Human skin has unique properties of which functioning as a physicochemical barrier is one of the most apparent. The human integument is able to resist the penetration of many molecules. However, especially smaller molecules can surpass transcutaneously. They are able to go by the corneal layer, which is thought to form the main deterrent. We argue that the molecular weight (MW) of a compound must be under 500 Dalton to allow skin absorption. Larger molecules cannot pass the corneal layer. Arguments for this "500 Dalton rule" are; 1) virtually all common contact allergens are under 500 Dalton, larger molecules are not known as contact sensitizers. They cannot penetrate and thus cannot act as allergens in man; 2) the most commonly used pharmacological agents applied in topical dermatotherapy are all under 500 Dalton; 3) all known topical drugs used in transdermal drug-delivery systems are under 500 Dalton. In addition, clinical experience with topical agents such as cyclosporine, tacrolimus and ascomycins gives further arguments for the reality of the 500 Dalton rule. For pharmaceutical development purposes, it seems logical to restrict the development of new innovative compounds to a MW of under 500 Dalton, when topical dermatological therapy or percutaneous systemic therapy or vaccination is the objective.

https://onlinelibrary.wiley.com/doi/pdf/10.1034/j.1600-0625.2000.009003165.x

The 500 Dalton rule for the skin penetration of chemical compounds and drugs

Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin To surmount this problem, we conjugated a heptamer of arginine to cy- closporin A through a pH-sensitive linker to produce R7-CsA In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflamma- tion These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders

Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation

Three-dimensional (3D) bioprinting, a flexible automated on-demand platform for the free-form fabrication of complex living architectures, is a novel approach for the design and engineering of huma...

/pdf/design-and-fabrication-of-human-skin-by-three-dimensional-28b3dl9ilo.pdf

Design and Fabrication of Human Skin by Three-Dimensional Bioprinting

The protective function of human skin imposes physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have a...

https://www.tandfonline.com/doi/pdf/10.1080/10717540500455975

Dermal and transdermal drug delivery systems: Current and future prospects

While the peptide and protein therapeutic market has developed significantly in the past decades, delivery has limited their use. Although oral delivery is preferred, most are currently delivered intravenously or subcutaneously due to degradation and limited absorption in the gastrointestinal tract. Therefore, absorption enhancers, enzyme inhibitors, carrier systems and stability enhancers are being studied to facilitate oral peptide delivery. Additionally, transdermal peptide delivery avoids the issues of the gastrointestinal tract, but also faces absorption limitations. Due to proteases, opsonization and agglutination, free peptides are not systemically stable without modifications. This review discusses oral and transdermal peptide drug delivery, focusing on barriers and solutions to absorption and stability issues. Methods to increase systemic stability and site-specific delivery are also discussed.

/pdf/basics-and-recent-advances-in-peptide-and-protein-drug-2j40r5932q.pdf

Basics and recent advances in peptide and protein drug delivery.

Cross-Reactivity of Human Nickel-Reactive T-Lymphocyte Clones with Copper and Palladium

Since oral cyclosporin A (CsA) has demonstrated its effectiveness in psoriasis and atopic dermatitis, efforts have been made to develop a topical CsA formulation, thus avoiding systemic adverse events. A limited number of publications are available on the use of topical CsA in allergic contact dermatitis and atopic dermatitis. Moreover the response rate of humans to topical CsA is about 50% or less. We now report our results with three new topical CsA formulations on allergic contact dermatitis and atopic dermatitis. No significant improvement was found in 16 atopic dermatitis patients and 7 allergic contact dermatitis (nickel sulphate) patients.

Lack of efficacy of topical cyclosporin A in atopic dermatitis and allergic contact dermatitis.

Antibodies to Mycobacterial 65-kDa Heat Shock Protein and Other Immunodominant Antigens in Patients with Psoriasis

We report a comparative study of the patch-test results obtained with a corticosteroid series, added to the standard series, in two centres, one in Belgium and the other in the Netherlands. The frequencies of positive reactions to the corticosteroids differed considerably between the two centres, and we suggest several reasons for this

M.M.H.M. Meinardi

Papers

The 500 Dalton rule for the skin penetration of chemical compounds and drugs

Cross-Reactivity of Human Nickel-Reactive T-Lymphocyte Clones with Copper and Palladium

Lack of efficacy of topical cyclosporin A in atopic dermatitis and allergic contact dermatitis.

Antibodies to Mycobacterial 65-kDa Heat Shock Protein and Other Immunodominant Antigens in Patients with Psoriasis

Contact allergy to corticosteroids : the results of a two-centre study