Drug delivery by the intravaginal route.

The human vagina represents a potential, accessible space that offers a valuable route for drug delivery through the use of specifically designed carrier systems for both local and systemic applications. Intravaginal drug delivery is particularly appropriate for drugs associated with women's health issues but may also have applications in general drug delivery within the female population. A range of drug delivery platforms suitable for intravaginal administration are discussed in this review, including hydrogels, vaginal tablets, pessaries/suppositories, particulate systems, and intravaginal rings. Drug release mechanisms and absorption pathways are reviewed with respect to a range of therapeutic and prophylactic indications for intravaginal delivery.

The concomitant development of poly(vinyl chloride)-related biofilm and antimicrobial resistance in relation to ventilator-associated pneumonia.

Ventilator-associated pneumonia is a major cause of death in intensive care patients and the endotracheal tube, commonly fabricated from poly(vinyl chloride) (PVC), is acknowledged as a significant factor in this. Bacteria colonise the biomaterial, thereby adopting a sessile mode of growth that progresses to the establishment of an antibiotic-resistant biofilm by the accretion of a protective glycocalyx. This study examined the sequential steps involved in the formation of biofilm on PVC by atomic force microscopy and the concomitant development of resistance to an antibiotic (ceftazidime) and to a non-antibiotic antimicrobial agent (hexetidine). Staphylococcus aureus and Pseudomonas aeruginosa isolated from ET tube biofilm were employed. The surface microrugosity of bacteria growing in sessile mode on PVC decreased significantly (p < 0.05) over the period 4, 24, 48 h and 5 d. The progressive accretion of bacterial glycocalyx was readily visualised in micrographs leading to a smoother surface topography with time. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) for ceftazidime and hexetidine against planktonic (suspension) S. aureus were lower than for Ps. aeruginosa. Furthermore, sessile populations of S. aureus and Ps. aeruginosa on PVC exhibited greater resistance to both ceftazidime and hexetidine when compared to planktonic bacterial growth. The efficacy of the agents, determined by kill kinetics, against sessile bacteria was dependent on age, with established biofilms (> or = 24 h) significantly more resistant (p < 0.05) than early sessile populations (< or = 4 h). Importantly, for practice, even newly colonised bacteria (1 h) were significantly more resistant to antibiotic than planktonic bacteria. Hexetidine was significantly more active (p < 0.05) than ceftazidime on biofilms of both isolates, irrespective of age, with total kill within 24 h treatment. Hexetidine may offer promise in the resolution of infection associated with PVC endotracheal tubes.

Role of physiological conditions in the oropharynx on the adherence of respiratory bacterial isolates to endotracheal tube poly(vinyl chloride).

Pneumonia is a major problem in intensive care patients and can be induced by pathogenic bacteria adhering to poly(vinyl chloride) (PVC) endotracheal (ET) tubes. This study examines the influence of surface properties on the adherence of the respiratory isolates Staphylococcus aureus and Pseudomonas aeruginosa to PVC. In particular, the influence of respiratory tract physiological conditions, 5% CO2 and saliva, on adherence was investigated. In general, decreased adherence to PVC was observed when bacteria were grown in CO2. When these CO2-grown bacteria were treated with saliva their adherence to PVC significantly increased; however, their adherence was significantly reduced to saliva-treated PVC. Treatment of both bacterial isolates with saliva decreased their negative zeta potential, a factor which may directly contribute to the observed increased microbial (saliva pretreated) adherence to PVC. Cell surface hydrophobicity (CSH) was evaluated by measuring the initial rates of microbial removal from a buffered aqueous phase, to ensure the absence of electrostatic interactions, to an organic phase (xylene). Under physiological conditions, CSH did not appear to be a dominant factor in biomaterial adherence as the CSH of S. aureus was decreased by saliva treatment but was unchanged for Ps. aeruginosa. Additionally, CSH also differed for the two isolates when grown in CO2, significantly decreasing with S. aureus but remaining unaltered with Ps. aeruginosa. Saliva treatment of PVC also decreased the advancing and receding contact angles of the biomaterial and its surface roughness, which may be a factor in the decreased adherence of saliva-treated bacteria to this surface. Alternative biomaterials or surface modifications appear necessary for the desired improvements in ET tube effectiveness. This study highlights the influence of physiological conditions on biomaterial and bacterial surface characteristics and subsequent interactions. It is imperative that the physiological conditions predominating in the clinical area of biomaterial use be considered when investigating device biocompatibility.

