OBJECTIVES: The aim was to assess mathematically the nature of a skin permeability dataset and to determine the utility of Gaussian processes in developing a predictive model for skin permeability, comparing it with existing methods for deriving predictive models. METHODS: Principal component analysis was carried out in order to determine the nature of the dataset. MatLab software was used to assess the performance of Gaussian process, single linear networks (SLN) and quantitative structure-permeability relationships (QSPRs) using a range of statistical measures. KEY FINDINGS: Principal component analysis showed that the dataset is inherently non-linear. The Gaussian process model yielded a predictive model that provides a significantly more accurate estimate of skin absorption than previous models, particularly QSPRs (which were consistently worse than Gaussian process or SLN models), and does so across a wider range of molecular properties. Gaussian process models appear particularly capable of providing excellent predictions where previous studies have shown QSPRs to fail, such as where penetrants have high log P and high molecular weight. CONCLUSIONS: A non-linear approach was more appropriate than QSPRs or SLNs for the analysis of the dataset employed herein, as the prediction and confidence values in the prediction given by the Gaussian process are better than with other methods examined. Gaussian process provides a novel way of analysing skin absorption data that is substantially more accurate, statistically robust and reflective of our empirical understanding of skin absorption than the QSPR methods so far applied to skin absorption.

Synopsis The foaming properties of solutions of purified samples of the C(10) to C(18) even-numbered sodium alkyl sulphates in water have been studied using three methods of foam generation. Foam volumes increased with increase in surfactant concentration, and reached a limiting value at the C.M.C. At post-C.M.C. concentrations, foam volumes increased to a maximum with temperature, and then decreased. The point at which the maximum occurred, the maximum foam temperature (M.F.T.), varied from one surfactant to another, but was independent of the experimental method. M.F.T. was inversely proportional to the hydrophile-lipophile balance (H.L.B.) value. The corresponding triethanolamine salts behaved in the same way. Similar results were observed with non-ionics, but the plots of H.L.B. value against M.F.T. were positive.

Synopsis The preparation and characterisation of purified C(10) to C(18) even-numbered triethano-lamine alkyl sulphates are described. Critical micelle concentrations were determined at 25 degrees C, using both conductance and drop volume methods. The authenticity and purity of the products are established, and evidence presented for amending the accepted melting points for two of the compounds.

OBJECTIVES: To determine the metabolism of captopril n-carboxyl derivatives and how this may impact on their use as transdermal prodrugs. The pharmacological activity of the ester derivatives was also characterised in order to compare the angiotensin converting enzyme inhibitory potency of the derivatives compared with the parent drug, captopril. METHODS: The metabolism rates of the ester derivatives were determined in vitro (using porcine liver esterase and porcine ear skin) and in silico (using molecular modelling to investigate the potential to predict metabolism). KEY FINDINGS: Relatively slow pseudo first-order metabolism of the prodrugs was observed, with the ethyl ester displaying the highest rate of metabolism. A strong relationship was established between in-vitro methods, while in-silico methods support the use of in-vitro methods and highlight the potential of in-silico techniques to predict metabolism. All the prodrugs behaved as angiotensin converting enzyme inhibitors, with the methyl ester displaying optimum inhibition. CONCLUSIONS: In-vitro porcine liver esterase metabolism rates inform in-vitro skin rates well, and in-silico interaction energies relate well to both. Thus, in-silico methods may be developed that include interaction energies to predict metabolism rates.

The feasibility of using 10% 1,8-cineole as an enhancer for transdermal delivery of haloperidol has been examined. In-vitro transdermal delivery across full-thickness human, rabbit and hairless mouse skins was measured from three polymer gel systems, hypromellose (hydroxypropylmethylcellulose), Carbomer (Carbopol) 940 and macrogol (polyethylene glycol) using Franz cells. Values for the permeability coefficient k(p), calculated as the product (Kh)x(D/h(2)) where these two factors were obtained from curve fitting of the non-steady-state equation over 24 h, were similar from the three formulations. The value of k(p) from hypromellose was significantly enhanced by cineole by factors of 6.2 (4.6-8.1), 5.6 (5.0-6.2) and 3.0 (2.6-3.4) for human, rabbit and mouse, respectively (mean and 95% confidence intervals). Enhancement ratios for K: 13.3 (8.3-20), 3.1 (2.5-3.9) and 2.0 (1.5-2.6), were higher than those for D: 0.47 (0.41-0.55), 1.8 (1.6-2.1) and 1.5 (1.3-1.8). This suggested that the barrier function of the skin lipids was marginally affected and the main effect was to increase the thermodynamic activity of the drug in the barrier. The enhancement achieved in human skin suggested that delivery could be safely enhanced by terpenoids.

The challenge to develop efficient gastroretentive dosage forms began about 20 years ago, following the discovery of Helicobacter pylori by Warren and Marshall. In order to understand the real difficulty of increasing the gastric residence time of a dosage form, we have first summarized the important physiologic parameters, which act upon the gastric residence time. Afterwards, we have reviewed the different drug delivery systems designed until now, i.e. high-density, intragastric floating, expandable, superporous hydrogel, mucoadhesive and magnetic systems. Finally, we have focused on gastroretentive dosage forms especially designed against H. pylori, including specific targeting systems against this bacterium.

