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Biomedical subjects

O I Corrigan

Publications and source records attributed to O I Corrigan.

At least 19 recordsLinked to original sources
PubMed2006

Drug-polymer interactions and their effect on thermoresponsive poly(N-isopropylacrylamide) drug delivery systems.

Potential interactions between model drugs (benzoates, diltiazem, cyanocobalamin, dextrans) and a thermoresponsive poly(N-isopropylacrylamide) (PNIPA) hydrogel and corresponding linear polymer were investigated. The influence of the drugs on the equilibrium swelling level of the hydrogel was examined and drug-hydrogel binding isotherms were established where appropriate. Differential scanning calorimetry (DSC) was used to investigate the influence of the drugs on the lower critical solution temperature (LCST) of the linear polymer solution. Phase solubility studies were preformed to investigate binding. Drug-polymer co-precipitated blends were also prepared and analysed by X-ray diffraction (XRD), thermal analysis and Fourier transform infrared (FT-IR) spectroscopy. Hydrophobic binding was apparent between PNIPA and the aromatic ring/ester side chain of the unionised benzoate. The effect of this binding on hydrogel swelling was clarified in terms of the influence of the binding on the LCST of the system. The drug release rates of the benzoates from the hydrogel were shown to be dependent on drug binding properties. Ionisation of the benzoate prevented such hydrophobic binding, with a weaker salting out effect apparent with sodium benzoate. Significant interactions between diltiazem, cyanocobalamin (Vitamin B12) or the dextrans and PNIPA were not apparent. High concentrations of the hydrophilic drugs did, however, interfere with the magnitude of hydrogel equilibrium swelling. Hydrophobic binding, the salting out effect and the influence of the drugs on hydrogel swelling under non-sink conditions were therefore shown to be important effects which depended on the chemical nature of the drug present.

Acrylic Resins↗
PubMed2006

Preparation and release of model drugs from thermally sensitive poly(N-isopropylacrylamide) based macrospheres.

Emulsion polymerization was employed to prepare poly(N-isopropylacrylamide) hydrogel spheres, which exhibited an LCST of 32 degrees C. The hydrogels were loaded with model drugs (benzoic acid (BA), sodium benzoate and diltiazem HCl (DHCl)) and release investigated at 25 degrees C and 37 degrees C. The temperature at which gel formation occurred was vital for successful hydrogel preparation, macrosphere formation not occurring when the temperature was close to the LCST. Sphere size increased on decreasing the stirring rate and on slowing the rate of addition of the aqueous phase. Pulsatile delivery was investigated using BA and DHCl. For both compounds a pulse was observed with a change in temperature. Pulsed release of the smaller model drug of lowest solubility, BA, was more successful. Drug release from hydrogel spheres was, therefore, found to be dependent on the physicochemical properties of the drugs, with pulsatile release of low molecular weight compounds, by temperature cycling, difficult to control.

Acrylic Resins↗
PubMed2005

Hydrodynamic simulation (computational fluid dynamics) of asymmetrically positioned tablets in the paddle dissolution apparatus: impact on dissolution rate and variability.

The aim of this work was to investigate the dissolution rate from both the curved and planar surfaces of cylindrical compacts of benzoic acid, which were placed centrally and non-centrally at the base of the vessel of the paddle dissolution apparatus. The effect of fixing the compacts to a particular position on the variability of dissolution results was also examined. In addition, computational fluid dynamics (CFD) was used to simulate fluid flow around compacts in the different positions in the vessel, and the relationship between the local hydrodynamics in the region of the compacts and the dissolution rate determined. The dissolution rate was found to increase from the centre position to the off-centre positions for each surface examined. There was a corresponding increase in maximum fluid velocities calculated from the CFD fluid flow simulations at a fixed distance from the compact. There was less variability in dissolution from compacts fixed to any of the positions compared with those that were not fixed. Fluid flow around compacts in different positions could be successfully modelled, and hydrodynamic variability examined, using CFD. The effect of asymmetric fluid flow was evident visually from the change in shape of the eroded compacts.

Benzoic Acid↗
PubMed2004

Effect of drug physicochemical properties on swelling/deswelling kinetics and pulsatile drug release from thermoresponsive poly(N-isopropylacrylamide) hydrogels.