In vivo ac impedance spectroscopy of human skin. Theory and problems in monitoring of passive percutaneous drug delivery.

The use of impedance spectroscopy to evaluate transdermal drug delivery is discussed and new techniques and protocols are suggested to avoid or minimize potential problems. A novel multichannel impedance analyzer, exploiting the advantages of the "three-electrode" configuration, was employed to measure the effects of differing topically applied concentrations of the percutaneous local anesthetic amethocaine on the electrical properties of the treated skin sites. Each measured impedance spectrum was modeled by an equivalent circuit consisting of a resistor in series with the parallel combination of a pseudocapacitance and a resistor. Due to differences in skin sites and to the finite times taken to apply each electrode, it was difficult to satisfactorily compare and contrast the results obtained from adjacent skin sites. Normalization of data highlighted differences in relative impedance changes and aided the meaningful comparison of treated skin sites.

Design of a silicone reservoir intravaginal ring for the delivery of oxybutynin.

Oxybutynin, a drug of choice in the treatment of urinary incontinence, has low oral bioavailability due to extensive first-pass metabolism. A toxic metabolite, N-desethyloxybutynin, has been linked to adverse reactions to oral oxybutynin. This study, therefore, reports on the design of an oxybutynin intravaginal ring (IVR) of reservoir design, comprising an oxybutynin silicone elastomer core encased in a non-medicated silicone sheath, manufactured by reaction injection moulding at 50 degrees C. An unusually high initial burst release of oxybutynin (42.7 mg in 24 h) was observed in vitro with a full length core (100 mg drug loading), with subsequent non-zero order drug release. Use of fractional segment cores substantially reduced the burst effect, yielding linear cumulative drug release versus time plots from days 2 to 14. Thus, a 1/8 fractional segment core gave a 24 h burst of 11.28 mg oxybutynin and, thereafter, zero order release at the target dose of 5 mg/day over 14 days. Two oxybutynin cores, each 1/16 of full length, gave a greater release than a single 1/8 core, due to core segment end effects resulting in an increased surface area for release. The burst release was investigated by determining drug solubilities in the propan-1-ol product of elastomer condensation cure (390 mg/ml) and in the elastomer itself (13.9-20.21 mg/ml, by direct extraction and indirect thermal methods). These high oxybutynin solubilities were considered the major contributors to the burst effect. It was concluded that use of a fractional segment core would allow development of a suitable oxybutynin reservoir IVR.

Rheological, mechanical and membrane penetration properties of novel dual drug systems for percutaneous delivery.

In this study it has been demonstrated that mixtures of two solid drugs, ibuprofen and methyl nicotinate, with different but complementary pharmacological activities and which exist as a single liquid phase over a wide composition range at skin temperature, can be formulated as o/w emulsions without the use of an additional hydrophobic carrier. These novel dual drug systems provided significantly enhanced in vitro penetration rates through a model lipophilic barrier membrane compared to conventional individual formulations of each active. Thus, for ibuprofen, drug penetration flux enhancements of three- and 10-fold were observed when compared to an aqueous ibuprofen suspension and a commercial alcohol-based ibuprofen formulation, respectively. Methyl nicotinate penetration rates were shown to be similar for aqueous gels and emulsified systems. Mechanisms explaining these observations are proposed. Novel dual drug formulations of ibuprofen and methyl nicotinate, formulated within the liquid range at skin temperature, were investigated by oscillatory rheology and texture profile analysis, demonstrating the effects of drug and viscosity enhancer concentrations, and disperse phase type upon the rheological, mechanical and drug penetration properties of these systems.

Design of an intravaginal ring for the controlled delivery of 17 beta-estradiol as its 3-acetate ester.

