Reduced skin irritation with tretinoin containing polyolprepolymer-2, a new topical tretinoin delivery system: a summary of preclinical and clinical investigations.

Novel tretinoin cream and gel formulations have been developed that incorporate polyolprepolymer-2, which is a material designed to help retain drug molecules in and on the skin when applied in topical vehicles. The results of preclinical and clinical investigations have confirmed the beneficial impact of such a vehicle on tretinoin tolerability. In vitro studies with selected polyolprepolymer-containing formulations have reduced initial and cumulative tretinoin percutaneous penetration, and guinea pig studies showed that the gel formulation containing polyolprepolymer-2 caused less erythema and edema than did the corresponding commercially-available tretinoin gel formulation. Human studies with tretinoin containing polyolprepolymer-2 have consistently demonstrated a favorable tolerability profile when compared with commercially-available tretinoin. Use of the polyolprepolymer-2-containing tretinoin formulation in human studies has resulted in reductions in peeling--a problem commonly associated with use of standard tretinoin formulations. These reductions in irritation have not been at the expense of efficacy; acne clinical trial results indicate comparable effectiveness between tretinoin containing polyolprepolymer2 and commercially-available tretinoin.

Topical delivery system for tretinoin: research and clinical implications.

A novel topical tretinoin gel formulation containing a patented TopiCare Delivery Compound, polyolprepolymer-2 (PP-2), was shown to significantly reduce local irritation relative to a marketed tretinoin gel preparation while maintaining clinical efficacy in the treatment of acne. Several in vitro percutaneous absorption studies were conducted with 0.025% tretinoin as a model compound to determine the possible mechanism of action of PP-2 on drug delivery into and through human cadaver skin. Results of these studies have repeatedly shown that a new topical gel formulation containing PP-2 significantly reduces tretinoin penetration while potentially enhancing epidermal deposition compared with a commercial topical gel preparation at the same tretinoin concentration. These studies further support a mechanism of action whereby PP-2 serves as a retentate for drug delivery by formation of a liquid reservoir of polymer and solubilized drug on the skin surface and in the upper layers of the skin, thereby modifying delivery of tretinoin into and through skin. This reservoir of drug and polymer was established within 15 min after topical application, and tretinoin was shown to be highly associated with PP-2. These in vitro findings provide a model by which a new tretinoin gel formulation containing PP-2 reduces irritation relative to a commercial tretinoin gel while maintaining clinical efficacy in the treatment of acne vulgaris.

Percutaneous absorption of hydrocortisone and testosterone on the vulva and forearm: effect of the menopause and site.

The percutaneous absorption of hydrocortisone and testosterone was studied following their application to the vulvar and ventral forearm regions of pre- and post-menopausal women. Percutaneous absorption of hydrocortisone was significantly greater in vulvar skin than forearm skin in both pre- and post-menopausal women (P < 0.05, respectively), whereas the percutaneous absorption of testosterone was significantly increased (P < 0.01) on the vulva compared with the arm only in post-menopausal women. The effect of age on the percutaneous absorption of hydrocortisone and testosterone was evaluated by using the menopause as a biological chronometric end point. It is a common misconception that older skin has a diminished barrier capacity, and that percutaneous absorption is therefore greater. Our studies showed that absorption of hydrocortisone vulval skin of pre-menopausal women was significantly greater (P < 0.01) than in post-menopausal women. The ventral forearm skin of pre-menopausal women tended to show increased absorption compared with post-menopausal women, but statistical significance was not reached. No significant differences (P > 0.05) in the percutaneous absorption of testosterone in vulval or forearm skin were observed between the two age groups.

Human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide.

