摘要:

In this paper, an attempt is made to find functional definitions of bioavailability and bioequivalence for topical products and to examine critical factors that influence topical bioavailability and bioequivalence. A physical model approach for quantifying the problem and increasing our understanding is presented here. The key assumptions are (1) that the target site is in the lower epidermis (basal layer) or in the dermis, and (2) that it is the thermodynamic activity (i.e., the free drug concentration, C*, of the active drug species) at the target site that is the true correlate of drug effectiveness. Studies initiated to implement the physical model approach involved first validating a ‘three-tiered’ model for finite dose drug uptake/transport in skin with experimentally determined input parameters (partition coefficient, K, and steady-state permeability coefficients, P, for the stratum corneum, viable epidermis, and dermis). Hydrocortisone was used as the model drug with hairless guinea pig skin as the model membrane. The physical model is used to show, via the C* concept, how formulation factors may influence bioavailability and bioequivalence. Finally, a method is presented for predicting the efficacy of topical formulations employing appropriate in vitro data and physical model calculations.

ISSN:1660-5527    

DOI:10.1159/000211030

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

The Living Skin Equivalent (LSETM) is an organotypic coculture of human dermal fibroblasts in a collagen-containing matrix and a stratified epidermis composed of human epidermal keratinocytes. In order to establish the feasibility of using this in vitro system as a model for cutaneous biotransformation, the metabolic fate of topically applied testosterone (T) was monitored in the LSE. After a 24-hour exposure period (37 °C) to radiolabelled T, LSE extracts analyzed by high-performance thin-layer chromatography showed that approximately 50% of the applied T had been metabolized. Identified metabolites included bands which comigrated with polar metabolites and products of T 5α-reductase. The general distribution of the observed metabolites was similar to that obtained usingbiopsied human skin. The rates of T penetration (32 °C) through the LSE were monitored after application of T in two vehicles (water and petrolatum) and yielded permeability constants (Kps) of 29 and 1.6 × 10-3 cm/h, respectively. These Kp values were 4- to 6-fold higher than those reported for human abdominal skin, and reflect the vehicle-related shift in penetration seen in human skin. The Kp values for two additional steroids, estradiol and hydrocortisone, and for T were also determined at 22 °C and compared to published Kp values. These Kp values in the LSE were, respectively, 63-, 187-and 35-fold higher than those reported for human skin. The data suggest that compared to human skin the LSE has only a partial barrier function to the passage of test chemicals. The magnitude of the difference in the rates of penetration between the LSE and human skin depends on the test chemical. For specific chemicals, such as T, the LSE simulates certain aspects of skin metabolism and percutaneous absorption.

ISSN:1660-5527    

DOI:10.1159/000211031

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

A study was performed to investigate the local penetration into the nail, the systemic absorption into the rest of the body, and the routes of excretion of sodium pyrithione following topical application to the nail. Approximately 20 μ1 of a film-forming 3% sodium 14C-pyrithione solution was applied once daily to 5 fingernails and 5 toenails of 4 rhesus monkeys for 6 or 7 days. Following dose removal on study day 7, 2 animals were sacrificed, and the treated nails were analyzed for radioactivity. The other 2 monkeys received the topical dose for 1 more day and were monitored during the postdosing period. Sodium 14C-pyrithione was absorbed slowly into and across the nail following topical application, with the nails serving as reservoirs for the drug. Further evidence of the slow movement of sodium pyrithione across the nail was provided by peak plasma 14C equivalents obtained on day 9, 1 day after the last dose had been removed from the nails. Only slight drug concentrations were measurable in plasma, with no radioactivity observed beyond day 12. The urinary excretion data exhibited a delay in peak urinary excretion (days 8 and 9), and an elimination half-life of 2 days, so that approximately 90% of the absorbed drug was eliminated within 1 week following treatment. Including a minor excretion pathway through the feces, total excretion as a percent of dosage was 8.5 %, indicating that less than 10% of the applied topical dose of sodium pyrithione was absorbed systemically. Because monkey and human nails have similar absorptive characteristics, it is likely that corresponding levels of sodium pyrithione equivalents would be absorbed across human nails treated with sodium pyrithione.

