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W J Irwin

Publications and source records attributed to W J Irwin.

At least 19 recordsLinked to original sources
PubMed2002

A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. II. Dissolution studies and in vitro/in vivo correlation.

The objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH 5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro-in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH 5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r = 0.773; p < .00001) was established between in vivo release and in vitro dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro-in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration-time profiles.

Acetaminophen↗
PubMed2002

The development of a modified dissolution method suitable for investigating powder mixtures.

A novel dissolution method was developed, suitable for powder mixtures, based on the USP basket apparatus. The baskets were modified such that the powder mixtures were retained within the baskets and not dispersed, a potential difficulty that may arise when using conventional USP basket and paddle apparatus. The advantages of this method were that the components of the mixtures were maintained in close proximity, maximizing any drug: excipient interaction and leading to more linear dissolution profiles. Two weakly acidic model drugs, ibuprofen and acetaminophen, and a selection of pharmaceutical excipients, including potential dissolution-enhancing alkalizing agents, were chosen for investigation. Dissolution profiles were obtained for simple physical mixtures. The f1 fit factor values, calculated using pure drug as the reference material, demonstrated a trend in line with expectations, with several dissolution enhancers apparent for both drugs. Also, the dissolution rates were linear over substantial parts of the profiles. For both drugs, a rank order comparison between the f1 fit factor and calculated dissolution rate, obtained from the linear section of the dissolution profile, demonstrated a correlation using a significance level of P = 0.05. The method was proven to be suitable for discriminating between the effects of excipients on the dissolution of the model drugs. The method design produced dissolution profiles where the dissolution rate was linear for a substantial time, allowing determination of the dissolution rate without mathematical transformation of the data. This method may be suitable as a preliminary excipient-screening tool in the drug formulation development process.

Acetaminophen↗
PubMed2000

Ionisation and the effect of absorption enhancers on transport of salicylic acid through silastic rubber and human skin.

PURPOSE: to investigate if salicylic acid (SA)-permeation through excised human skin (HS) and silastic rubber (SR) conforms to the pH-hypothesis and to assess the influence of a range of absorption enhancers on the transport of SA with and without a transmembrane pH-gradient. METHODS: Franz cells were used to study SA permeation from solutions and saturated suspensions. McIlvaine buffers were used to maintain transmembrane pH-gradients. Membrane pretreatment was used to study the action of absorption enhancers. RESULTS: the flux of SA from solutions was dependent upon the vehicle pH and permeant concentration was directly related to the degree of ionisation of the solute. Flux from suspensions was independent of pH, since the level of unionised drug, the predominant diffusing species, was maintained at the intrinsic saturated solubility at all pH values. The observed SA flux enhancement across human skin without a transmembrane pH-gradient was not significantly different from the enhancement with a pH-gradient for all of the absorption enhances used, except for dodecylamine. CONCLUSIONS: the results showed that SA permeation conformed to the p H-partition hypothesis. The evidence from absorption-enhancer pretreatment demonstrated that, under certain conditions, the transdermal penetration enhancement of a number of topical enhancing compounds, including Azone and oleic acid can be explained without recourse to ion-pair phenomena.

Absorption↗
PubMed2000

A rapid screening system to determine drug affinities for the intestinal dipeptide transporter 1: system characterisation.

PURPOSE: To establish an in vitro system for the rapid assessment of the affinities of potential substrates for the di/tri/oligopeptide transport system (DTS). METHODS: Monolayers of Caco-2 cells were cultured in plastic wells for 7-9 days and the uptake of Gly-[3H]L-Pro, a specific and relatively stable substrate for the DTS was used as an affinity probe. Gly-[3H]L-Pro (50 nM), together with excess L-Pro (10 mM), to suppress uptake of any [3H]L-Pro produced by degradation of the probe, was incubated with the test compound (usually 1 mM) at pH 6 for 3 min. The uptake of radiolabel was determined by liquid scintillation counting. RESULTS: High specific-uptake (> 85%) of Gly-[3H]L-Pro was obtained with cells grown for 7-9 days. Gly-[3H]L-Pro uptake had a substantial active concentration-dependent component (Km of 0.39 +/- 0.02 mM, Vmax of 0.98 +/- 0.04 nmol min(-1) (mg protein)(-1). This process was shown to be specific for the DTS as evidenced by the significant inhibition by compounds reported to be transported by this system and the lack of inhibition by amino acids. The use of low competitor concentrations (1 mM) enabled a range of inhibition values (0-89%) of a series of competitors (amino acids, dipeptides and beta-lactam antibiotics) to be estimated, illustrating that structurally similar compounds can be ranked for affinity to the DTS. CONCLUSION: A screening system, using Caco-2 cells and the dipeptide Gly-[3H]L-Pro as a displaceable probe, was developed to assess a variety of compounds for recognition by the di/tri/oligopeptide transport system. This fully describes the first system that allows structurally related compounds to be ranked on the basis of their affinity for the DTS recognition site.

