Hydrocortisone penetration

Topical corticoids are minimally absorbed from healthy skin. On the forearm, approximately 1% of the applied dose of hydrocortisone penetrates [21, 59]. Other corticoids for which data exist are not necessarily absorbed to a greater degree than hydrocortisone [23], suggesting that they may owe their increased efficacy to their potency rather than enhanced penetration. To put this in perspective, only 1% of corticoids applied to healthy skin is therapeutically active, with approximately 99% being wasted either by being rubbed off, washed off, or exfoliating with the stratum corneum. 

Frankild S, Andersen KE, Nielsen GD. 1995. Effect of sodium lauryl sulfate (SLS) on in vitro percutaneous penetration of water, hydrocortisone and nickel. Contact Dermatitis 32 338-345. 

Experimental studies on the percutaneous absorption of hydrocortisone fail to reveal a significant increase in absorption when applied on a repetitive basis and a single daily application may be effective in most conditions. Ointment bases tend to give better activity to the corticosteroid than do cream or lotion vehicles. Increasing the concentration of a corticosteroid increases the penetration but not proportionately. For example, approximately 1% of a 0.25% hydrocortisone solution is absorbed from the forearm. A 10-fold increase in concentration causes only a fourfold increase in absorption. Solubility of the corticosteroid in the vehicle is a significant determinant of the percutaneous absorption of a topical steroid. Marked increases in efficacy are noted when optimized vehicles are used, as demonstrated by newer formulations of betamethasone dipropionate and diflorasone diacetate. 

As recently reviewed by Gupta and Garge (2002), there are some materials known to penetrate the skin readily and appear to be capable of acting as penetration enhancers for certain selected drugs. These enhancers sometimes work more effectively in the presence of solvents such as ethanol or propylene glycol. A well-known example is the use of the insect repelent DEET (N,N diethyl-m-toluamide) as an enhancer for corticosteroids or the use of isopropyl myristate and propylene glycol for diclofenac sodium. Indeed, cyclodextrins have also been employed as penetration enhancers for hydrocortisone although how this system functions is not easy to visualize (see later section on cyclodextrins). 

Terpenes continue to be a popular choice as experimental enhancers for delivering materials across skin membranes. For example, L-menthol facilitated in vitro permeation of morphine hydrochloride through hairless rat skin [37], imipramine hydrochloride across rat skin [59], and hydrocortisone through hairless mouse skin [60]. Recently, niaouli oil was found to be the most effective of six essential oils in promoting estradiol penetration through hairless mouse skin [61]. It is noteworthy that there is currently little control on the topical use of most terpenes, and many aromatherapy oils and formulations contain appreciable quantities of these chemicals. Their excessive use offers potential for permeation of hazardous compounds from the same formulations into the skin some terpenes also have pharmacological activity. 

Corticosteroids are only minimally absorbed following application to normal skin for example, approximately 1% of a dose of hydrocortisone solution applied to the ventral forearm is absorbed. Long-term occlusion with an impermeable film such as plastic wrap is an effective method of enhancing penetration, yielding a tenfold increase in absorption. There is a marked regional anatomic variation in corticosteroid penetration. Compared with the absorption from the forearm, hydrocortisone is absorbed 0.14 times as well through the plantar foot arch, 0.83 times as well... 

W. Wohlrab, and J. Lasch, Penetration kinetics of liposomal hydrocortisone in human skin, Dermatologica 174 18-22 (1987). 

Feldmann, R.J. and H.I. Maibach, Percutaneous penetration of hydrocortisone with urea. Arch. Dermatol., 1974, 109 58-9. 

Urea has been shown to be an efficient accelerant for the penetration of different drugs.52-57 Increased levels of hydrocortisone, triamcinolone acetonide,53 dithranol,54 and retinoic acid52 were found in various layers of isolated human skin after 1000 min of exposure time to creams containing 10 to 12% urea. Also the penetration of ketoprofen through isolated rat skin was enhanced by the addition of urea.56 Furthermore, it has been shown that the time of onset of erythema, induced by hexyl nicotinate, was significantly reduced by simultaneous exposure to an oily cream containing urea.55... 