Suitable ester prodrugs of 17beta-estradiol are identified, thus permitting effective sustained and controlled estrogen replacement therapy (ERT) from an elastomeric, silicone intravaginal ring (IVR). IVR devices of reservoir design were prepared by blending silicone elastomer base with n-propylorthosilicate (cross-linker) and 10% w/w of 17beta-estradiol or an ester prodrug, the mix being activated with 0.5% w/w stannous octoate and cured at 80 degrees C for 2 min. A rate-controlling membrane was similarly prepared, without the active agent. IVR devices were of cross-sectional diameter 9 mm, outer diameter 54 mm, with core cross-sectional diameter of 2 mm and core length varied as required. Sink conditions were evident for the 17beta-estradiol esters in 1.0% aqueous benzalkonium chloride solution. The low release rates into 0.9% w/v saline of the lipophilic valerate and benzoate esters were due to their intrinsically low aqueous solubilities. In vivo, these esters failed to raise plasma estradiol above baseline levels in postmenopausal human volunteers, despite good in vitro release characteristics under sink conditions. The best release rates under sink conditions, in combination with substantial aqueous solubilities as indicated by the release rates into saline, were observed for the acetate and propionate esters. A combination of drug release characteristics, short plasma half-life and a toxicologically acceptable hydrolysis product indicated that 17beta-estradiol-3-acetate was the prodrug of choice for IVR delivery of ERT. In vivo, an IVR device releasing 100 microg/day of estradiol as its 3-acetate ester maintained over 84 days a circulating plasma concentration in the region of 300 pmoll(-1), within the clinically desirable range for ERT.

Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease.

This study describes the formulation, characterisation and preliminary clinical evaluation of mucoadhesive, semi-solid formulations containing hydroxyethylcellulose (HEC, 1-5%, w/w), polyvinylpyrrolidine (PVP, 2 or 3%, w/w), polycarbophil (PC, 1 or 3%, w/w) and tetracycline (5%, w/w, as the hydrochloride). Each formulation was characterised in terms of drug release, hardness, compressibility, adhesiveness (using a texture analyser in texture profile analysis mode), syringeability (using a texture analyser in compression mode) and adhesion to a mucin disc (measured as a detachment force using the texture analyser in tensile mode). The release exponent for the formulations ranged from 0.78+/-0.02 to 1. 27+/-0.07, indicating that drug release was non-diffusion controlled. Increasing the concentrations of each polymeric component significantly increased the time required for 10 and 30% release of the original mass of tetracycline, due to both increased viscosity and, additionally, the unique swelling properties of the formulations. Increasing concentrations of each polymeric component also increased the hardness, compressibility, adhesiveness, syringeability and mucoadhesion of the formulations. The effects on product hardness, compressibility and syringeability may be due to increased product viscosity and, hence, increased resistance to compression. Similarly, the effects of these polymers on adhesiveness/mucoadhesion highlight their mucoadhesive nature and, importantly, the effects of polymer state (particularly PC) on these properties. Thus, in formulations where the neutralisation of PC was maximally suppressed, adhesiveness and mucoadhesion were also maximal. Interestingly, statistical interactions were primarily observed between the effects of HEC and PC on drug release, mechanical and mucoadhesive properties. These were explained by the effects of HEC on the physical state of PC, namely swollen or unswollen. In the preliminary clinical evaluation, a formulation was selected that offered an appropriate balance of the above physical properties and contained 3% HEC, 3% PVP and 1% PC, in addition to tetracycline 5% (as the hydrochloride). The clinical efficacy of this (test) formulation was compared to an identical tetracycline-devoid (control) formulation in nine periodontal pockets (>/=5 mm depth). One week following administration of the test formulation, there was a significant improvement in periodontal health as identified by reduced numbers of sub-gingival microbial pathogens. Therefore, it can be concluded that, when used in combination with mechanical plaque removal, the tetracycline-containing semi-solid systems described in this study would augment such therapy by enhancing the removal of pathogens, thus improving periodontal health.

Controlled release of a model antibacterial drug from a novel self-lubricating silicone biomaterial.

There is considerable interest in developing medical devices that provide controlled delivery of biologically active agents, for example, to reduce the incidence of device-related infection. Silicone elastomers are one of the commonest biomaterials used in medical device production. However, they have a relatively high coefficient of friction and the resulting lack of lubricity can cause pain and tissue damage on device insertion and removal. Novel silicone cross-linking agents have recently been reported that produce inherently 'self-lubricating' silicone elastomers with very low coefficients of friction. In this study, the model antibacterial drug metronidazole has been incorporated into these self-lubricating silicone elastomers to produce a novel bioactive biomaterial. The in vitro release characteristics of the bioactive component were evaluated as a function of cross-linker composition and drug loading. Although conventional matrix-type release kinetics were observed for metronidazole from the silicone systems, it was also observed that increasing the concentration of the cross-linking agent responsible for the lubricious character (tetra(oleyloxy)silane) relative to that of the standard non-lubricious cross-linking agent (tetrapropoxysilane) produced an increase in the metronidazole flux rate by up to 65% for a specified drug loading. The results highlight the potential for developing lubricious silicone medical devices with enhanced drug release characteristics.

