A team of researchers from the University of Bradford, UK, are pioneering the use of computer models to design ways of infusing drugs through the skin - without the pain of needles.
Their method could help develop stick-on skin patches for many drugs that currently have to be injected, such as insulin for diabetes.
Few drugs can be delivered using such patches, because the molecules are too large to pass through the skin's tough barrier. But why this happens is not entirely understood and investigating it is a challenge - despite being too large to pass through the skin, molecules of both kinds are still too small to be studied in experiments.
Jamshed Anwar and his colleagues at the Institute of Pharmaceutical Innovation are using computer mock-ups to work out how to get the skin to soak up the drug particles without having to inject them.
Unlike taking drugs in tablet form, where up to 80% of a dose may be broken down by the liver and lost, delivering a drug via the skin is much more efficient.
By modelling the molecules of the skin and those that make up a particular drug, the team can watch the progress of the drug through the skin layers - and then devise chemical ways of modifying the membrane molecules to allow the drugs to pass.
The application of molecular simulation in drug delivery and formulation is still in its infancy but the interest is increasing rapidly. In broad terms, current applications can be grouped into three categories: biopharmaceutics and soft condensed matter, solid state, and process technology. Modelling of processes, because of the large length scales involved, is generally not molecular, though molecular level simulations may be important in identifying the critical features of the process. Applications in the biopharmaceutics area include investigations of self assembly of lipids, vesicle formation, liposomal systems, permeation of molecules through membranes, mechanism of action of penetration enhancers for transdermal delivery, and interactions of DNA with dendrimers. In the solid state area the team were able to predict, with some success, crystal habits and polymorphs given a molecular structure.
According to Anwar, in topical and transdermal drug delivery an important objective is to develop an ability to enhance (and control) the transport of drug molecules into or via the skin. One approach is to use chemical penetration enhancers that interact with the skin lipids to facilitate the transport of active molecules through the skin.
Anwar admits that how such molecules increase the skin permeability is essentially still a mystery but a greater understanding of their mechanism of action in this respect would be invaluable for the rational design of molecules that modulate the transport of active molecules in membranes.
The effects of the penetration enhancer dimethylsulfoxide (DMSO) on model bilayers ofdipalmitoylphosphatidylcholine (DPPC) has been investigated by molecular dynamics simulation.While the lipids of the stratum corneum are predominantly ceramides (with fatty acids and cholesterol), DPPC is a wellcharacterised model which exhibits qualitatively some of the features of the stratum corneum lipids. The simulations reveal that DMSO at high concentrations induces water pore formation in the bilayer. Consequently, aqueous pore formation has been proposed as a possible pathway for the enhancement of hydrophilic molecules through lipid membranes. More recent investigations are focussing on ceramide bilayers which are the primary constituents of the stratum corneum.
Also, in-silico screening methods are being developed to identify molecules that enhance and/or retard the permeability of the stratum corneum and other membranes.