Donald A. Godwin

Influence of Drug Lipophilicity on Terpenes as Transdermal Penetration Enhancers

Percutaneous absorption-enhancing effects on the skin of hairless mice of 11 monoterpenes [1, (+)-limonene; 2, (-)-menthone; 3, (+)-terpinen-4-ol; 4, alpha-terpineol; 5, 1,8-cineole; 6, (+)-carvone; 7, (-)-verbenone; 8, (-)-fenchone; 9, p-cymene; 10, (+)-neomenthol; and 11, geraniol] were investigated using three different model drugs (caffeine, hydrocortisone, triamcinolone acetonide [TA]) with varying lipophilicities. Terpenes were applied at 0.4 M in propylene glycol (PG) to mouse skin. The model drugs were applied as suspensions in PG 1 hr following enhancer pretreatment. The combination of terpenes in PG provided significant enhancement of the permeation of caffeine through mouse skin. The most active compounds 10 and 11 increased permeation by between 13-fold and 16-fold. The terpenes also enhanced the delivery of hydrocortisone, but not to as great an extent. The most active compounds 3 and 4 increased permeation between 3.9-fold and 5-fold. The compounds examined did not significantly increase the delivery of TA. The most active compound 4 only increased delivery 2.5-fold, while the next most active compound 6 only increased delivery 1.7-fold. Overall, these results indicate that the combination of terpenes with PG can significantly increase the transdermal penetration of the hydrophilic drug caffeine and the polar steroid hydrocortisone.

Influence of Transcutol CG on the skin accumulation and transdermal permeation of ultraviolet absorbers.

The objective of this study was to determine the influence of Transcutol CG concentration on the transdermal permeation and skin accumulation of two ultraviolet (UV) absorbers, 2-hydroxy-4-methoxybenzophenone (oxybenzone) and 2-octyl-4-methoxycinnamate (cinnamate). The concentration of the UV absorber was held constant at 6% (w/w) for all vehicle systems while the concentration of Transcutol CG was varied from 0 to 50% (w/w). Data showed that both UV absorbers exhibited increases in skin accumulation with increasing concentrations of Transcutol CG. Skin accumulation of oxybenzone was significantly (P<0.05) greater than that of cinnamate for all formulations investigated. Oxybenzone skin accumulation ranged from 22.9+/-2.8 microg/mg (0% Transcutol CG) to 80.8+/-27.2 microg/mg (50% Transcutol CG). Cinnamate skin accumulation ranged from 9.0+/-0.9 microg/mg to 39.8+/-12.2 microg/mg at 0 and 50% Transcutol CG, respectively. No significant differences were found in the transdermal permeation of oxybenzone or cinnamate for any of the formulations tested. The results of this study demonstrate that the inclusion of Transcutol CG in sunscreen formulations increases the skin accumulation of the UV absorbers oxybenzone and cinnamate without a concomitant increase in transdermal permeation.

Influence of hydroxypropyl-β-cyclodextrin on transdermal penetration and photostability of avobenzone

The objective of the present study was to determine the effects of hydroxypropyl-beta-cyclodextrin (HPCD) complexation on the transdermal penetration and photostability of a model ultraviolet A (UVA) absorber, butyl methoxydibenzoylmethane (avobenzone), and to determine the influence of complexation on in vivo photoprotection. Avobenzone-HPCD complexation was demonstrated by differential scanning calorimetry. Formulations containing 0.12 mg/ml avobenzone and up to 30% (w/w) HPCD were prepared. Transdermal penetration was conducted using a modified Franz diffusion cell apparatus. As the concentration of HPCD was increased from 0% to 20%, transdermal permeation increased. Maximum flux occurred at 20% HPCD, where sufficient cyclodextrin was present to completely solubilize all avobenzone. When the concentration of HPCD was increased to 30%, transdermal penetration decreased, suggesting the formation of an avobenzone reservoir on the skin surface. Photostability of avobenzone was investigated under 100, 250, and 500 kJ/m2 UVA irradiation. The 30% HPCD formulation was the most photostable, followed by 20%, 10%, and 0% formulations. In vivo, the 30% HPCD formulation afforded the best photoprotection, as evidenced by the lowest extent of sunburn cell formation and edema induction. This work indicates that inclusion of HPCD in sunscreen formulations may enhance photoprotection by reducing both skin penetration and photodecomposition of UV absorbers.