The effect of drug physicochemical properties on swelling/deswelling kinetics and pulsatile drug release from a thermoresponsive hydrogel was examined. Hydrogels were loaded with drug and thermally triggered swelling/deswelling and release experiments were performed. Two series of drugs of contrasting hydrophilicity and varying physicochemical properties were examined. Benzoic acid (BA), its methyl and propyl esters, and diltiazem base were used as model hydrophobic drugs. Sodium benzoate (NaB), diltiazem HCl (DHCl), vitamin B12 (VB12) and various dextrans (MW 4300, 10,200, 42,000, 68,800) were used as model hydrophilic agents of increasing size. The hydrogel swelling rate was slowed by the presence of the hydrophobic drugs and this decreased rate was solubility dependant for the benzoates. The hydrophilic series increased the rate of swelling compared to the unloaded system. In all cases, the magnitude and rate of hydrogel contraction were proportional to the extent of swelling prior to temperature switch. Drug release was by diffusion below the lower critical solution temperature (LCST), while a solubility-dependent drug pulse release on temperature switch was observed for the hydrophobic series. Effectiveness of thermal control of hydrophobic drug release increased with increasing solubility. The hydrophilic series produced a molecular size-dependent drug pulse on temperature switch above the LCST. Pulsatile on-off drug release was shown with DHCl, VB12 and the various dextrans. Drug solubility, size and chemical nature were shown to be of particular importance in the control of hydrogel swelling and drug release from thermosensitive hydrogels.

Acrylic Resins↗
PubMed2003

Iontophoretic and chemical enhancement of drug delivery. Part I: across artificial membranes.

This paper reports on measurements of the release characteristics of the model drug salbutamol base from a liquid crystalline vehicle across a non-rate limiting synthetic membrane. The measured passive release rates were compared with analogous behaviour: (i) when a penetration enhancer such as oleic acid was incorporated into the vehicle; (ii) when the release was iontophoretically assisted; and (iii) when the penetration enhancer and iontophoretic assistance were used simultaneously. The effects of using isotonic phosphate buffer solution as the aqueous domain of the vehicle and in the receptor were also separately assessed. The passive release from the standard system was consistent with matrix diffusion control. The addition of oleic acid indicated association of the drug with the fatty acid so that its release into an aqueous medium was significantly retarded. With buffer ions present in the vehicle the release rate increased consistent with reduced association, and when phosphate buffer was used as a receptor medium the release rate exceeded that of the standard vehicle due to an ion exchange process. The delivery of salbutamol from the fatty acid containing systems was substantially enhanced by iontophoresis and the rates were shown to be approximately proportional to the assisting currents. The data clearly indicate the iontophoretic process to be significantly less efficient in the presence of buffer ions but with the iontophoretic delivery rates being enhanced by the presence of a fatty acid.

Albuterol↗
PubMed2002

The problem of bias in training data in regression problems in medical decision support.

This paper describes a bias problem encountered in a machine learning approach to outcome prediction in anticoagulant drug therapy. The outcome to be predicted is a measure of the clotting time for the patient; this measure is continuous and so the prediction task is a regression problem. Artificial neural networks (ANNs) are a powerful mechanism for learning to predict such outcomes from training data. However, experiments have shown that an ANN is biased towards values more commonly occurring in the training data and is thus, less likely to be correct in predicting extreme values. This issue of bias in training data in regression problems is similar to the associated problem with minority classes in classification. However, this bias issue in classification is well documented and is an on-going area of research. In this paper, we consider stratified sampling and boosting as solutions to this bias problem and evaluate them on this outcome prediction problem and on two other datasets. Both approaches produce some improvements with boosting showing the most promise.

Bias↗
PubMed2002

Sensitivity of dissolution rate to location in the paddle dissolution apparatus.