In order to determine the human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide, a commercial formulation containing either [14C]pyrethrin (3.8 mCi/mmol) or [14C]piperonyl butoxide (3.4 mCi/mmol) was applied to the ventral forearm of six human volunteers. The formulation contained 0.3% pyrethrin and 3.0% piperonyl butoxide. Spreadability studies showed that concentrations of 5.5 micrograms pyrethrin/cm2 and 75.8 micrograms piperonyl butoxide/cm2 (used in this study) would be consistent with levels found in actual use. The forearms were thoroughly cleansed with soap and water 30 min after application (as recommended for actual use). Percutaneous absorption was determined by urinary cumulative excretion following dose application. With a 7-day urinary accumulation, 1.9 +/- 1.2% (SD) of the dose of pyrethrin and 2.1 +/- 0.6% of the dose of piperonyl butoxide applied was absorbed through the forearm skin. 1 hr after application blood samples contained no detectable radioactivity. The percutaneous absorption of pyrethrin and piperonyl butoxide from the scalp was calculated to be 7.5% of the applied dose for pyrethrin and 8.3% for piperonyl butoxide. The calculated half-life of 14C excretion was 50 hr for pyrethrin and 32 hr for piperonyl butoxide. The data should be of relevance to appropriate risk assessment in extrapolating animal data to humans.

Uptake of two zwitterionic surfactants into human skin in vivo.

To evaluate the potential risk associated with dermal exposure to nitrogen-containing amphiphiles commonly found in household and personal-care products, the uptake of N,N-dimethyl-N-dodecylglycine (dodecylbetaine, C12BET) and N,N-dimethyl-N-hexadecylglycine (hexadecylbetaine, C16BET) into human skin in vivo has been measured. The 14C-radiolabeled chemicals were applied in aqueous solution (C12BET concentrations 16, 100, and 800 mM; C16BET concentrations 0.14, 1.0, and 5.4 mM) to the dorsal upper arms of male volunteers for 30 min. At the end of this exposure period, the remaining applied solution was removed, the skin surface was thoroughly washed, and the stratum corneum at the administration site was removed by repeated tape-stripping. Dermal uptake was assessed (i) by direct measurement of the radioactivity recovered on the tape-strips, and (ii) from a predictive relationship previously derived from other research using a similar protocol. As expected, agreement between the two approaches was reasonable (generally within a factor of 3-4); the predictive relationship attempts to account for penetrant which cannot be recovered by the tape-stripping process, and anticipates, therefore, greater chemical exposure to the body than that expected on the basis of the tape-strip associated material alone. A positive control, using the previously studied penetrant, caffeine, demonstrated that the experimental procedure was conducted appropriately. Absorption of the betaines into human skin was significant (for C12BET, uptake was 28-160 nmol/cm2; that for C16BET was 2.3-19.5 nmol/cm2) and was primarily localized (as was caffeine) in the outer layers of the stratum corneum. In parallel experiments, in which unlabeled betaines were applied for 30 min, instead of tape-stripping, skin barrier function (measured by transepidermal water loss) was assessed. No betaine-induced effects on the stratum corneum were observed (in contrast to the sometimes large perturbations seen in vitro following considerably longer exposure times). Overall, the results indicated that the use of these betaines in personal care products, when intended for limited use and rinse-off application, gives no reason for safety concerns.

In vivo percutaneous absorption of hydrocortisone: multiple-application dosing in man.

Percutaneous absorption of hydrocortisone was measured in six healthy adult men from whom informed consent had been obtained. The study compared a single topical dose to multiple-topical dose treatments (one vs three applications) on the same day. 14C-Labeled hydrocortisone in acetone was applied to 2.5 cm2 of ventral forearm skin and protected with a nonocclusive polypropylene chamber. The amount of 14C measured in urine collected over 7 days was used to determine hydrocortisone absorption. The treatments, performed 2 to 3 weeks apart, each utilized adjacent sites on the same individuals. A single dose of 13.33 micrograms/cm2 delivered 0.056 microgram/cm2 of hydrocortisone through the skin. When the single dose was tripled to 40 micrograms/cm2, the amount delivered through the skin increased by nearly three times, from 0.056 to 0.140 micrograms/cm2; the expected delivery was 3 x 0.056 micrograms/cm2 = 0.168 microgram/cm2. Three serial doses of 13.33 micrograms/cm2 (total, 40 micrograms/cm2) were also expected to deliver 0.168 micrograms/cm2 with or without soap and water washing between doses, but the observed amount of hydrocortisone delivered through the skin significantly exceeded our expectations. This indicates that multiple-dosing treatments resulted in a significant increase in bioavailability. It is postulated that increased vehicle application and washing dissolved and mobilized previously dosed hydrocortisone and increased bioavailability.

