A medical probe device comprises a catheter having a stylet guide housing with one or more stylet ports in a side wall thereof and a stylet guide for directing a flexible stylet outward through the stylet port and through intervening tissue at a preselected, adjustable angle to a target tissue. The total catheter assembly includes a stylet guide lumen communicating with the stylet port and a stylet positioned in said stylet guide lumen for longitudinal movement from the port through intervening tissue to a target tissue. The stylet can be an electrical conductor enclosed within a non-conductive layer, the electrical conductor being a radiofrequency electrode. Preferably, the non-conductive layer is a sleeve which is axially moveable on the electrical conductor to expose a selected portion of the electrical conductor surface in the target tissue. The stylet can also be a microwave antenna. The stylet can also be a hollow tube for delivering treatment fluid to the target tissue. It can also include a fiber optic cable for laser treatment. The catheter can include one or more inflatable balloons located adjacent to the stylet port for anchoring the catheter or dilation. Ultrasound transponders and temperature sensors can be attached to the probe end and/or stylet. The stylet guide can define a stylet path from an axial orientation in the catheter through a curved portion to a lateral orientation at the stylet port.

Medical probe device and method

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

A controlled release powder containing discrete micro-particles for use in edible, pharmaceutical and other controlled release compositions is disclosed. The micro-particles have an average size in the range of from 0.1 to 125 μm. Each of the micro-particles is in the form of a micromatrix of an active ingredient uniformly distributed in at least one non-toxic polymer. The micro-particles have a predetermined release of active ingredient when the dissolution rate thereof is measured according to the Paddle Method of U.S. Pharmacopoeia XX at 37° C. and 75 r.p.m.

Controlled release powder and process for its preparation

Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system

Size and shape effects in the biodistribution of intravascularly injected particles.

Controlled release drug delivery systems comprised of spherical microporous polymeric network of interconnecting channels containing pore incorporated drugs or other agents wherein the drugs or agents are confined within the pore channel are described. Also disclosed are processing parameters in connection with the novel method of the invention for obtaining drug delivery systems especially suited for parenteral as well as oral administration.

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Porous microspheres for drug delivery and methods for making same

Microspheres containing methylene blue and prednisolone acetate were prepared by one of three methods: freeze-drying, evaporation, and solvent-extraction-precipitation. An extremely porous structure was obtained by the freeze-dry and solvent-extraction-precipitation procedures. The specific surface area of 6.33-µm particles was 20.6 m2/g, or 35 times that of a particle devoid of pores, and the void space was 59–61%. The sphericity, size, and yields of the microspheres were influenced by the preparation procedure, surfactant type and concentration, temperature of the continuous phase, polymer concentration in the dispersed phase, and ratio of marker to polymer. The most suitable processing conditions were a polymer concentration of 5–10%, a marker loading of 10%, 0.1% sorbitan sesquioleate as the surfactant, and temperature adjustment of the continuous phase from 15 to 50°C following the addition of the dispersed phase. Complete release of the highly water soluble methylene blue occurred within 72 hr, while the less soluble prednisolone acetate released much more slowly, i.e., 90% after 7 days. The microspheres remained relatively intact during the in vitro release of methylene blue, confirming that the incorporated agent was confined to the walls of the porous network. Collapse of the polymer structure was evident after 7 days. The release therefore was believed to be governed principally by the solubility of the drug and the porosity of the matrix.

Porous biodegradable microspheres for controlled drug delivery. I. Assessment of processing conditions and solvent removal techniques.

Acute hemodynamic effects and blood pool kinetics of polystyrene microspheres following intravenous administration.

The binding of several drugs to an inline i.v. filter that had been treated to inhibit drug-binding was studied. Solutions of mithramycin, vincristine sulfate, digitoxin, insulin, dactinomycin, and nitroglycerin in both 5% dextrose injection and 0.9% sodium chloride injection were allowed to flow through an i.v. administration set containing a 0.22-micron cellulose ester filter that had been treated with a proprietary agent. Actual administration conditions were simulated by using drug concentrations and flow rates commonly employed in clinical practice. The amount of each drug retained by the filter was determined by assaying aliquots of the solutions sampled before and after the solution passed through the filter membrane. In a second experiment, drug binding to the filter membrane was measured by incubating small pieces of the treated membrane in drug solutions and determining concentrations periodically until equilibrium was reached. Untreated filter membrane pieces were used as a control. In the experiment simulating actual i.v. administration, cumulative binding of mithramycin, vincristine sulfate, dactinomycin, and nitroglycerin to the treated filter was less than 6% of the initial dose infused; approximately 8-12% of the initial amounts of digitoxin and insulin were bound to the filter. In the equilibrium binding studies, the untreated filters bound twice as much digitoxin, 5-7 times as much mithramycin, vincristine sulfate, and dactinomycin, and 20 times as much insulin as the treated filters. The amount of nitroglycerin bound to the treated and untreated filters was not substantially different. Insulin had a greater binding tendency in 5% dextrose injection than in 0.9% sodium chloride injection in both experiments regardless of the filter treatment. Treatment of a cellulose ester i.v. filter with the proprietary agent used in this study facilitates drug delivery through this filter.

Motoko Kanke

Papers

Porous microspheres for drug delivery and methods for making same

Porous biodegradable microspheres for controlled drug delivery. I. Assessment of processing conditions and solvent removal techniques.

Acute hemodynamic effects and blood pool kinetics of polystyrene microspheres following intravenous administration.

Binding of Selected Drugs to a Treated Inline Filter