The aim of the present study was to determine the apparent diffusion boundary layer and dissolution rate constant for various surfaces of compacts and at various locations in the USP paddle dissolution apparatus. Benzoic acid compacts were coated with paraffin wax leaving only the surface under investigation free for dissolution. The dissolution rates for various surfaces at varying locations in the paddle dissolution vessel were determined from the slope of the dissolution profile (amount dissolved (mg) versus time (min)). The apparent diffusion boundary layer and dissolution rate constant were calculated and were found to vary depending on the surface of the compact from which dissolution took place and also on the location and size of the compact. It may be concluded that, in developing models to describe the dissolution from solid dosage forms, it is not accurate to assume constant hydrodynamics and mass transfer rates at all surfaces of the system, or in different locations within the test device. A more exact description of the hydrodynamics would be necessary in order to precisely model drug dissolution in the paddle dissolution apparatus.

Antifungal Agents↗
PubMed2001

Factors influencing drug release from stearic acid based compacts.

Fatty acids are potentially suitable carriers for use in the design of drug delivery systems, being biocompatible, biodegradable inexpensive and of low toxicity. The release of the model compound benzoic acid from fatty acid compacts of stearic acid was evaluated using the USP Apparatus 2 dissolution assembly in phosphate buffer pH 7.4. Matrix controlled drug release was expected. Release profiles were approximated by square root of time kinetics. Release rate was independent of stirring speed in the rpm range 50-150, however, at 200 rpm a significant increase in release rate was observed particularly at later times, the amount released versus square root of time plots becoming non-linear. Release was independent of compression pressure in the range 1-7 tons. The particle size of the benzoic acid and stearic acid used had a significant influence on release. The use of particles in the range 250-500 microm gave release rate constants (k, g/cm(2) per min(0.5)) approximately 1.5 greater than those of smaller particle size (63-125 microm). The formation factor (F) tended to increase exponentially with drug loading, the increase being steeper for compacts prepared from the larger particle sizes. At 80% drug loading for large sized systems the matrix appeared to offer little resistance to drug release and F approached one.

Algorithms↗
PubMed2001

Preparation and characterisation of a range of diclofenac salts.

Physicochemical properties of diclofenac salts prepared using eight different counterions and including five novel salts, obtained with the bases 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methylpropanol, tert-butylamine, benzylamine and deanol, were compared. Four of the bases used to prepare these salts were related in their chemical structure, differing only in the number of hydroxy groups. Characterisation techniques included X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, thermomicroscopy, Karl Fischer titration, FT-IR spectroscopy and elemental analysis. In the case of salts prepared from 2-amino-2-methylpropanol and benzylamine, two polymorphic forms of each salt were identified. For the 2-amino-2-methyl-1,3-propanediol salt, a pseudopolymorphic form was identified. The aqueous solubilities of the salts studied ranged from 3.95 mM (tris(hydroxymethyl)aminomethane salt) to 446 mM (deanol salt), corresponding to a 113-fold difference in solubility. The solubility of diclofenac deanol was higher than the solubilities for diclofenac salts reported earlier. Correlation was found between the inverse of the salt melting point and the logarithm of salt solubility. A log-log relationship was observed between salt solubility and hydrogen ion concentration in the salt solution. Relationships between the properties of the salt-forming agents and those of the resulting diclofenac salts were explored. Reasonable correlation was found between the free base melting point and the salt melting point.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Comparison of the physicochemical properties of the N-(2-hydroxyethyl) pyrrolidine, diethylamine and sodium salt forms of diclofenac.

Non steroidal anti-inflammatory agents (NSAIDs) such as diclofenac have very low aqueous solubilities and consequently salt formation may be used to enhance solubility and dissolution rate. In this study, we examined the physicochemical properties of three diclofenac salts, diclofenac sodium (DNa), diclofenac N-(2-hydroxyethyl)pyrrolidine (DHEP) and diclofenac diethylamine (DDEA), and their different solid state forms to determine the influence of salt form on solubility, dissolution rate and membrane transport. The equilibrium solubility of DDEA at 25 degrees C was determined as 33 mM, lower than the solubilities of DHEP (273 mM) and DNa (66 mM) previously reported (Ledwidge and Corrigan, 1998). In addition to the dihydrate form of DHEP previously characterised, monohydrate forms of DHEP and DDEA were identified. Intrinsic dissolution rate studies were used to determine the solubility ratios of the hydrated and anhydrous forms. The monohydrate form of DHEP was found to be 1.8 times less soluble than the anhydrate, whereas DDEA anhydrate was approximately 1.7 times as soluble as the monohydrate form. On investigation of the pH-solubility profile (25 degrees C) of DDEA, appreciable supersaturation (76 mM) relative to the theoretical profile, was detected at the pH(max). This contrasts with values of >800 and 67 mM for DHEP and DNa, respectively. The transport of salt solutions through a porous membrane (Visking) was investigated. A linear relationship between concentration (mM) and rate of transport (mmol/h) was established for DNa and DHEP solutions. The mass transfer coefficient determined for DHEP was lower than that for the other two salts. Nevertheless, the maximum transport rate obtained for DHEP is almost six times higher than that obtained for DDEA.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Mechanistic aspects of the release of levamisole hydrochloride from biodegradable polymers.