Percutaneous absorption and skin decontamination of PCBs: in vitro studies with human skin and in vivo studies in the rhesus monkey.

Knowledge of the entry of polychlorinated biphenyls through the skin into the body and subsequent disposition aids estimation of potential for human health hazard. [14C]Aroclor 1242 and [14C]Aroclor 1254 were separately administered intravenously and topically to rhesus monkeys. Following iv administration, 30-d excretion was 39.4 +/- 5.9% urine and 16.1 +/- 0.8% feces (total 55.5 +/- 5.1%) for Aroclor 1242, and 7.0 +/- 2.2% urine and 19.7 +/- 5.8% feces (total 26.7 +/- 7.5%) for Aroclor 1254. Mineral oil and trichlorobenzene are common PCB cosolvents in transformers. Skin absorption of Aroclor 1242 was 20.4 +/- 8.5% formulated in mineral oil and 18.0 +/- 3.8% in trichlorobenzene (p greater than .05). Absorption of Aroclor 1254 was 20.8 +/- 8.3% in mineral oil and 14.6 +/- 3.6% in trichlorobenzene (p greater than .05). PCBs are thus absorbed through skin, and excretion from the body is slow. Vehicle (trichlorobenzene or mineral oil) did not affect percutaneous absorption. In vitro skin absorption in human cadaver skin did not correlate with in vivo findings. This was due to lack of PCB partition from skin into the water receptor fluid, even with addition of 6% Oleth 20 (Volpo 20) solubilizer. Skin decontamination of PCBs showed soap and water to be as effective as or better than the solvent ethanol, mineral oil, and trichlorobenzene in removing PCBs from skin. There is a dynamic time lapse for PCBs between initial skin contact and skin absorption (irreversible removal). Thus initially most PCBs could be removed from skin, but this ability decreased with time to the point where at 24 h only about 25% of the initial PCB skin dose could be recovered with skin washing.

Percutaneous absorption of [14C]DDT and [14C]benzo[a]pyrene from soil.

The objective was to determine percutaneous absorption of DDT and benzo[a]pyrene in vitro and in vivo from soil into and through skin. Soil (Yolo County 65-California-57-8; 26% sand, 26% clay, 48% silt) was passed through 10-, 20-, and 48-mesh sieves. Soil then retained by 80-mesh was mixed with [14C]-labeled chemical at 10 ppm. Acetone solutions at 10 ppm were prepared for comparative analysis. Human cadaver skin was dermatomed to 500 microns and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/hr flow rate) for a 24-hr skin application time. With acetone vehicle, DDT (18.1 +/- 13.4%) readily penetrated into human skin. Significantly less DDT (1.0 +/- 0.7%) penetrated into human skin from soil. DDT would not partition from human skin into human plasma in the receptor phase (less than 0.1%). With acetone vehicle, benzo[a]pyrene (23.7 +/- 9.7%) readily penetrated into human skin. Significantly less benzo[a]pyrene (1.4 +/- 0.9%) penetrated into human skin from soil. Benzo[a]pyrene would not partition from human skin into human plasma in the receptor phase (less than 0.1%). Substantivity (skin retention) was investigated by applying 14C-labeled chemical to human skin in vitro for only 25 min. After soap and water wash, 16.7 +/- 13.2% of DDT applied in acetone remained absorbed to skin. With soil only 0.25 +/- 0.11% of DDT remained absorbed to skin. After soap and water wash 5.1 +/- 2.1% of benzo[a]pyrene applied in acetone remained absorbed to skin. With soil only 0.14 +/- 0.13% of benzo[a]pyrene remained absorbed to skin.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo percutaneous absorption of chemicals: a multiple dose study in rhesus monkeys.

