the requirement of an exterior coat. Methods. The formulation uses three polysaccharides: sodium alginate, hypromellose and gellan gum to provide acid insolubility and the ability to form capsules using standard industrial equipment. Key findings. The rheological profile, on cooling, of the base material, water content and thickness of the films were shown to be comparable with those of commercial capsules. The capsules remained intact for 2 h in 100 mm HCl at pH 1.2, and within 5 min of being removed from the acid and submerged in phosphate-buffered saline at pH 6.8 were ruptured. Conclusions. Selected formulations from this study have potential for use as delayed release capsules.

Stability studies on pencillin derivatives

Current analytical assay methods for ampicillin sodium and cloxacillin sodium are discussed and compared, High Performance Liquid Chromatography (H.P.L.C.) being chosen as the most accurate, specific and precise. New H.P.L.C. methods for the analysis of benzathine cloxacillin; benzathine penicillin V; procaine penicillin injection B.P.; benethamine penicillin injection; fortified B.P.C.; benzathine penicillin injection; benzathine penicillin injection, fortified B.P.C.; benzathine penicillin suspnsion; ampicillin syrups and penicillin syrups are described. Mechanical or chemical damage to column packings is often associated with H.P.L.C. analysis. One type, that of channel formation, is investigated. The high linear velocity of solvent and solvent pulsing during the pumping cycle were found to be the cause of this damage. The applicability of nonisotherrnal kinetic experiments to penicillin V preparations, including formulated paediatric syrups, is evaluated. A new type of nonisotherrnal analysis, based on slope estimation and using a 64K Random Access Memory (R.A.M.) microcomputer is described. The name of the program written for this analysis is NONISO. The distribution of active penicillin in granules for reconstitution into ampicillin and penicillin V syrups, and its effect on the stability of the reconstituted products, are investigated. Changing the diluent used to reconstitue the syrups was found to affect the stability of the product. Dissolution and stability of benzathine cloxacillin at pH2, pH6 and pH9 is described, with proposed dissolution mechanisms and kinetic analysis to support these mechanisms. Benzathine and cloxacillin were found to react in solution at pH9, producing an insoluble amide.

Aspects of the prevention and repair of chloride-induced corrosion of steel in concrete

Sodium formate, potassium acetate and a mixture of calcium and magnesium acetate (CMA) have all been identified as effective de-icing agents. In this project an attempt has been made to elucidate potentially deleterious effects of these substances on the durability of reinforced concrete. Aspects involving the corrosion behaviour of embedded steel along with the chemical and physical degradation of the cementitious matrix were studied. Ionic diffusion characteristics of deicer/pore solution systems in hardened cement paste were also studied since rates of ingress of deleterious agents into cement paste are commonly diffusion-controlled. It was found that all the compounds tested were generally non-corrosive to embedded steel, however, in a small number of cases potassium acetate did cause corrosion. Potassium acetate was also found to cause cracking in concrete and cement paste samples. CMA appeared to degrade hydrated cement paste although this was apparently less of a problem when commercial grade CMA was used in place of the reagent grade chemical. This was thought to be due to the insoluble material present in the commercial formulation forming a physical barrier between the concrete and the de-icing solution. With the test regimes used sodium formate was not seen to have any deleterious effect on the integrity of reinforced concrete. As a means of restoring the corrosion protective character of chloride-contaminated concrete the process of electrochemical chloride removal has been previously developed. Potential side-effects of this method and the effect of external electrolyte composition on chloride removal efficiency were investigated. It was seen that the composition of the external electrolyte has a significant effect on the amount of chloride removed. It was also found that, due to alterations to the composition of the C3A hydration reaction products, it was possible to remove bound chloride as well as that in the pore solution. The use of an external electrolyte containing lithium ions was also tried as a means of preventing cathodically-induced alkali-silica reaction in concretes containing potentially reactive aggregates. The results obtained were inconclusive and further practical development of this approach is needed.

Design and evaluation of compound metformin/glipizide elementary osmotic pump tablets

A simple elementary osmotic pump (EOP) system that could deliver metformin hydrochloride (MT) and glipizide (GZ) simultaneously for extended periods of time was developed in order to reduce the problems associated with multidrug therapy of type 2 non-insulin-dependent diabetes mellitus. In general, both highly and poorly water-soluble drugs are not good candidates for elementary osmotic delivery. However, MT is a highly soluble drug with a high dose (500 mg) while GZ is a water-insoluble drug with a low dose (5 mg) so it is a great challenge to pharmacists to provide satisfactory extended release of MT and GZ. In this paper sodium carbonate was used to modulate the solubility of GZ within the core and MT was not only one of the active ingredients but also the osmotic agent. The optimal EOP was found to deliver both drugs at a rate of approximately zero order for up to 10 h in pH 6.8, independent of environment media. In-vivo evaluation was performed relative to the equivalent dose of conventional MT tablet and GZ tablet by a cross-study in six Beagle dogs. The EOP had a good sustained effect in comparison with the conventional product. The prototype design of the system could be applied to other combinations of drugs used for cardiovascular diseases, diabetes, etc.