Rheological characterization of bioadhesive, antimicrobial, semisolids designed for the treatment of periodontal diseases: transient and dynamic viscoelastic and continuous shear analysis.

This study examined the creep behavior and oscillatory and flow properties of tetracycline-containing, bioadhesive semisolid formulations, designed for localized treatment of periodontal disease. Formulations were prepared containing hydroxyethylcellulose (HEC, 1, 3, or 5% w/w), poly(vinylpyrrolidone) (PVP, 2 or 3% w/w), polycarbophil (PC, 1 or 3% w/w), and tetracycline (5% w/w, as the hydrochloride). In creep analysis, each formulation exhibited several distinct regions that were mathematically modelled using a multi-element Voigt model with a residual spring and dashpot. Increasing the concentrations of each polymeric component decreased the elastic compliance (J(0)) yet increased the residual viscosity. In oscillatory analysis, increased polymer concentrations increased the storage modulus (G'), the loss modulus (G") and the dynamic viscosity (eta'), yet decreased the loss tangent (tan delta). The relationships between G' or G" and frequency were observed to plateau at higher frequencies, which is indicative of polymer chain entanglement and network formation. With the exception of formulations containing 1% HEC, the formulations were elastic (tan delta < 1), with large G' and small J(0) values. All formulations exhibited pseudoplastic flow with thixotropy. Increasing concentrations of each polymeric component increased the zero-shear viscosity (determined using the Cross model) and was further evidence of polymer chain entanglement. Formulations containing 1% w/w HEC possessed excellent flow properties, however, their thixotropic behavior and essentially elastoviscous nature (large J(0) and tan delta) would be disadvantageous for use in the treatment of periodontal disease because of rapid removal from the pocket and relatively uncontrolled drug release. Despite their advantageous viscoelastic properties, the flow properties of formulations containing 5% w/w HEC were inappropriate, rendering administration through a periodontal syringe potentially difficult. Based on their rheological behavior, formulations containing HEC (3% w/w), PVP (2 or 3% w/w), and PC (1 or 3% w/w) would be suitable for clinical application. However, consideration of other physicochemical properties (e.g., bioadhesion, drug release kinetics) must be performed prior to selection of the most suitable formulation for clinical examination. This study has highlighted the successful complimentary application of creep analysis and oscillatory and flow rheometry for the characterization and development of bioadhesive semisolid formulations for the treatment of periodontal disease.

Physicochemical characterization and preliminary in vivo efficacy of bioadhesive, semisolid formulations containing flurbiprofen for the treatment of gingivitis.

In this study, the physicochemical properties and preliminary in vivo clinical performance of formulations containing hydroxyethylcellulose (HEC; 3, 5, 10% w/w), poly(vinylpyrrolidone) (PVP; 3, 5% w/w), polycarbophil (PC; 1, 3, 5% w/w), and flurbiprofen (5% w/w) were examined. Flurbiprofen release into PBS pH 7.4 was performed at 37 degrees C. The mechanical properties (hardness, compressibility, adhesiveness, initial stress) and syringeability of formulations were determined using a texture analyzer in texture profile analysis (TPA) and compression modes, respectively. In general, the time required for release of 10 and 30% of the original mass of flurbiprofen (t10%, t30%) increased as the concentration of each polymeric component increased. However, in the presence of either 5 or 10% HEC and 5% PC, increased PVP concentration decreased both t10%, t30% due to excessive swelling (and disintegration) of these formulations. Increased concentrations of HEC, PVP, and PC significantly increased formulation hardness, compressibility, work of syringe expression, and initial stress due to the effects of these polymers on formulation viscoelasticity. Similarly, increased concentrations of PC (primarily), HEC, and PVP increased formulation adhesiveness due to the known bioadhesive properties of these polymers. Clinical efficacies of formulations containing 3% HEC, 3% PVP, 3% PC, and either 0% (control) or 5% (test) flurbiprofen, selected to offer optimal drug release and mechanical properties, were evaluated and clinically compared in an experimental gingivitis model. The test (flurbiprofen-containing) formulation significantly reduced gingival inflammation, as evaluated using the gingival index, and the gingival crevicular fluid volume, whereas, these clinical parameters were generally increased in volunteers who had received the control formulation. There were no observed differences in the plaque indices of the two subject groups, confirming that the observed differences in gingival inflammation could not be accredited to differences in plaque accumulation. This study has shown both the applicability of the in vitro methods used, particularly TPA, for the rational selection of formulations for clinical evaluation and, additionally, the clinical benefits of the topical application of a bioadhesive semisolid flurbiprofen-containing formulation for the treatment of experimental gingivitis.