The effect of daily topical application on the in vivo percutaneous absorption of benzoic acid, parathion and salicylic acid in rhesus monkeys has been investigated. The study was designed to test further the hypothesis that topical bioavailability, or body burden, of a chemical following chronic exposure may be accurately predicted from the result of a single acute-dose experiment. No significant change in percutaneous absorption from that following the initial dose was observed following the eighth daily dose of a 14-day multidose regimen for each of the three penetrants considered. The results are consistent with those of recent experiments in humans with malathion and steroids, but not entirely consistent with the results of other animal studies.

In vitro percutaneous absorption and stratum corneum binding of alachlor: effect of formulation dilution with water.

The effect of vehicle dilution on the percutaneous absorption of alachlor, 2-chloro-2',6'-diethyl-N-(methoxymethyl)acetanilide, through excised human skin was determined using flowthrough design glass penetration cells and 14C radiotracer methodology. Three dilutions of alachlor (in the solubilizing commercial formulation) with distilled water were utilized: 1:20, 1:40, and 1:80 (v/v); corresponding to concentrations of 23.0, 11.8, and 5.98 mg alachlor per milliliter, respectively. Skin from the penetration studies and human powdered stratum corneum from the binding studies demonstrated a high capacity for alachlor. A soap and water (1:1, v/v) solution effectively decontaminated powdered stratum corneum. Using plasma as the receptor solution, penetration ranged from 0.5 to 4% of the applied dose for an 8-hr exposure period. Lag times of 1.2 to 1.8 hr were observed. Increasing dilution resulted in significant enhancement (p less than 0.01) in the rate and extent of alachlor penetration. Although the biological significance of this observation is unclear, this phenomenon might be explored in future studies because of its ramifications for human toxicity and for decontamination opportunities.

Bioavailability of topically administered steroids: a "mass balance" technique.

The percutaneous absorption of four steroids (hydrocortisone, estradiol, testosterone, and progesterone) has been measured in vivo in man under occluded and "protected" (i.e., covered, but non-occlusive) conditions. The experimental approach, involving simple modifications of standard radiochemical methodology, has enabled excellent "mass balance" and dose accountability to be achieved. Consequently, the utility of the procedure for the measurement of in vivo topical bioavailability can be inferred. In addition, because of the precision and accountability of the results, the technique offers a potential means to establish quantitative structure-penetration relationships for skin absorption in man. It was found that steroid absorption increased with increasing lipophilicity up to a point, but that penetration of progesterone (the most hydophobic analog studied) did not continue the trend and was at least partly rate-limited by slow interfacial transport at the stratum corneum-viable epidermis boundary. Comparison of data obtained from the occluded and "protected" experiments permitted the effect of occlusion (defined as the complete impairment of passive transepidermal water loss at the application site) to be assessed. Occlusion significantly increased percutaneous absorption of estradiol, testosterone, and progesterone but did not effect the penetration of hydrocortisone. A mechanism is proposed to explain why the absorption of the more lipophilic steroids is enhanced by occlusion but that of the most water-soluble (i.e., hydrocortisone) is not. It is suggested that the rate-determining role of the sequential steps involved in percutaneous absorption can be revealed by experiments of the type described using related series of homologous or analogous chemicals.

Percutaneous absorption of hydroquinone in humans: effect of 1-dodecylazacycloheptan-2-one (azone) and the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid (Escalol 507).