Algorithms↗
PubMed2000

A rapid screening system to determine drug affinities for the intestinal dipeptide transporter 2: affinities of ACE inhibitors.

PURPOSE: To assess the affinities of a series of ACE inhibitors for the di/tri/oligopeptide transport system (DTS) using a rapid in vitro system. METHODS: Monolayers of Caco-2 cells were cultured in plastic wells for 7-9 days and the uptake of Gly-[3H]L-Pro was used as an affinity probe. Gly-[3H]L-Pro (50 nM), together with excess L-Pro (10 mM), to suppress uptake of any [3H]L-Pro produced by degradation of the probe, was incubated with the test compound (usually 1 mM) at pH 6 for 3-mins. The uptake of radiolabel was determined by liquid scintillation counting. RESULTS: A 2-dimensional six-domain model of the transporter based on the structure of a phosphinate ACE inhibitor (SQ-29852) was constructed to facilitate interpretation of the competitor affinities. The SQ-29852 molecule was divided into six binding domains (A-F) based on functional groups within these regions and the effects of structural variation in four of these domains (A, C-E) were explored. A series of dipeptide-like compounds varying within specific domains were selected from a large number of commercially available ACE inhibitors and SQ-29852 analogues. Domain A had a preference for an uncharged group, with bulky hydrophobic groups reducing affinity. Domain C exhibited a preference for a positive charge over a neutral function, with the space this functional group occupies contributing to affinity. Domain D favoured lipophilic residues and domain E retained activity when the carboxylic acid was esterified. CONCLUSION: The test system is able to reveal structure-activity relationships of peptidomimetic agents and may well serve as a design tool to optimise affinity for the DTS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Transdermal macromolecular delivery: real-time visualization of iontophoretic and chemically enhanced transport using two-photon excitation microscopy.

PURPOSE: To investigate the transdermal delivery of a model macromolecule by passive and iontophoretic means following pretreatment with C12-penetration enhancers and to visualise transport across human stratum corneum (SC) in real time. METHODS: Transport studies of dextran, labelled with fluorescent Cascade Blue (D-CB: M(R) = 3 kDa) across human stratum corneum, were conducted during passive and iontophoretic modes of delivery following pretreatment with either dodecyltrimethylammonium bromide (DTAB), sodium dodecyl sulphate (SDS) or Azone. Size-exclusion chromatography was used to assess maintenance of dextran structural integrity throughout experimental lifetime. Two-photon excitation microscopy was employed to visualise real-time dextran transport during current application. RESULTS: The positively charged C12-enhancer DTAB elevated passive D-CB steady-state flux (J(ss)) and was the only enhancer to do so above control during iontophoresis. The negatively charged SDS had the least effect during both stages. On-line macromolecular transport was visualised, indicating both inter- and intra-cellular pathways across SC during current application. No transport was visible across untreated SC during passive transport. CONCLUSIONS: Use of a positively charged enhancer may improve J(ss) of anionic macromolecular penetrants during passive and iontophoretic delivery. On-line visualisation of iontophoresis across SC was possible and can provide mechanistic insight into SC transport pathways.

Administration, Cutaneous↗
PubMed1999

Protection of the enzyme L-asparaginase during lyophilisation--a molecular modelling approach to predict required level of lyoprotectant.