Influence of Hydroxypropyl- β-Cyclodextrin on the Transdermal Permeation and Skin Accumulation of Oxybenzone

ABSTRACT The objective of the present study was to determine the effects of hydroxypropyl-β-cyclodextrin (HPCD) concentration on the transdermal permeation and skin accumulation of a model ultraviolet (UV) absorber, oxybenzone. The concentration of oxybenzone was held constant at 2.67 mg/mL for all formulations, while the HPCD concentrations varied from 0 to 20% (w/w). Complexation of oxybenzone by HPCD was demonstrated by differential scanning calorimetry. A modified Franz cell apparatus was used in the transdermal experiments, with aliquots of the receptor fluid assayed for oxybenzone by high-performance liquid chromatography. From the permeation data, flux of the drug was calculated. Skins were removed from the diffusion cells at specified time points over a 24-hr period and the oxybenzone content in the skin determined. The aqueous solubility of oxybenzone increased linearly with increasing HPCD concentration, following a Higuchi AL-type complexation. The stability constant of the reaction was calculated from the phase-solubility diagram and found to be 2047 M−1. As the concentration of HPCD was increased from 0 to 10%, transdermal permeation and skin accumulation of oxybenzone increased. Maximum flux occurred at 10% HPCD, where sufficient cyclodextrin was added to completely solubilize all oxybenzone. When the concentration of HPCD was increased to 20%, both transdermal permeation and skin accumulation decreased. These data suggest the formation of a drug reservoir on the surface of the skin.

Transdermal Kinetics of A Mercurous Chloride Beauty Cream: An In Vitro Human Skin Analysis

Background: Crema de Belleza-Manning is a popular mercurous chloride-containing beauty cream used to smooth and lighten the complexion and treat acne. Hundreds of people in the Southwestern US border states have been identified with elevated (>20 μg/L) urine mercury levels believed to be secondary to using this cream. The kinetic characteristics of percutaneous mercury absorption are incompletely defined. The objective of this study was to determine the transdermal kinetics of two formulations of mercurous chloride from a beauty cream in an in vitro human skin model. Methods: A proprietary formulation and an aqueous formulation of the beauty cream were studied using modified Franz diffusion cells. Mercury content in the skin samples and the underlying diffusion buffer was determined using atomic absorption spectrophotometry. Results: A rapid initial increase in mercury content both in the skin and the buffer was noted for both formulations. Mercury concentrations in the aqueous samples were significantly (p < 0.05) higher in both the skin and the diffusion buffer compared to parallel samples containing glycerol. Conclusions: Mercury was readily absorbed through the skin in this in vitro human skin model. The aqueous preparation had a markedly increased rate and extent of mercury absorption relative to the proprietary formulation.

Synthesis and investigation of urea compounds as transdermal penetration enhancers

Abstract Twelve urea and thiourea compounds were examined for their transdermal penetration enhancing properties in vitro using hairless mouse skin and hydrocortisone as a model drug. Skins were pretreated for 1 h with the enhancer in propylene glycol before application of the drug also in propylene glycol. Enhancement ratios ( ER ) were calculated for permeability coefficient ( P ), 24 h receptor concentration ( Q 24 ), and skin content of drug ( SC ) and compared to control values (no enhancer present). Control values for permeability coefficients were 0.71±0.27 cm h −1 , 24 h receptor concentration: 11.9±3.4 μ M, and skin content of drug 44.6±18.5 μ g g −1 . The most effective enhancer of the series was 1-dodecyl-3-methylthiourea. This enhancer produced the highest values for all three penetration parameters with a permeability coefficient 4.7±1.8×10 −4 cm h −1 ( ER P 6.6), a 24 h receptor concentration of 62.7±16.3 μ M ( ER Q 24 5.3), and a skin content of 90.1±17.7 μ g g −1 ( ER SC 2.0). A structure-activity relationship was observed in that the thio-substituted analogs were more effective enhancers than the oxygen-containing compounds. Although these compounds show promise as penetration enhancers, further study is needed to determine their effectiveness with other drugs and their irritation potential.

Investigation into the mechanism by which cyclodextrins influence transdermal drug delivery.

The objective of this study was to investigate the mechanism by which hydroxypropyl-β-cyclodextrin (HPCD) increases transdermal permeation. Hairless mouse skin was pretreated with HPCD solutions for up to 4 h. After removing the HPCD, corticosteroid-containing suspensions were applied and the transdermal flux and skin accumulation of two model drugs were investigated. After pretreatment, changes to the stratum corneum endothermic melting transitions were determined as an indication of HPCD-induced lipid disorganization. Results demonstrated that HPCD pretreatment had no significant effect on the transdermal permeation or skin accumulation of the model corticosteroids. These findings suggest that HPCD functions to enhance the apparent solubility of the drug in the formulation, thus increasing transdermal permeation rather than extracting lipids from the skin.