Hydroquinone was found to penetrate readily human forehead skin in vivo following a single topical exposure, in an alcoholic vehicle, of 24 h duration. Percutaneous absorption was estimated using radiotracer methodology and 14C-labeled hydroquinone. The effects of a penetration enhancer, 1-dodecylazacycloheptan-2-one, and a sunscreen, the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid, on the percutaneous absorption of hydroquinone were investigated. In vivo penetration of hydroquinone was significantly decreased (a less than 0.05) by the addition of the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid (3% w/w) to the vehicle. The penetration enhancer, 1-dodecylazacycloheptan-2-one (0.5% w/w), did not significantly increase (a greater than 0.05) the absorption of hydroquinone. From all hydroquinone preparations, percutaneous absorption was rapid and peak elimination occurred within the first 12 h following application. Elimination was complete within 5 d.

Skin absorption from patch test systems.

The development of topical drug products requires testing for skin toxicology reactions. A variety of patch test systems are available with which chemicals are applied to skin. The purpose of this study was to determine the skin absorption of paraphenylenediamine (PPDA) from a variety of such systems. [14C]-PPDA (1% pet., USP) was placed in a variety of patch test systems at a concentration normalized to equal surface area (2 mg/mm2). Skin absorption was determined in the guinea pig by urinary excretion of 14C. There was a six-fold difference in the range of skin absorption (p less than 0.02). In decreasing order, % skin absorption from the systems were Hill Top Chamber (53.4 +/- 20.6) greater than Teflon Control patch (48.6 +/- 9.3) greater than Small Finn Chamber with paper disc insert (34.1 +/- 19.8) greater than Small Finn Chamber (29.8 +/- 9.0) greater than Large Finn Chamber (23.1 +/- 7.3) greater than AL-Test Chamber (8.0 +/- 0.8). Thus, the choice of patch system could produce a false negative error if the system inhibits skin absorption, with a subsequent skin toxicology reaction.

Transdermal drug delivery and cutaneous metabolism.

The delivery of drugs via the skin to achieve systemic therapeutic effect is currently under intense investigation. The skin offers unique advantages and limitations for drug input into the body. For example, while hepatic first pass may be circumvented, the excellent barrier function of the stratum corneum (the thin outermost layer of skin) precludes, at present, all but the most potent drugs from this route of administration. Examples of approved transdermally delivered drugs are scopolamine, nitroglycerin, clonidine and estradiol. The delivery systems which have been formulated for these agents have been designed to provide essentially zero-order input kinetics for between 1 and 7 days. The impact of cutaneous metabolism on transdermal drug delivery has not yet been evaluated rigorously. Limited in vivo data for nitroglycerin suggest a cutaneous first pass effect of between 10 and 20%. More work has been directed towards the use of topical prodrugs and the design of molecules better able to transport across the stratum corneum and then undergo local enzymatic activation. Further research in this area will require a more specific quantitative understanding of the metabolic capabilities of human skin in vivo.

Percutaneous penetration of nicotinates: in vivo and in vitro measurements.

The relationship between chemical structure and percutaneous absorption has been explored with nicotinic acid and its methyl, ethyl, hexyl, and benzyl esters. Skin penetration has been measured in vitro across hairless mouse skin and in vivo in humans. In vitro, methyl and ethyl nicotinates (when applied in acetone) were delivered into skin such that the stratum corneum barrier was effectively bypassed. The lipophilic esters, on the other hand, were not solubilized in this way and penetrated more slowly. Nicotinic acid penetrated poorly, yielding essentially zero-order skin transport kinetics. Tape-stripping experiments, in which penetration was monitored across skin with no stratum corneum, confirmed these observations. In vivo absorption of the esters was determined from the urinary excretion of total radioactivity following topical administration of 14C-labeled penetrant. Kinetic analysis of the data yielded rate constants, the ratio of which correlated acceptably with the penetrant octanol-water partition coefficient (K). The dependence of the rate constants on K was interpreted in terms of the relative affinity of the substrate for the stratum corneum compared with the viable tissue; the relationship agrees well with a previous evaluation involving structurally unrelated molecules.