Examination of the physical state of chlorhexidine within viscoelastic, bioadhesive semisolids using raman spectroscopy.

This study examined the effects of polymeric components on the physical state of chlorhexidine within bioadhesive, semisolid formulations using Raman spectroscopy. Semisolid formulations were prepared in which chlorhexidine base (CHX, 5%w/w, particle size <63 microm) was dispersed in aqueous (phosphate-buffered saline, pH 6.8) polymer matrices consisting of one or more polymeric components, namely HEC (3%w/w), PVP (3%), and PC (PC, 3%). Raman spectra were recorded using 785-nm excitation and were typically accumulated for 360 s. The Raman spectra were dominated by the presence of CHX. The spectra of CHX in HEC and in HEC/PVP gels were indistinguishable from that for solid CHX as a result of the insolubility of CHX in these formulations. However, in systems containing PC and CHX, there was a shift in the strongest band from 1564 cm(-1) to 1608 cm(-1), which may be accredited to protonation of the basic CHX by the numerous carboxylic acidic groups on PC. Identical shifts in the band positions were observed when this protonation was modeled using ethanoic acid, supporting the view that there was a simple acid base reaction between PC and CHX. However, there were notable differences in the relative intensities of the peaks from these samples, with the spectrum of CHX in the PC matrix displaying properties intermediate between those of CHX dissolved in ethanoic acid and solid CHX diacetate. This may be accredited to the limited solubility of the CHX-PC ion pair. In matrices containing HEC and PC, no peak was observed at 1564 cm(-1), whereas the intensity of the peak at 1608 cm(-1) was increased. Therefore, in these formulations CHX was completely converted to the di-cation as a result of the synergistic effects of PC (which protonated CHX) and HEC (which solubilized the di-cation). In the absence of either HEC or PC, complete protonation was not achieved. It is suggested that this enhancement of solubility of H(2)CHX(2+) may be due to hydrogen bonding, given the hydroxylated nature of HEC. In conclusion, this study has shown the applicability of Raman spectroscopy for both the analysis of opaque, semisolid formulations and, additionally, for the examination of the state of therapeutic agents within such matrices. In particular, using Raman spectroscopy, it was uniquely possible to identify the roles of various polymeric components on both the ionization and solubilization of CHX within aqueous semisolid systems.

Response surface methodology as a predictive tool for determining the effects of preparation conditions on the physicochemical properties of poly(isobutylcyanoacrylate) nanoparticles.

Preparation conditions of nanoparticles greatly influence their physicochemical characteristics. A factorial design was used to evaluate the influence of these conditions on the particle diameter, zeta potential, polydispersity, percentage recovery, and molecular weight of poly(isobutylcyanoacrylate) nanoparticles. The relationship between these responses and the effects of simultaneously varying three preparation factors (monomer concentration, surfactant concentration, pH of the polymerization medium) were modelled by response-surface methodology. Three levels were chosen for each factor, giving 27 trials. The responses obtained in the experimental design were found to be modelled by either a reduced quadratic or second-order model. Particle diameter was found to be a function of the pH, whereas zeta potential depended on pH and to a lesser extent of the monomer concentration. Polydispersity depended on the pH and an interaction term between pH and the surfactant concentration. The particle recovery was significantly influenced by all three factors, whereas the pH was the primary influence on the molecular weight. Thus, response surface methodology gave detailed information on the predicted physicochemical characteristics found on poly(isobutylcyanoacrylate) nanoparticles prepared using a wide range of experimental conditions.

Breaking out of the ivory tower: from academia to clinic.

This paper considers the relationship between academic research and industry in terms of the commercial exploitation of product or process driven programmes originating in academic institutions. The commercial exploitation of pharmaceutical research is the only practical means of achieving the desired end-point of all research programmes in the pharmaceutical sciences-achieving patient benefits. The requirements for generating intellectual property rights (IPR), types of IPR likely to be encountered, time scales, costs, potential partnerships and commercial routes for exploitation are discussed. The ability to link up with industry to exploit new pharmaceutical products or processes is exemplified through two models. Model 1 involves out-licensing of IPR generated wholly within an academic setting and is illustrated by reference to the development of Ametop Gel, a novel percutaneous anaesthetic preparation. Model 2 involves a partnership with industry in a risk-sharing format, with both partners contributing expertise to the project. This latter model is illustrated by reference to a new controlled and sustained release intravaginal ring delivery system for oestrogen replacement therapy.