Many novel therapeutic agents are proteins and peptides which need stabilisation due to their inherent instability in aqueous solution. Freeze-drying is an established method for protein stabilisation, although the use of additives is often necessary in order to preserve protein structure and activity during lyophilisation itself. The molecular interactions between protein and protective additive are as yet unclear. In this study, we examined the use of a range of saccharide additives to stabilise the model multi-subunit enzyme L-asparaginase during lyophilisation, assessed post-drying enzyme activity and quaternary structure, and related the extrapolated levels of additive necessary to provide full stabilisation to the theoretical levels predicted from an existing hypothesis using molecular modelling. It was found that each of the saccharides tested here displayed similar levels of protection towards L-asparaginase under the conditions used. Amounts of additive required to give full stabilisation to the enzyme were extrapolated from the activity data and were found to be in good agreement with theoretical amounts calculated from molecular modelling studies. Our data suggest that the existing hypothesis may be relevant to the prediction of optimum levels of lyoprotectant for the freeze-drying of proteins. However, further studies would be necessary in order to obtain a full picture of protein-additive interactions at the molecular level.

Asparaginase↗
PubMed1999

Ultrasound-enhanced diffusion into coupling gel during phonophoresis of 5-fluorouracil.

PURPOSE: To investigate the competitive transport across skin and back-diffusion of 5-fluorouracil into coupling gel under the influence of ultrasound, heat-alone and Azone enhancement. METHODS: The ultrasound effect on 5-fluorouracil penetration through whole rat skin was investigated in modified diffusion cells using a commercial ultrasound generator which was calibrated with a bilaminar membrane hydrophone. RESULTS: Ultrasonic dosimetry measurements demonstrated that the skin membrane was subjected to a complex and unpredictable standing wave field which induced physiologically acceptable heating of the tissue. Surprisingly, ultrasonication produced a decrease in percutaneous drug penetration. Quantification studies indicated that this effect was due to the diffusive loss of the hydrophilic substance 5-fluorouracil from the skin surface into the overlying volume of coupling gel. This phenomenon could be duplicated by the application of conductive heating, indicating that the thermal effects of ultrasound were probably responsible for accelerated 5-fluorouracil diffusion through the gel. CONCLUSION: This study acutely demonstrates how formulation design of the donor vehicle/coupling gel may radically affect therapeutic efficacy in phonophoretic systems.

Animals↗
PubMed1998

Low intensity ultrasound as a probe to elucidate the relative follicular contribution to total transdermal absorption.

PURPOSE: To investigate the effect of ultrasound on the histological integrity and permeability properties of whole rat skin in vitro. METHODS: A defined, field-free source of ultrasound was used to irradiate excised rat skin prior to in vitro transport studies in Franz-type cells using sucrose, mannitol, hydrocortisone, 5-fluorouracil and aminopyrine. RESULTS: High intensity ultrasound irradiation (1 to 2 W cm-2) irreversibly damaged cutaneous structures and increased the percutaneous transport rate of permeants. In contrast, skin integrity was largely maintained with low intensity ultrasound (0.1 to 1 W cm-2) which merely discharged sebum from the sebaceous glands so as to fill much of the hair follicle shafts. This effect caused the transfollicular absorption pathway to be blocked for hydrophilic molecules that penetrate via this route and reduced the transport rate significantly. CONCLUSIONS: This phenomenon may be used as a probe to elucidate the relative follicular contribution to total penetration for hydrophilic permeants. It was demonstrated that the shunt pathway was responsible for virtually all mannitol and sucrose penetration, perhaps half of hydrocortisone transport but negligible aminopyrine and 5-fluorouracil penetration.

Aminopyrine↗
PubMed1998

Development of a sustained-release biodegradable polymer delivery system for site-specific delivery of oligonucleotides: characterization of P(LA-GA) copolymer microspheres in vitro.

Development of a Sustained-Release Biodegradable Polymer Delivery System for Site-Specific Delivery of Oligonucleotides: Characterization of P(LA-GA) Copolymer Microspheres In Vitro Antisense oligodeoxynucleotides (ODNs) can selectively inhibit individual gene expression provided they gain access to and remain stable at the target site for a sufficient period of time. Biodegradable sustained-release delivery systems may facilitate site-specific delivery and also prevent degradation of ODNs by nucleases whilst delivering the nucleic acid in a controlled manner to the desired site of action. In this study, we have characterized biodegradable poly (lactide-co-glycolide) (P(LA-GA)) 50:50 microspheres for the potential delivery of antisense oligonucleotides in vivo. Phosphodiester (PO) oligonucleotides complementary to either c-myc proto-oncogene or the tat gene in HIV-RNA were adequately incorporated within P(LA-GA) microspheres with entrapment efficiencies up to 60% depending on particles size. In vitro release profiles of antisense nucleic acids from 10-20 microm size microspheres over 56 days in physiological buffer were triphasic. Profiles were characterised by an initial burst effect during the first 48 hours (phase 1) of release followed by a more sustained release (phase 2) with an additional increased release (phase 3) being observed after 25 days which corresponded with bulk degradation of the copolymer matrix. The release profiles were influenced by microsphere size, copolymer molecular weight, ODN loading, ODN length and by the pH of release medium used. The serum stability of PO ODNs was significantly improved when entrapped within P(LA-GA) microspheres and the hybridization capability, as assessed by duplex melting (Tm) measurements, of released ODN was not impaired by the double-emulsion microsphere fabrication procedure used. Thus, P(LA-GA) microspheres appear to be promising candidates for improving site-specific delivery profiles for ODNs and are worthy of further evaluation in vivo.

