D.F. McCafferty

Development and characterisation of a moisture-activated bioadhesive drug delivery system for percutaneous local anaesthesia

This study describes the design, formulation and characterisation of a moisture-activated device incorporating the tetracaine phase-change system for percutaneous local anaesthesia. Gel intermediates for candidate devices were formulated with various concentrations of bioadhesive polymer, viscosity builder and tetracaine at pH values from 5 to 10. Gels were cast onto a release liner, dried and a backing layer attached, thus forming a percutaneous anaesthetic patch system. Patches were characterised by in vitro measurement of tetracaine flux through a polydimethylsiloxane barrier membrane, apparent viscosities of the casting gels, patch bioadhesion to a porcine skin substrate, uniformity of drug content and chemical stability of the active agent in the system. The clinical efficacy of candidate formulations was evaluated by a volunteer trial. Patches were of a consistent appearance and exhibited a uniform thickness and drug distribution throughout the matrix. Varying formulation parameters significantly (p<0.05) affected drug release, patch viscosity and, thus, clinical efficacy. Tetracaine was stable in the patch system during storage for 6 months at 4 and 25°C. Patches with lower concentrations of bioadhesive and thickener, formulated at pH 8 or above, demonstrated the highest levels of drug flux and provided optimum percutaneous anaesthetic activity. All volunteers reported complete cutaneous anaesthesia at the treated site, with a mean onset time for anaesthesia of 44+6.7 min. The optimised bioadhesive patch device offered a more patient-compliant and convenient alternative to tetracaine percutaneous anaesthetic gel, particularly where large areas of skin are to be treated.

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.

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.

Stabilisation of hydrotropic temazepam parenteral formulations by lyophilisation

Abstract The solubilisation of temazepam by hydrotropic complexation has been investigated. Sodium salicyate and nicotinamide were used as hydrotropes. The former allowed appreciable solubilisation of temazepam but the effect was less marked in the case of diazepam. Increased solubilisation with temazepam was attributed to an increase in hydrogen bonding between drug and hydrotrope. Solutions of temazepam solubilised with sodium salicylate developed an unacceptable yellow colour on storage. This problem was overcome by lyophilisation. Lyophilised injections were readily reconstituted and initial assessment in rabbits indicated a satisfactory pharmacological response. Lyophilisation resulted in a preparation with excellent storage characteristics.

Synthesis, hydrolysis kinetics and anti-platelet effects of isosorbide mononitrate derivatives of aspirin

Two isomeric aspirin derivatives of isosorbide-5-mononitrate (ISMN) were prepared and evaluated as potential mutual prodrugs of aspirin and nitric oxide. The hydrolysis of both compounds was studied in pH 7.4 phosphate buffer solution, buffered alpha-chymotrypsin solution and 10% buffered rabbit plasma. The benzodioxin-4-one derivative was hydrolysed to salicylic acid and ISMN acetate in buffer solution (t(1/2) 32.1 h), 10% buffered rabbit plasma (t(1/2) 25.7 min) and alpha-chymotrypsin (t(1/2) 86.6 min). The carboxylic acid ester derivative ISMNA was hydrolysed via the salicylate ester in buffer solution (t(1/2) 48.5 h) but was rapidly and almost exclusively hydrolysed to aspirin and ISMN in plasma solution (t(1/2) 2.8 min). The hydrolysis appeared to be enzyme mediated as it was suppressed by co-incubation with eserine. ISMNA was evaluated for its ability to inhibit platelet aggregation in rabbit PRP in response to the following agonists: arachidonic acid (AA) (100 microM), ADP (1.2 microM), phorbol ester (0.5 microM), platelet activating factor (PAF) (5 nM) and the thromboxane mimic U46619 (1.5 microM). ISMNA suppressed platelet response to AA at 1 microM whereas 10 microM aspirin showed no inhibitory effects.

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.

Determination of three-component partial solubility parameters for temazepam and the effects of change in partial molal volume on the thermodynamics of drugs solubility

Abstract Three-component partial solubility parameters for temazepam were determined by the extended Hansen regression model. A high level of correlation was observed when the Flory-Huggins entropy correction was incorporated into the model. The partial molal volume of temazepam was determined in the saturated solutions and these experimental values further improved the correlation. The changes in molal volume are shown to affect both the entropy change and the enthalpy change, attributable to dispersion forces, occurring in the solution process. The dispersion forces operating between solute and solvent are corrected for changes in molal volume by the use of a derived equation. The final model for temazepam solubility showed a high degree of correlation, giving as values for the partial (Hansen) solubility parameters of temazepam: δ D = 10.71, δ P = 4.79, δ H = 4.02 cal 1 2 cm −3 2 . The experimental partial solubility parameters predicted the solubility of temazepam in 29 solvents with an average error of 33.4%.

The metabolism of amethocaine by porcine and human skin extracts : influence on percutaneous anaesthesia

Abstract Amethocaine, a local anaesthetic of the ester class, produces effective percutaneous anaesthesia of the skin when applied as a novel preparation. The metabolism of the drug by cutaneous esterases was investigated using enzymatic extracts of porcine and human whole skin, and of human epidermis. Analysis of the incubation mixture indicated the production of p-(butyl)aminobenzoic acid, confirming that metabolism of the substrate occurred via cleavage of the ester side chain. In all cases, the rate of metabolic transformation was slow, requiring about 24 h for a 50% reduction in substrate concentration. There was evidence that amethocaine, but not its metabolite, was bound to proteinaceous components of the cutaneous extracts. Given the prolonged in vivo anaesthetic activity of amethocaine percutaneous anaesthetic preparations, the ability of the skin to metabolise the drug is likely to be of significance in determining the duration of anaesthetic activity but is too slow to influence speed of onset of the anaesthetic effect. The lack of systemic toxicity with percutaneous amethocaine may be explained by a combination of slow drug release from the stratum corneum and metabolism by cutaneous esterases.

Non-invasive monitoring of percutaneous local anaesthesia using laser-Doppler velocimetry

Abstract The dermal absorption of amethocaine from percutaneous local anaesthetic preparations has been monitored in a panel of 10 volunteers using laser-Doppler velocimetry (LDV). LDV is a non-invasive technique which responds to increased perfusion in the cutaneous microcirculation. The study was fully randomised and double-blinded. A standard regimen involving a 30 min application time for the preparations was followed in all cases. Statistical analysis of the LDV results was made using one-way analysis of variance and the Newman-Keuls multiple-range test. A significant increase in peak blood cell flux resulted from application of the formulations, correlating with an increase in the drug concentration. In all cases the increased perfusion was significantly different from placebo. The time at which the peak flux occurred was in good agreement with the previously determined mean onset times for anaesthesia with these preparations. However, the area under the perfusion curve was not a reliable indicator of the duration of anaesthesia. The transient erythema occasionally observed with amethocaine percutaneous anaesthetic preparations was confirmed as a pharmacological property of the drug rather than a slight side-effect of the formulation.