PubMed · 1462347
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A Heijn. 1992-12-01. [Pannus].. https://pubmed.ncbi.nlm.nih.gov/1462347/
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The feasibility of topical delivery in the skin of 3' end modified phosphodiester oligonucleotides using electroporation was investigated. Experiments were performed in vitro, using hairless rat skin. Five pulses of (200 V, 450 ms) were applied. The 3' end modifications of the 15 mer oligonucleotide were: (1) 3'-aminohexyl, (2) biotin, with a triethyleneglycol arm, (3) methylphosphonate links between nucleotides 13, 14 and 15, and (4) 2-O-methyl nucleotides at 13, 14 and 15 positions. All the modifications were efficient to protect the oligonucleotides against degradation in the skin. Electroporation increased the topical delivery of the 3' end-modified phosphodiesters by two orders of magnitude compared to passive diffusion, without significant differences between the derivatives. Oligonucleotide concentrations in the range of 1 microm could be achieved in the viable skin. The delivery of a phosphorothioate congener was lower than phosphodiester delivery due to the interaction of phosphorothioate with the stratum corneum. Consequently, 3' end-protected phosphodiesters could be an interesting alternative to phosphorothioate oligonucleotides for topical treatment of cutaneous diseases.
In this study it has been demonstrated that mixtures of two solid drugs, ibuprofen and methyl nicotinate, with different but complementary pharmacological activities and which exist as a single liquid phase over a wide composition range at skin temperature, can be formulated as o/w emulsions without the use of an additional hydrophobic carrier. These novel dual drug systems provided significantly enhanced in vitro penetration rates through a model lipophilic barrier membrane compared to conventional individual formulations of each active. Thus, for ibuprofen, drug penetration flux enhancements of three- and 10-fold were observed when compared to an aqueous ibuprofen suspension and a commercial alcohol-based ibuprofen formulation, respectively. Methyl nicotinate penetration rates were shown to be similar for aqueous gels and emulsified systems. Mechanisms explaining these observations are proposed. Novel dual drug formulations of ibuprofen and methyl nicotinate, formulated within the liquid range at skin temperature, were investigated by oscillatory rheology and texture profile analysis, demonstrating the effects of drug and viscosity enhancer concentrations, and disperse phase type upon the rheological, mechanical and drug penetration properties of these systems.
The effects of two antipsoriatic compounds, calcipotriol and anthralin, separately or in combination on ribonuclease P (RNase P), were investigated using a cell-free system from the slime mold Dictyostelium discoideum. RNase P is an ubiquitous and essential enzyme which endonucleolytically cleaves all tRNA precursors to produce the mature 5' end. The substrate for RNase P assays was an in vitro (32)P-labeled transcript of the Schizosaccharomyces pombe tRNA(Ser) gene supS1. Enzyme assays were carried out at 37 degrees in 20 microL 50 mM Tris-HCL 7.6 buffer, containing 10 mM NH(4)Cl, 5 mM MgCl(2), and 10% isopropanol. Calcipotriol or anthralin alone exerted a dose-dependent inhibitory effect on RNase P activity, with the former being more active than the latter in this respect. Simultaneous exposure of the enzyme to both drugs resulted in an enhancement of RNase P inhibition, which was additive. Considering the lack of structural similarities between the substrate (precursor tRNA) of RNase P and the tested drugs, it seems reasonable to suggest that their effects may be due to binding to allosteric inhibition sites of the enzyme. Although our in vitro findings cannot be directly extrapolated to the in vivo human condition, they do suggest that the inhibitory effects of calcipotriol and anthralin on tRNA biogenesis may be implicated in the mechanisms of their antipsoriatic action. Moreover, the additive inhibitory effect of these compounds on RNase P activity provides an experimental basis for their possible combined therapeutic application in the management of psoriasis.