Base Sequence↗
PubMed1997

Interaction of oligonucleotide-conjugates with the dipeptide transporter system in Caco-2 cells.

Oligonucleotide-based therapies represent novel strategies for manipulating the expression and function of target proteins and are undergoing clinical evaluation for the treatment of viral diseases and malignancies. However, poor biological stability and cellular delivery represent potential limitations to the therapeutic development of oligonucleotides. Conjugation of oligonucleotides to lipophilic groups can improve delivery to cells but the enhanced cellular binding may also facilitate nonspecific interactions. In this report, we show that phosphorothioate oligonucleotides conjugated to lipophilic groups, either tocopherol (Vitamin E) or 2-Di-O-hexadecyl-3-glycerol, can significantly inhibit the functioning of the dipeptide transporter system (DTS) in cultured Caco-2 intestinal cells. Because the DTS mediates the binding and absorption of nutrient peptides and important drugs, such as the cephalosporin and penicillin antibiotics, this finding has important implications in relation to the potential toxicity of lipophilic conjugates in vivo. It also suggests a potential drug interaction with lipophilic oligonucleotide-conjugates if they were to be delivered orally.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Interactions of phosphodiester and phosphorothioate oligonucleotides with intestinal epithelial Caco-2 cells.

PURPOSE: Oral bioavailability for antisense oligonucleotides has recently been reported but the mechanistic details are not known. The proposed oral delivery of nucleic acids will, therefore, require an understanding of the membrane binding interactions, cell uptake and transport of oligonucleotides across the human gastro-intestinal epithelium. In this initial study, we report on the cell-surface interactions of oligonucleotides with human intestinal cells. METHODS: We have used the Caco-2 cell line as an in vitro model of the human intestinal epithelium to investigate the membrane binding interactions of 20-mer phosphodiester (PO) and phosphorothioate (PS) oligonucleotides. RESULTS: The cellular association of both an internally [3H]-labelled and a 5'end [32P]-labelled PS oligonucleotide (3.0% at 0.4 microM extracellular concentration) was similar and was an order of magnitude greater than that of the 5'end [32P]-labelled PO oligonucleotide (0.2%) after 15 minutes incubation in these intestinal cells. The cellular association of PS was highly saturable with association being reduced to 0.9% at 5 microM whereas that of PO was less susceptible to competition (0.2% at 5 microM, 0.1% at 200 microM). Differential temperature-dependence was demonstrated; PS interactions were temperature-independent whereas the cellular association of PO decreased by 75% from 37 degrees C to 17 degrees C. Cell association of oligonucleotides was length and pH-dependent. A decrease in pH from 7.2 to 5.0 resulted in a 2- to 3-fold increase in cell-association for both backbone types. This enhanced association was not due to changes in lipophilicity as the octanol:aqueous buffer distribution coefficients remained constant over this pH range. The ability of NaCl washes to remove surface-bound PS oligonucleotides in a concentration-dependent manner suggests their binding may involve ionic interactions at the cell surface. Cell-surface washing with the proteolytic enzyme, Pronase, removed approximately 50% of the cell-associated oligonucleotide for both backbone types. CONCLUSIONS: Binding to surface proteins seems a major pathway for binding and internalization for both oligonucleotide chemistries and appear consistent with receptor (binding protein)-mediated endocytosis. Whether this binding protein-mediated entry of oligonucleotides can result in efficient transepithelial transport, however, requires further study.