The relation between molecular connectivity and gas chromatographic retention data.

The recently developed topological index, molecular connectivity (chi), has been correlated using multiple regression analysis with gas chromatographic retention time (Rt) for various series of compounds. For saturated and unsaturated aliphatic hydrocarbons, and aliphatic aldehydes, good correlation with log Rt was achieved by one-parameter linear equations in terms of the first-order conncectivity index. (1chi). The equation for aliphatic alcohols required an additional parameter, the valence connectivity (vchi) for satisfactory correlation. One-parameter equations using 1chi also good correlation with log Rt for three series of drug molecules, amphetamines, barbiturates and phenothiazines. In all cases the equations generated gave good agreement between calculated and observed log Rt values.

Molecular connectivity and gas chromatographic retention parameters.

The relation between gas chromatographic retention parameters and molecular connectivity has been investigated for several series of compounds including hydrocarbons, compounds containing oxygen functional groups (esters, aldehydes, ketones, alcohols and ethers) and drug molecules., With the oxygenated compounds good correlation was observed with the first order valence connectivity index, whilst for the other groups multiparameter equations were required for satisfactory correlation. The effect of column to column variation within a series was also investigated.

The application of differential pulse voltammetry at the glassy carbon electrode to multivitamin analysis.

Differential pulse voltammetry at the glassy carbon electrode has been applied to the determination of ascorbic acid, pyridoxine and folic acid in a multivitamin preparation. The individual vitamins all gave well-defined peaks in the anodic region with a linear response of peak current to concentration. The water-soluble vitamins were extracted into aqueous solution and folic acid into dibasic potassium phosphate solution. Before determination of pyridoxine, the ascorbic acid peak was depressed by reaction with formaldehyde. Iron (II) present in the multivitamin preparation did not interfere with the analysis. The voltammetric method compared favourably in terms of accuracy and precision with official methods: it was found to be much simpler, with sample manipulation kept to a minimum. The method was found to be generally applicable to the determination of the vitamins in several multivitamin preparations, or, in simplified form, to the determination of the individual vitamin preparations.

The determination of aluminium in antacid formulations by Gran's Plot titration with sodium fluoride.

The aluminium content of a number of proprietary antacid formulations has been determined by titration with sodium fluoride, using the fluoride activity electrode as an end-point detector. Results compared favourably with the official method. The fluoride titration, however, involved less sample manipulation and was more rapid to carry out. End-point detection was made easier by treating titration data by the Gran's Plot method.

Sustained release of 5-fluorouracil from polymeric nanoparticles.

The use of biodegradable nanoparticles loaded with 5-fluorouracil was investigated as a potential means to sustain the release of this drug. Nanoparticles prepared from four biodegradable polymers were loaded with 5-fluorouracil using three loading concentrations of drug and three different concentrations of added polymer. Washing particles using a centrifugation/re-suspension with ultrasound protocol was found to dislodge the majority of drug, resulting in an over-estimation of incorporation efficiency and low levels of strongly entrapped drug. Increasing the initial 5-fluorouracil concentration before polymer/monomer addition increased the drug loading in both washed and unwashed particles. Increasing the amount of polymer used to make nanoparticles did not increase loadings, but did produce increased amounts of unusable polymer waste. Drug release from nanoparticles was evaluated using a Franz cell diffusion apparatus, which showed an initial burst effect followed by a slower release phase over 24 h. Indeed, nanoparticles prepared from poly(lactide-co-glycolide) released 66% of their 5-fluorouracil payload over this period. It was concluded that 5-fluorouracil-loaded nanoparticles could be readily included into a hydrogel-based delivery system to provide sustained drug release for trans-epithelial drug-delivery applications.

The relationship between molecular connectivity and partition coefficients.

Kier & Hall (1976) demonstrated that a relationship existed between molecular connectivity and Log P (the Log of the octanol/water partition coefficient) for several classes of compounds and also for the combined classes. This work utilized a number of Log P values calculated using Pi values. We have reinvestigated this relationship using experimentally determined Log P values. The results confirm Kier & Hall's findings although different connectivity indices are brought into the equations.