ISSN:1660-5527    

DOI:10.1159/000211032

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

The purpose of the present research was to test the ion pair absorption hypothesis with respect to the topical route of drug delivery. The experiment consisted of preparing various lido-cainen-alkanoate ion pairs, then characterizing them by proton magnetic resonance spectroscopy, elemental analysis and conductivity. Percutaneous absorption studies through excised hairless mouse skin were carried out using ethanolic solution of radiolabeled 14C-lidocaine-octanoate, 14C-lido-caine-decanoate and 14C-lidocaine-dodecanoate. Studies were conducted under steady-state conditions using Bronaugh’s flow-through apparatus and normal saline as the receptor fluid. Ethanolic solution of a lidocaine base served as a control. The apparent differences in flux between lidocaine and the various ion pairs were statistically significant (p < 0.05). The differences among the fluxes of the various ion pairs were not statistically significant (p > 0.05), nor were the differences in lag times (p > 0.05). The difference between the flux values of lidocaine- 1-14C-dodecanoate and 14C-lidocaine-dodecanoate infers that lidocaine-dodecanoate did not cross the excised, full-thickness, hairless mouse skin as an intact 1:1 ion pair. The formation of weakly associated ion pairs was suggested by the apparent low-association constants (Ka = 15-17 liters/mol) obtained at 25 °C in methanol by conductometric analysis.

ISSN:1660-5527    

DOI:10.1159/000211033

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

The purpose of this study was to assess the effect of several drugs on the increase in cutaneous capillary permeability induced by intradermal injection of substance P (SP) and Sar9Met(O2)11-SP in guinea pig skin. On the one hand, the increase in cutaneous capillary permeability was partly reduced by spantide, promethazine, atropine or SR 40037, an inhibitor of the angiotensin-converting enzyme. On the other hand, norepinephrine and B3824, a B2-antagonist of bradykinin, showed an enhancing effect. Our results suggest that the effect of SP and Sar9Met(O2)11-SP in guinea pigs is partly mediated by histamine and acetylcholine, and that there is a relationship between tachykinins and bradykinin.

ISSN:1660-5527    

DOI:10.1159/000211034

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

Microdialysis, a new bioanalytical sampling technique, enables the measurement of substances in the extracellular space. This study investigates the use of the technique in the in vivo measurement of histamine levels in human skin. Microdialysis probes are equipped at the tip with a semipermeable polycarbonate membrane which permits the passive diffusion of substances. 16 probes were inserted, via a guide, into the skin of the ventral forearm of 8 patients or volunteers. The probe was perfused at a flow of 5 μ1/min, with samples being collected at intervals of 10 min and analysed by RIA technique. The mean histamine level in the first 10-min sample following probe insertion was 39.4 nM. The mean histamine value fell with successive 10-min samples (8.8, 4.6, 2.3 nM). An equilibration period of 40 min following probe insertion is suggested for histamine studies, where provocation of the skin is to be performed. Microdialysis appears to be a promising new tool for quantitative and chronological studies of cutaneous inflammatory mediators.

ISSN:1660-5527    

DOI:10.1159/000211035

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

We have evaluated a subchronic model of contact hypersensitivity in the guinea pig to mimic human chronic/recurrent eczema. Repeated challenges of the ears of previously sensitized guinea pigs with 0.1 % dinitrochlorobenzene (once a week for 4 weeks) induced a typical oedema response, which increased during the first 48 h after each challenge. Crusts were detectable (48 h after challenge) and histological observations (72 h after challenge) revealed hyperplasia, papillomatosis, hyperkeratosis and some mononuclear cell infiltrates in the dermis. In agreement with clinical observations in humans, topical treatment of challenged animals with corticosteroid (1 % hydrocortisone) reduced the oedema, hyperplasia, papillomatosis, and leucocyte infiltrates, while application of 5% bufexamac (a non-steroidal drug) was associated with a slight enhancement of the inflammatory response. Thus, this model presents clinical and histological similarities with human eczema. Its pharmacological relevance is also suggested, although further investigations are required to better define its selectivity.

ISSN:1660-5527    

DOI:10.1159/000211036

出版商:S. Karger AG    

年代:1992

数据来源: Karger