Azides↗
PubMed1996

Suitability of enalapril as a probe of the dipeptide transporter system: in vitro and in vivo studies.

PURPOSE: Previous in situ and in vitro studies indicated that the intestinal absorption of enalapril is a saturable carrier-mediated process via the dipeptide transporter system (DTS); however, the oral absorption of enalapril has not been reported to be a saturable process in vivo. Our objectives were to: 1) evaluate the suitability of enalapril as a probe of the DTS, and 2) compare various experimental models as they pertain to studying the DTS. METHODS: The in vitro uptake of enalapril by rat intestinal rings and permeability across Caco-2 cells were studied as a function of concentration and in the presence of compounds that are known substrates of the DTS. The effect of enalapril on the uptake of [3H]-glycyl-L-proline (gly-L-pro) by Caco-2 cells was also examined. In vivo studies were conducted in rats (1 to 50 mg/kg) and dogs (0.06 to 6 mg/kg) to evaluate the oral absorption of enalapril over a wide dose range. RESULTS: In vitro intestinal uptake/permeability of enalapril was not saturable nor inhibited by beta-lactam antibiotics, gly-L-pro, or SQ-29852. Moreover, a 20,000-fold molar excess of enalapril did not inhibit the uptake of [3H]-gly-L-pro by Caco-2 cells. The in vivo studies in rats and dogs did not demonstrate saturable absorption. CONCLUSIONS: The present in vitro and in vivo results indicated that enalapril is primarily absorbed by a non-saturable, passive diffusion process and it is not a suitable model compound for studying the DTS.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

The influence of polarized epithelial (Caco-2) cell differentiation on the cellular binding of phosphodiester and phosphorothioate oligonucleotides.

Cell aging and the degree of cellular differentiation are thought to be important variables governing uptake of oligonucleotides but remain poorly understood. The Caco-2 colon carcinoma cell line has the ability to spontaneously differentiate into enterocytes in vitro and serves as a useful model to further investigate the effect of differentiation on oligonucleotide binding and uptake. In this study, we report that the extent of oligonucleotide association and the expression of cell surface binding proteins are governed by the age and thus the degree of differentiation of Caco-2 epithelial cells in culture. Cellular association (normalized for cell number) of an all phosphodiester (PO), all phosphorothioate (PS), and a phosphodiester oligonucleotide containing two terminal phosphorothioate internucleotide linkages at the 3' end (EC-PO) gradually increased from day 3 to around day 17 of the culture, followed by a plateau, or slight decrease, up to day 21 of the cell aging study. Overall, a threefold to fourfold increase in binding was observed from day 3 to day 17. Oligonucleotide binding was temperature and pH dependent, but the magnitude of the effect was influenced by cell aging and the degree of differentiation. PS oligonucleotides exhibited greater binding (up to threefold) at the basolateral surface compared with the apical surface within the pH range 5-7. These findings could be directly correlated with the expression levels of cell surface oligonucleotide binding proteins during the aging study. A Caco-2 cell surface protein binding complex of around 46 kDa was identified as the major site of binding for both PO and PS oligonucleotides, although the latter also bound to several other proteins, especially at low pH.

Caco-2 Cells↗
PubMed1996

A nonantisense sequence-selective effect of a phosphorothioate oligodeoxynucleotide directed against the epidermal growth factor receptor in A431 cells.

The overexpression of epidermal growth factor receptor (EGFr) has been implicated as a causative factor and a poor prognostic marker in a number of carcinomas. Therefore, strategies that down-regulate EGFr expression may be therapeutically useful. We designed antisense ODNs complementary to the initiation codon region of the EGFr mRNA and evaluated their efficacy in several tumor-derived cells, including the A431 cell line, that express amplified levels of EGFr. A 15-mer phosphorothioate (PS) antisense ODN (erbB1AS15) induced a concentration-dependent reduction in proliferation that was accompanied by a change in the morphology of A431 cells into more tightly clustered and discrete colonies. A 15-mer sense (PS) control oligodeoxynucleotide (ODN) and a phosphodiester (PO) version of erbB1AS15 had little or no effect on cell number of morphology, and erbB1AS15 (PS) did not induce these effects in control cell lines expressing lower levels of EGFr. The effects of erbB1AS15 (PS) on A431 cells were not mediated by a true antisense mechanism in that there was no reduction in the level of EGFr mRNA or protein over a 24-hr period, as determined by Northern and Western blotting, respectively. However, autophosphorylation of the receptor was significantly reduced by erbB1AS15 (PS) and not by control ODNs. The results of further studies suggested that this effect was mediated by a direct, dose-dependent inhibition of the EGFr tyrosine kinase enzyme and was not due to impairment of either ligand-binding or receptor dimerization. These data suggest that erbB1AS15 (PS) can inhibit proliferation and alter the morphology of A431 cells by a sequence-selective, but nonantisense, mechanism affecting receptor tyrosine kinase activity.

