Robert M. Gale

Skin adhesives and skin adhesion: 1. Transdermal drug delivery systems

The use of pressure-sensitive adhesives (PSAs) for skin-contact applications is discussed. The requirements of such adhesives in various applications are examined in detail. Commercially available classes of PSAs used for skin-contact applications are the acrylics, the polyisobutylenes, and the silicones. The main application examined in this review is transdermal drug delivery. The roles played by the PSA in two types of transdermal designs are described. Correlations between in vivo and ex vivo measurements of adhesion are discussed. Also, the reported human studies of various commercially available transdermals are examined critically, with a view to assessing the relative performance capabilities of each type of transdermal design. Finally, a comprehensive listing of currently commercialized transdermals is given.

Treatment of erectile dysfunction

Erectile dysfunction (ED) is an inability to attain or maintain an erection sufficient for satisfactory sexual intercourse. It is an undertreated and underdiagnosed condition that can be due to vasculogenic, neurogenic, hormonal and psychogenic factors. Effective treatment of ED should restore quality of life and allow patients to return to the sex life they had before. Current therapeutic options include non-pharmacological treatments, locally administered drugs and oral therapies. The oral phosphodiesterase-5 (PDE5) inhibitors are considered first-line treatments of ED and have revolutionized ED management in the last five years. Three PDE5 inhibitors are currently available, sildenafil, vardenafil and tadalafil. They are all effective with similar efficacy and good safety profiles. However, tadalafil has the added benefit of a broad window opportunity offering patients more freedom to choose when to initiate sexual activity.

System functionality and physicochemical model of fentanyl transdermal system

Fentanyl is an opioid traditionally administered by infusion or injection and more recently in a rate-controlled transdermal dosage form. This system is a four-layer laminate on a protective liner. A backing layer seals and protects the drug reservoir, the source for continuous delivery of fentanyl. A membrane controls the release rate of fentanyl from the system. An adhesive layer attaches the system to skin and releases an initial loading dose of fentanyl. The rate of fentanyl delivery through skin is determined by the system and the skin at the application site. The release rate from the system is approximated by Ficks first law of diffusion and is controlled by the rate-controlling membrane. A complete simulation model that combines both in vitro release data and the pharmacokinetic model has been developed and used to show the influence of various physiologic and system variables on serum fentanyl concentrations.

Use of osmotically active therapeutic agents in monolithic systems

Abstract The functionality of a new class of monolithic systems for the controlled release of drugs is discussed. The systems consist of uniformly dispersed particles of osmotically active therapeutic agents (drugs) in biocompatible polymeric matrices. The drug particles are encapsulated by polymers to form a multiplicity of microcapsules throughout the matrix. These osmotic film systems display zero-order drug delivery kinetics. The principal energy source governing the release of agents is osmotic in nature. When such a film is placed in an aqueous infinite sink, the film imbibes water into the outermost layer of the dispersion at a rate dictated by permeability of the polymer. Water transport into the film continues until volumetric rupture of the drug-containing capsules occurs, after which time saturated drug solution is pumped through channels created by the rupture. This process repeats itself in a serial fashion until the system is exhausted of agent. Due to the osmotic functionality of these systems, reduction of the thermodynamic activity of water outside the system can proportionally reduce the release of agent. In this paper the effects of varying drug particle size, osmotic pressure gradients, system area, drug type, polymer type, and temperature upon the drug release kinetics are presented. Application of this new technology has allowed the fabrication of several useful drug therapeutic systems.

Transference: a comprehensive parameter governing permeation of solutes through membranes

Experimental studies of the diffusion of moderate molecular weight drugs through synthetic polymeric membranes has led us to define a new parameter to characterize solute permeation. The accepted parameter which describes trans-membrane flux is permeability, P, defined as the product of the flux times the membrane thickness divided by the concentration difference across the membrane in the external solution. The parameter described here is called transference, T, and is defined as the mass of solute transferred from a saturated solution, under perfect sink conditions, across the membrane per unit time and area, multiplied by the thickness of the membrane. p]Regardless of whether there is solvent—membrane interaction or not, the permeability coefficient, P, for a given solute and membrane differs from one solvent to another. In contrast, transference is independent of solvent, unless there is solvent—membrane interaction, in which case the inconsistency of transference for a particular solvent signifies that the membrane is modified by the presence of that solvent or solvent—solute combination, It is for these reasons that transference is a more comprehensive parameter than permeability, and is basic at the same time to solute—membrane permeation. p]When transference is introduced into Ficks taw it is immediately obvious that the flux of solute through the membrane, at equal fraction of saturation in any donor solvent, is equal and independent of the donor solvent in the absence of solvent—membrane interaction, when the solute has a constant solvent—membrane partition coefficient. p]Two examples of the use of the transference parameter are provided.

Nitroglycerin Concentration in Plasma: Comparison Between Transdermal Therapeutic System and Ointment

This double-blind cross-over study evaluates in 12 male volunteers the time course of nitroglycerin concentration in plasma with use of the TTS-nitroglyc erin, a controlled-release transdermal dosage form for nitroglycerin, and com pares the bioavailability of nitroglycerin delivered from the transdermal system with that from three successive applications of 0.5 inch of 2% nitroglycerin ointment placed at 8 hr intervals over 10 cm 2 of skin. The mean amounts of nitroglycerin available when subjects wore the TTS-nitroglycerin or received successive applications of ointment were 15.8 mg ± 1.8 (SE) and 9.8 mg ± 0.8, respectively. Mean plasma concentrations for both treatments ranged from 10- 18 pg/ml-cm2. The normalized areas under the curves — 353 and 410 pg/hr/ml cm2, respectively — did not differ significantly. The ratio of clearance from the two dosage forms was 0.98±0.12. All subjects experienced mild-to-moderate side effects of nitrate therapy with both dosage forms and also decrease in blood pressure and increase in heart rate.