Structure-activity relationships were sought for 73 enhancers of hydrocortisone permeation from propylene glycol across hairless mouse skin. Enhancers had chain lengths (CC) from 0 to 16 carbon atoms, 1 to 8 H-bonding atoms (HB), molecular weight 60 to 450, log P (calculated)-1.7 to 9.7 and log S (calculated)-7.8 to 0.7. These predictive properties were chosen because of their ready availability. Enhancement ratio (ER) was defined as hydrocortisone transferred after 24 h relative to control. Values for the ER ranged from 0.2 to 25.3. Multiple regression analysis failed to predict activity; ER values for the 'good' enhancers (ER > 10) were underestimated. Simple guidelines suggested that high ER was associated with CC > 12 and HB 2-5. This was refined by multivariate analysis to identify significant predictors. Discriminant analysis using CC, HB, and molecular weight correctly assigned 11 of the 12 'good' enhancers (92%). The incorrectly assigned compound was a known, idiosyncratic Br compound. Seventeen of the 61 'poor' enhancers (28%) were incorrectly assigned but four could be considered marginal (ER > 8). The success of this simple approach in identifying potent enhancers suggested its potential in predicting novel enhancer activity.

Previous computational studies have explored the relative molecular similarity inherent in the ligands of neurotransmitter-regulated cell receptors and purine nucleotides. This study presents the results of an investigation of the major serotonin (5-HT) receptor classes, using molecular superimposition and fitting data. Ligands for 5HT(1B/C/D) and 5HT(4/7) receptors identified pharmacophores in the adenine ring of ATP. 5-HT(2) and 5-HT(3) receptor ligands identified pharmacophores in the guanosine nucleotide and cyclic nucleotide, respectively. The described molecular similarity is consistent with the cyclic nucleotide responses observed during signal transduction events initiated by 5-HT, and the reported similarity between ligands of the 5-HT(1B) and 5-HT(1D), 5-HT(1A) and 5-HT(7), and 5-HT(4) and 5-HT(3) receptors. The results are discussed in terms of current pharmacophoric models and signal transduction events involving interaction between G-protein receptors and catalytic sites.

Retinyl ascorbate (RA-AsA), an ester co-drug of vitamins A (RA) and C (AsA), is proposed as a topical antioxidant/cell division regulator for reducing UV-induced generation of free radicals and disrupted dermal cell growth. The efficacy of dermatological agents is influenced by their retention within the skin, which is increased by the interaction with skin components. Keratin is the major protein (approximately 95%) in the skin, and this paper reports the binding of RA-AsA, RA, AsA, retinol, ascorbic acid palmitate and retinol palmitate to three tissues-human callus, pig ear skin and bovine horn keratin. Tissue samples were incubated with solutions of compounds and the uptake measured as the ratio of bound/free compound at equilibrium. Binding to keratin was assessed using delipidised tissue, and was much higher for the polar compounds, suggesting dipolar/H-bonding interaction. Binding strength was ranked as human > porcine > bovine, but there was no distinction for highly lipophilic compounds. The binding characteristic of native tissues was complicated by lipid content of the tissues. There seemed to be a dual effect. The binding of very lipophilic materials increased with lipid content, implying that a substantial amount is dissolved in the lipid matrix. For highly polar AsA, lipid content decreased the binding, suggesting that the lipid reduced the strong polar interactions with skin protein/keratin.

PURPOSE: Simple rules based on readily accessible physicochemical properties enable identification of solutes that penetrate skin very slowly or rapidly. METHODS: Literature in vitro maximal flux values (Jmax) across human skin were collected for 87 penetrants. Penetrants were assigned as "good"(Jmax > 10(-5.52) mole x cm(-2) x h(-1)),"bad"(Jmax < 10(-8.84) mole x cm(-2) x h(-1)) or "intermediate" based on mean +/- 1SD. The feasibility of using readily available physicochemical properties, such as molecular weight (MW), melting point (MP, degrees K), octanol-water partition coefficient (K), water solubility (S, molarity), number of atoms available for H-bonding (HB), in assigning solutes was examined. RESULTS: Good penetrants had MW < or = 152, log S >-2.3, HB < or = 5, log K < 2.6, MP < or = 432. Bad penetrants had MW > 213, log S <-1.6, HB > or = 4, log K > 1.2, MP > or = 223. Discriminant analysis using MW, HB, log K correctly assigned 70% of compounds. Individual success rates were good (88%), intermediate (58%), bad (93%). Aqueous Jmax data for 148 test solutes were used for validation. Discriminant analysis assigned 76% of compounds, with individual rates of good (76%), intermediate (67%), and bad (97%). No good penetrants were misclassified as bad or vice versa. CONCLUSIONS: These rules enable rapid screening of potential drug delivery candidates and environmental exposure risks.