The release of levamisole hydrochloride from poly-DL-lactide-co-glycolide compacts prepared at 5, 10 and 20% drug loading using two different particle size fractions of drug (90-125 and 125-250 microm) was investigated. Release profiles were significantly different from those previously reported for compacts prepared using the base form of the drug. Release was found to occur in a biphasic manner, with an initial fast release phase followed by a slower polymer degradation controlled release phase. The drug release profiles were successfully described by a model combining contributions from a first-order initial release phase and a polymer degradation controlled drug release phase. The fraction of drug released in the initial burst phase (F(B)) was attributed to the dissolution of drug domains situated at the surface of the polymer-drug compact and this fraction tended to increase with increasing drug particle size, as expected from the model. The increase in F(B) with increased loading was attributed to the clumping of dispersed drug particles which effectively increased the proportion of drug linked to the compact surface.

Adjuvants, Immunologic↗
PubMed1997

The biopharmaceutic drug classification and drugs administered in extended release (ER) formulations.

A biopharmaceutic drug classification scheme for correlating the in-vitro drug product dissolution and in-vivo bioavailability for IR products was proposed by Amidon et al (1995). The classification arose from drug dissolution and absorption models which identified the key parameters controlling drug absorption as the dimensionless numbers; the Absorption number (A(n)), the Dissolution number (Dn) and the Dose number (D(o)). This led to a biopharmaceutic classification of drugs into four groups, the establishment of a basis for determining the conditions under which in-vitro-in-vivo (IVIV) correlation's are expected and the use of the classification to set drug bioavailability standards for IR products. These developments raise the issue of whether the biopharmaceutic classification has relevance to ER products. In contrast to IR products, drugs selected for ER products should have good gastrointestinal (GI) permeability and an extended site of absorption. However their permeability(Papp) may change depending on the site. Solubility(Cs), effective fluid volume and hence D(o) may also vary with site. Of particular relevance to both permeability and solubility is the degree of ionization of the drug. Residence time at each site, pH changes and the potential for drug degradation at different sites, the latter resulting in a restricted absorption window, will influence the time frame over which an IVIV relationship is possible. Of the drugs available in ER dosage forms approximately 63% are bases, 15% acids and the remainder either unionizable or small inorganic ions. Acidic drugs will tend to have lower solubility's high up in the gastrointestinal tract (GIT), with solubility increasing down the GIT. In contrast with increased ionization permeability should fall. Thus with acids, as the dosage form moves to a more alkaline environment down the GIT, absorption may change from dissolution control to membrane control depending on the pK.a of the drug. In contrast bases will loose solubility with transit down the GIT, but become more permeable; absorption becoming more dissolution/release controlled or in extreme cases solubility controlled in the latter stages of the absorption phase. In the light of the above considerations a modified biopharmaceutic classification is proposed for ER products.

Biological Availability↗
PubMed1996

Physicochemical characterization of diclofenac N-(2-hydroxyethyl)pyrrolidine: anhydrate and dihydrate crystalline forms.

