A. D. Woolfson

Textural analysis and flow rheometry of novel, bioadhesive antimicrobial oral gels

AbstractPurpose. This study examined the rheological and textural characteristics (hardness, compressibilty, adhesiveness and cohesiveness) of bioadhesive oral gels containing the antimicrobial agent chlorhexidine. Methods. Textural analysis was performed using a Stable Micro Systems texture analyser (model TA-XT 2) in texture profile analysis (TPA) mode. In this, an analytical probe was twice compressed into each formulation to a defined depth (15 mm) and at defined rates (2, 4, 6, 8, 10 mm s−1), allowing a delay period (15 s) between the end of the first and beginning of the second compressions. Flow rheograms were performed using a Carri-Med CSL2-100 rheometer with parallel plate geometry under controlled shearing stresses at 20.0 ± 0.1°C. Results. All formulations exhibited pseudoplastic flow with thixotropy. Increasing concentrations of each polymer significantly increased formulation hardness, compressibility, adhesiveness and zero-rate viscosity. Increased hardness and compressibility were due to the attendent increased viscosities of these formulations. Increased adhesiveness was related to the concentrations of the (bioadhesive) polymers employed in these formulations and, in addition, was dependent on the physical state of polycarbophil. Formulation viscosity contributed to product adhesiveness, reflecting the importance of product rheology on this parameter. Decreased formulation cohesiveness, observed as the concentrations of the PVP, PC and HEC (3−5%w/w) were increased, was due an increase in semi-solid character. Numerical values of hardness, compressibility and adhesiveness were affected by the choice of probe speed, a parameter related to rate of shear in flow rheometry. Statistical interactions were observed and were assigned to the effects of HEC on the physical state of PVP (dissolved or dispersed) and PC (swollen or unswollen). Conclusions. This study has demonstrated both the applicability of textural analysis for the mechanical characterisation of bioadhesive semi-solid gel systems and, additionally, the direct influence of viscosity on the parameters defined by textural analysis, namely, hardness, compressibility and adhesiveness.

Design of an intravaginal ring for the controlled delivery of 17β-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 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.

A bioadhesive patch cervical drug delivery system for the administration of 5-fluorouracil to cervical tissue

Abstract A novel bioadhesive cervical patch drug delivery is described, containing 5-fluorouracil for the treatment of cervical intraepithelial neoplasia (CIN). The patch was of bilaminar design, with a drug-loaded bioadhesive film cast from a gel containing 2% (w/w) Carbopol® 981 plasticised with 1% (w/w) glycerin. The casting solvent was ethanol/water 30:70, chosen to give a non-fissuring film with an even particle size distribution. The film, which was mechanically stable on storage under ambient conditions, was bonded directly to a backing layer formed from thermally-cured polyvinyl chloride emulsion. Bioadhesive strength was independent of drug loading in the bioadhesive matrix over the range investigated but was influenced by both the plasticiser concentration in the casting gel and the thickness of the final film. Release of 5-fluorouracil from the bioadhesive layer into an aqueous sink was rapid but was controlled down to an undetectable level through the backing layer. The latter characteristic was desirable to prevent drug spill from the device onto vaginal epithelium in vivo. Despite the relatively hydrophilic nature of 5-fluorouracil, substantial drug release through human cervical tissue samples was observed over approximately 20 h. Drug release, which was clearly tissue rather than device dependent, may have been aided by a shunt diffusion route through aqueous pores in the tissue. The bioadhesive and drug release characteristics of the 5-fluorouracil cervical patch indicated that it would be suitable for further clinical investigation as a drug treatment for CIN.

A COMPARATIVE STUDY OF THE MICROBIAL ANTI‐ADHERENCE CAPACITIES OF THREE ANTIMICROBIAL AGENTS

The antimicrobioal agents, taurolidine, chlorhexidine and povidone‐iodine were examined for microbial anti‐adherence activity. Two adherence systems were investigated using light microscopic and radio‐isotopic assay methods: that of an oral isolate of Candida albicans to human buccal epithelial cells and of a urine isolate of Escherichia coli to human uroepithelial cells. Each of the three agents exhibited significant anti‐adherence activity which was concentration dependent. The activity was expressed at sub‐minimum inhibitory concentrations of the agents. Treatment of either the microbial or epithelial cells resulted in significant reductions in adhering micro‐organisms. Consideration of the data in respect of the skewness coefficient and percentage clear epithelial cells indicated that the agents exhibited a broadly based anti‐adherence capacity.

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.

The relation between molecular connectivity and gas chromatographic retention data

The recently developed topological index, molecular connectivity (&cH), 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 connectivity index. (1&cH). The equation for aliphatic alcohols required an additional parameter, the valence connectivity (v&cH) for satisfactory correlation. One‐parameter equations using 1&cH also gave 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.

In Vivo ac Impedance Spectroscopy of Human Skin: Theory and Problems in Monitoring of Passive Percutaneous Drug Delivery

Abstract: 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.

Percutaneous penetration characteristics of amethocaine through porcine and human skin

Abstract Percutaneous amethocaine gels produce clinically effective local anaesthesia of intact skin. The present study establishes the percutaneous penetration characteristics of amethocaine from such gels through human stratum corneum, epidermis and whole skin barriers. Results are compared with neonate porcine stratum corneum, porcine whole skin and Silastic® as alternative model barrier membranes. Silastic® was shown to overestimate considerably the flux of amethocaine but neonate porcine skin proved to be a good model for the penetration of the drug through human skin. Differences in barrier membrane resistance to amethocaine penetration, and the effect on drug flux of varying the amethocaine concentration in the gel, were analysed separately by a one-way analysis of variance and the Newman-Keuls multiple range test. The main barrier to percutaneous penetration of amethocaine was the stratum corneum. The efficiency of the gel formulation in promoting the percutaneous penetration of amethocaine was reflected in the relatively high fluxes of the drug through both types of stratum corneum. The percutaneous penetration characteristics of amethocaine observed in this study, together with the pharmacological properties of the drug itself, explain the rapid onset and long duration of anaesthesia obtained clinically with the use of amethocaine percutaneous anaesthetic gel.

Percutaneous local anaesthesia: drug release characteristics of the amethocaine phase-change system

Abstract Differential scanning calorimetry has been used to demonstrate that amethocaine base, when formulated as a percutaneous anaesthetic gel, undergoes a phase change at or below normal skin temperature. Under aqueous conditions the melting point of amethocaine was lowered by approx. 10°C. The influence of the phase change on drug release characteristics was investigated in respect of both gelled, saturated amethocaine solutions and formulations containing a reservoir of undissolved drug. Drug release from the formulation, and subsequent penetration of iipophilic barriers, was shown to proceed from the aqueous diffusion layer at the formulation/barrier membrane interface. A more rapid replenishment of the diffusion layer can be achieved after the phase change has occurred. Under these conditions the drug is present both in solution and as undissolved oil droplets, the latter having an enhanced dissolution rate compared to solid drug particles in suspension. Given the low solubility of amethocaine base, and therefore the comparatively low concentration gradient established across the diffusion layer, the proven percutaneous anaesthetic efficacy of amethocaine is largely related to its lipophilicity and anaesthetic potency. An overall scheme is proposed for the drug release characteristics of the amethocaine phase-change system.