Influence of Cyclodextrin Complexation on the In Vivo Photoprotective Effects of Oxybenzone

The objective of the current study was to investigate the influence of cyclodextrin complexation on the in vivo photoprotective effects of a model ultraviolet (UV) absorber, oxybenzone, and to compare these novel sunscreens to a commercial SPF 30 sunscreen product. Aqueous‐based solutions and suspensions containing 2.7 mg/mL oxybenzone and up to 20% (w/w) hydroxypropyl‐β‐cyclodextrin (HPCD) were prepared. The sunscreens were applied to the dorsal skin of SKH‐1 hairless mice and the animals were exposed to up to two minimal erythemal doses (MEDs) of UV radiation. Control animals received no sunscreen treatment. Lipid damage, as quantified by decreases in the lipid melting temperature of the epidermis, was determined using differential scanning calorimetry immediately after UV exposure. The number of sunburn cells (SBCs) and the extent of edema were measured 24 hours postexposure. Results showed that all oxybenzone‐containing formulations decreased the number of SBCs formed, diminished swelling, and reduced the physical damage to the skin structure, in comparison to control. Thus, complexation did not prevent oxybenzone from reacting with light. The 20% HPCD formulation exhibited more substantial photoprotection at UV exposures of one or two MEDs, as evidenced by the formation of fewer SBCs. The 5% HPCD formulation also provided substantial protection against epidermal lipid damage. These studies demonstrate that inclusion of HPCD in sunscreen formulations may enhance the in vivo photoprotective effects of the UV absorbers. No single HPCD‐containing sunscreen, however, was found to be equivalent to a commercially available sunscreen product for all biomarkers investigated.

Stability of a Baclofen and Clonidine Hydrochloride Admixture for Intrathecal Administration

Implantable infusion pumps for the intrathecal administration of analgesics are commonly used in the treatment of severe or intractable chronic pain. Drugs used in these pumps include morphine, baclofen, clonidine, hydromorphone, meperidine, fentanyl, and bupiva-caine. This study investigates the chemical and physical stability of baclofen (1000 mcg/mL) and clonidine hydrochloride (200 mcg/mL) at 37°C for 10 weeks using a stability-indicating HPLC assay. The formulations included baclofen alone, clonidine hydrochloride alone, and a mixture of the two drugs. At each time point, the amount of drug remaining was greater than 90% of original. Week 10 percentages were 99.7% for baclofen alone, 100.7% for clonidine alone, and 103.2% and 101.1% for baclofen and clonidine hydrochloride, respectively in the drug mixture. These results demonstrate the stability of this admixture for long-term intrathecal administration.

In vitro evaluation of azone analogs as dermal penetration enhancers. V. Miscellaneous compounds

Abstract Dermal penetration enhancers were evaluated (14) using diffusion cell techniques, hairless mouse skin and hydrocortisone as the model drug. The following were synthesized: 1-dodecanoylpiperidine ( 1 ), 1-dodecanoylpyrrolidine ( 2 ), 1-dodecanoyl-2-piperidinone ( 3 ), 1-dodecanoyl-2-pyrrolidinone ( 4 ), 2-decylcyclohexanone ( 5 ), 2-decylcyclopentanone ( 6 ), 4-(dodecanoyl)-thiomorpholine ( 7 ), N,N -didodecylacetamide ( 8 ) and N -dodecyltricyclo [3.3.1.1 3,7 ]decane-1-carboxamide ( 11 ). N -Acetylcaprolactam ( 9 ), 4-acetylmorpholine ( 10 ) and N -dodecylpyrrolidinone ( 13 ) were purchased. The syntheses of Azone, N -(1-oxododecyl)morpholine ( 12 ) and N -dodecyl-2-piperidinone ( 14 ) have been reported previously. Enhancers were applied at 0.4 M in propylene glycol (PG) (or as a suspension) to mouse skin. Hydrocortisone (0.03 M in PG) was applied 1 h following enhancer treatment. Controls (no pretreatment) yielded 24 h diffusion cell receptor concentrations ( Q 24 ) of 9.93±3.15 μ M and model drug skin retention of 26.1±5.6 μ g g −1 . Compound 7 yielded a high Q 24 of 208.18±39.52 μ M. The highest skin retention was observed with 6 of 566.7±39.7 μ g g −1 . Azone gave values of 218.96±47.84 μ M for Q 24 and 294.9±66.7 μ g g −1 for skin retention. Compounds 13 and 14 gave Q 24 values of 274.44±50.90 and 220.21±59.63 μ M and skin retention values of 226.5±51.8 and 259.0±62.2 μ g g −1 , respectively.