Base Sequence↗
PubMed1995

The transport of acidic amino acids and their analogues across monolayers of human intestinal absorptive (Caco-2) cells in vitro.

The X-AG system, a sodium-dependent, acidic amino-acid transport system has been implicated in the transport of L-aspartate and L-glutamate across monolayers of human Caco-2 cells, an in vitro model of intestinal absorption. This system, which shares many properties with the L-glutamate carrier present in the human jejunum, is highly saturable (> 95% at 50 microM), vectorial (apical-to-basolateral >> basolateral-to-apical) and sodium-, pH- and temperature-dependent. L-Aspartate was also transported against a 10-fold reverse concentration gradient. These data are consistent with a major (saturable) carrier-mediated pathway superimposed onto a minor non-saturable (diffusional) pathway. The carrier has an absolute sodium-dependence and the Michaelis constants for the sodium-dependent transport component (Km) for L-aspartate and L-glutamate were 56 +/- 3 microM and 65 +/- 6 microM, respectively. Cross-inhibition studies showed that strong interaction with the carrier was limited to close analogues of the natural substrates. Potent inhibitors included L-aspartate, D-aspartate (Ki, 70 microM), L-glutamate (Ki 180 microM) and threo-beta-hydroxy-DL-aspartate (Ki, 55 microM), while partial inhibitors included alpha-methyl-DL-aspartate, D-glutamate, L-asparagine, L-proline and L-alanine. Replacement of the side-chain -COO- group (aspartate) with -SO-3 (L-cysteate, Ki, 65 microM) or -(H)P(O)O- (DL-3-(hydroxyphosphoryl)alanine, Ki, 60 microM) maintained strong interaction with the carrier while -As(O)(OH)O- (DL-3-arsonoalanine, Ki, 1100 microM) and -P(O)(OH)O- (DL-3-phosphonoalanine, Ki, 3270 microM) were much more weakly bound, with the larger, but probably less ionised, arsono analogue being more tightly bound than the phosphono compound. The corresponding analogues of glutamate (homologous extension of the methylene chain) showed negligible interaction. We conclude that Caco-2 monolayers are a relevant experimental model for the study of the transport of acidic amino acids and their analogues in man.

Amino Acids, Dicarboxylic↗
PubMed1995

Chemical stability of fluocinolone acetonide ointment and fluocinonide cream diluted in emollient bases.

The chemical stability of fluocinolone acetonide ointment and fluocinonide cream was studied when diluted in emollient bases. Fluocinolone acetonide ointment was diluted 1 in 4 with Unguentum Merck and Lipobase. Fluocinonide cream was also studied in these bases, with the addition of Metosyn Diluent, at dilutions of 1 in 4 and 1 in 10. Regression analysis gave the time for 5% degradation of fluocinolone acetonide at a dilution of 1 in 4 in Unguentum Merck and in Lipobase as 12 weeks in both cases. The lower 95% confidence bound of each regression line was used to set shelf lives, for additional safety, and gave values of 1 month for the Unguentum Merck dilution and 2 months for the Lipobase dilution. Fluocinonide dilutions were more stable than the corresponding fluocinolone acetonide dilutions, with no degradation detectable during the study. The base made no observable difference to stability. Shelf lives, based on the lower 95% confidence bound of the regression data, of more than 6 months would be feasible for all of the fluocinonide 1 in 4 dilutions studied and for the 1 in 10 dilution in Unguentum Merck. However, for fluocinonide 1 in 10 in Metosyn Diluent, a shelf life of only 6 weeks could be assured, due to there being more variation in the analytical results. There were insufficient data to determine a storage life based on the lower 95% confidence bound of the regression for fluocinonide 1 in 10 in Lipobase. More data would be required to determine if there was significant interbatch variation in the stability of the dilutions.

Administration, Topical↗