This study on diclofenac N-(2-hydroxyethyl)pyrrolidine (DHEP) characterizes and compares the anhydrate (DHEPA) and dihydrate (DHEPH) solid state forms using powder X-ray diffraction, infrared spectroscopic, and thermal analyses. Heats of solution and intrinsic dissolution rates are determined. The thermodynamics of hydration are discussed and the entropic cost of dihydrate formation is calculated. Reported differences in the solution behavior of DHEP crystallized from different solvents are explained. The molecular structures of both solid forms were determined and are presented. Crystal data for DHEPA: triclinic, space group P-1 (No 2), a = 11.662(2) A, b = 11.874(2) A, c = 15.296(3) A, alpha = 76.183(14) degrees, beta = 84.575(12) degrees, gamma = 87.028(12) degrees V = 2046.8(6)A3, Z = 4. Crystal data for DHEPH: triclinic, space group P-1 (No 2), a = 9.356(3) A, b = 9.920(2) A, c = 13.5413(12) A, alpha = 69.915(12) degrees, beta = 82.05(2) degrees, gamma = 71.51(2) degrees, V = 1118.9(4) A3, Z = 2. The experimentally observed ease of dehydration under conditions of nitrogen purge is explained in terms of crystal packing within the dihydrate.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

The relationship between rat intestinal permeability and hydrophilic probe size.

PURPOSE: The relationship between rat intestinal permeability (Papp) of a range of hydrophilic probe molecules and probe geometry was examined. METHODS: Molecules studies included mannitol, the polyethylene glycols (PEGs) 400, 900, and 4000, the dextran conjugated dye Texas Red (MW 3000) and the polysaccharide inulin (MW 5500). Molecular surface area, volume and cross-sectional diameter for each probe were determined from computer models. The effect of the bile salt sodium cholate, and bile salt: fatty acid mixed micelles on probe intestinal permeability was also studied. RESULTS: Of the size parameters tested, cross-sectional diameter correlated best with log intestinal permeability. The data was fitted to a relationship of the form Papp = Papp zero exp(-Krca) where rca is the molecular cross sectional radius. Papp zero and K are constants. Estimates of equivalent pore radii (R) were also made; the use of rca giving the most reasonable estimate of R. Absorption of all probes was enhanced by both simple and mixed micellar systems. CONCLUSIONS: For large hydrophilic probes and possibly protein drugs, cross sectional diameter is a more important size parameter than volume based values for evaluating size-related retarded absorption. The relationship established may be used as a tool to assess absorption enhancement potential of excipients.

Animals↗
PubMed1995

Dissolution rate of cholesterol and palmitic acid mixtures in cholelitholytic cosolvent systems.

The dissolution rates and solubilities of cholesterol monohydrate, palmitic acid, and their mixtures in the cholelitholytic solvents monooctanoin (MO) and methyl tert-butyl ether (MTBE) and mixtures of these two solvents were determined. The dissolution rates obtained were consistent with the diffusion-controlled two-component noninteracting model. The addition of MTBE as cosolvent to MO resulted in an increase in the solubility of both cholesterol monohydrate and palmitic acid; in the case of the former, the solubility peaked at 80% MTBE. Neither solute exhibited a log-linear solubility relationship on addition of MTBE as cosolvent. Furthermore the increases in the dissolution rates of both components were much larger than could be explained by the solubility increases alone. Mass transfer coefficients increased dramatically with increasing MTBE content of the solvent, were consistently higher for palmitic acid, and reflected the decline in solvent viscosity. Incorporation of relationships among solubility, viscosity, and cosolvent composition into the two-component noninteracting model gave good correlation between predicted and observed rates over nearly 3 orders of magnitude.

Caprylates↗
PubMed1993

Non-surgical approaches to stones in the biliary tree.

Medical treatment of cholesterol gall stones aims to dissolve the stones leaving the biliary tract stone-free and the gall bladder in situ. The introduction of extracorporeal shock wave lithotripsy and contact solvent therapy with methyl tert butyl ether have revolutionised the medical management of both gall bladder stones and bile duct stones which are too large to be treated by sphincterotomy. Both approaches represent a major advance over cheno- and ursodeoxycholic acid which are effective in less than 30% of cases and require prolonged therapy. All medical treatments require a functioning gall bladder and suffer from relapse rates in the order of 10% per annum. Secondary prophylaxis is expensive and the rate of compliance and long term safety have yet to be established.

Bile Acids and Salts↗