PubMed · 2864616
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J C Cowan, K J Beatt, D O Williams, D S Reid. 1985-10-19. Transdermal nitroglycerin.. https://doi.org/10.1016/s0140-6736(85)90168-0
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Burst release as well as sustained release has been reported for SLN suspensions. For dermal application, both features are of interest. Burst release can be useful to improve the penetration of a drug. Sustained release becomes important with active ingredients that are irritating at high concentrations or to supply the skin over a prolonged period of time with a drug. Glyceryl behenate SLN were loaded with vitamin A and the release profiles were studied. Franz diffusion cells were used to assess the release kinetic over a period of 24 h. Within the first 6 h retinol SLN displayed controlled release. After longer periods (12-24 h) the release rate increased and even exceeded the release rate of comparable nanoemulsions. Pure SLN dispersions are characterised by low viscosity. In contrast to membranous vesicles, SLN can also be stably incorporated in convenient topical dosage forms like hydrogels or creams. In the Franz diffusion cell these preparations showed a controlled release over 12-18 h. Similar to SLN dispersions an increase in release rate over a 24-h period was found. A good correlation between polymorphic transitions and increased drug release was observed in this study. Sustained release was often related to the metastable beta' polymorph. Drug expulsion is explained by a reduction of amorphous regions in the carrier lattice due to a beta'-->beta(i) polymorphic transition. This transformation can be controlled with surfactant mixtures or, in the case of the hydrogel and oil/water cream, with humectants or gelling agents. Thus, the release rate for the topical route of application is adjustable.
The effects of constant DC iontophoresis (0-1.5 mA/0.966 cm(2)) on the permeation of three hydrophilic compounds, antipyrine (ANP, M.W. 188.23), sucrose (SR, M.W. 342.30) and 1-kestose (KT, M.W. 506.73), through excised hairless rat skin were evaluated using hydrodynamic pore theory. The electro-osmotic flow caused by iontophoresis was measured using deuterium oxide (D(2)O). The penetration-enhancing mechanism of iontophoresis was found to increase solvent flow through electro-osmosis and pore enlargement and/or new pore production in the skin barrier, together with enhancement of electrochemical potential difference across the skin. These effects were closely related to the strength of the current applied. The electro-osmotic flow of D(2)O (J(D(2)O)) greatly enhanced the skin permeation clearance of all hydrophilic penetrants (CL(drug)). Pore production was classified into reversible and irreversible processes, which resulted from lower (0-0.5 mA/0.966 cm(2)) and higher (0.5-1. 5 mA/0.966 cm(2)) currents, respectively. Thus, the enhancing effects of iontophoresis on skin permeation of nonionic hydrophilic compounds can be explained by increase in pore size and higher solvent flow.
In vivo low frequency EPR was used to measure the enhancement of topical delivery of hydrophilic substances by use of multilamellar liposomes. The contribution of transepidermal or/and transfollicular routes of transport was investigated using hairless and normal mice. Two liposome dispersions that previously had been shown to have different enhancement properties on ex vivo skin were used. The kinetics of the reduction of hydrophilic spin probe GluSL (N-(1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl)-2,3,4,5, 6-pentahydroxy-hexaneamide) applied to the skin encapsulated into the liposomes was measured. To distinguish the reduction of GluSL on the skin surface from its reduction inside the skin, the oxidizing agent potassium ferricyanide (KFeCN) was used. This does not penetrate into the skin and therefore it oxidizes hydroxylamines back to nitroxide only on the surface of the skin. We observed significant differences in the properties of the two types of liposomes with respect to their stability when in contact with skin and their transport characteristics. The results measured in vivo are consistent with those obtained ex vivo, indicating that in vivo L-band EPR is a powerful technique for following pharmacokinetics in the skin of live animals. The results also show that clearance by blood flow and possible alterations of skin after sacrifice of animal do not influence the results of penetration of liposome entrapped substances into the skin during the time of our experiment (typically around 60 min). The reduction of GluSL in the skin of hairless vs. normal mice was similar, indicating that the transfollicular penetration was not of major importance in vivo in this experimental model.