However, not all studies support the belief that urea is an effective penetration promoter.25,58-61 For instance, the latency time to induce erythema was not changed by three-weeks treatment with a moisturizer containing 5% urea62 or by pre-treatment of forearm skin with an aqueous solution of 10% urea.59 Moreover, urea (10%) had a minimal effect on the penetration of hydrocortisone through excised human and guinea pig skin.58 Hydrocortisone acetate was even retarded through hairless mouse skin with increasing concentrations of urea (up to 12%).25... 

Rranz, G., Schaefer, H., Zesch, A. (1977). Hydrocortisone (cortisol) concentration and penetration gradient. Acta Derm. Venereal. 57 269-73. 

Barry, B. W. and Bennett, S. L. Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin. Journal of Pharmacy and Pharmacology 39(7) 535-546, 1987. 

Experiments have been conducted on two of these compounds to determine their penetration retardation effect on two compounds, hydrocortisone and diethyl toluamide (DEET). Fig. 5 shows that the retarders could reduced the permeation of hydrocortisone, while... 

Tang-Liu, D.D.S. Neff, J. Zolezio, H. Sandri, R. Percutaneous and systemic disposition of hexamethylene laura-mide and its penetration enhancement effect on hydrocortisone in a rat sandwich skin-flap model. Pharm. Res. 1988, 5, 477 81. 

To emphasize this, Behl et al. reported that only in the absence of the SC were differences in the penetration of hydrocortisone observed between the abdomen and the dorsal sites of rats. This was believed to be due to the thicker dorsal dermis as compared with that of the abdomen. 

The state of hydration of the stratum corneum, which is normally maintained at 10-15%, affects the rate of penetration of chemical substances. By increasing the state of hydration to 50%, the rate of permeation of some chemical substances through the epidermis can be increased up to 10-fold. ° Occlusion has been shown to enhance the pharmacological effect of topically applied hydrocortisone and fluocinolone acetonide " however, percutaneous absorption of drugs is not necessarily increased. The degree of occlusion-induced absorption enhancement appears to increase with increasing lipophilicity of drug substances. 

The therapeutic effectiveness of topically applied corticosteroids is attributed primarily to their antiinflammatory activity. The relative efficacy of topical corticosteroids appears to be in the following order hydrocortisone, prednisolone, betamethasone < hydrocortisone valerate or butyrate, betamethasone valerate, triamcinolone acetonide, flucinolone acetonide < betamethasone dipropionate, fluocino-nide. In addition to the nature of the corticosteroid, its solubility, and, to a lesser extent, the concentration used, clinical efficacy is influenced by the formulation of the preparation. Glucocorticoids appear to have greater efficacy when formulated in ointment bases than in cream or lotion vehicles. This could be attributed to the occlusive effect provided by ointments. The application of an occlusive dressing further enhances penetration and persistence of the steroid (reservoir effect) in the stratum corneum. " ... 

Solute molecules may penetrate the skin not only through the stratum corneum but also by way of the hair follicles or through the sweat ducts, but these offer only a comparatively minor route because they represent such a small fraction of the surface area. Only in the case of molecules that move very slowly through the stratum corneum may absorption by these other routes predominate. Passage through damaged skin is increased over normal skin. Skin with a dismpted epidermal layer will allow up to 80% of hydrocortisone to pass into the dermis, but only 1% is absorbed through intact skin. 

The penetration rates of four steroids through intact abdominal autopsy skin were, in the order of their physiological activity, betamethasone 17-valerate (I) > desonide > triamcinolone acetonide (II) > hydrocortisone (III). Triamcinolone itself is five times more active systemically than hydrocortisone, but has only one-tenth of its topical activity. The acetonide of triamcinolone has a topical activity 1000 times that of the parent steroid... 

Hammeshige S, Potts AM. The penetration of cortisone and hydrocortisone into ocular structures. Am J Ophthalmol 1955 40 3211-3215. 

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