Gaylen M. Zentner

Biodegradable block copolymers for delivery of proteins and water-insoluble drugs

Release of several drugs from new ABA-type biodegradable thermal gels, ReGel, including proteins and conventional molecules, are presented. These are biodegradable, biocompatible polymers that demonstrate reverse thermal gelation properties. Organic solvents are not used in the synthesis, purification, or formulation of these polymers. The unique characteristics of ReGel hinge on the following two key properties: (1) ReGel is a water soluble, biodegradable polymer at temperatures below the gel transition temperature; (2) ReGel forms a water-insoluble gel once injected. This is consistent with a hydrophobically bonded gel state where all interactions are physical, with no covalent crosslinking. An increase in viscosity of approximately 4 orders of magnitude accompanies the sol--gel transition. The gel forms a controlled release drug depot with delivery times ranging from 1 to 6 weeks. ReGels inherent ability to solubilize (400 to >2000-fold) and stabilize poorly soluble and sensitive drugs, including proteins is a substantial benefit. The gel provided excellent control of the release of paclitaxel for approximately 50 days. Direct intratumoral injection of ReGel/paclitaxel (OncoGel) results in a slow clearance of paclitaxel from the injection site with minimal distribution into any organ. Efficacies equivalent to maximum tolerated systemic dosing were observed at OncoGel doses that were 10-fold lower. Data on protein release (pGH, G-CSF, insulin, rHbsAg) and polymer biocompatibility are discussed.

New biodegradable polymers for injectable drug delivery systems

Many biodegradable polymers were used for drug delivery and some are successful for human application. There remains fabrication problems, such as difficult processability and limited organic solvent and irreproducible drug release kinetics. New star-shaped block copolymers, of which the typical molecular architecture is presented, results from their distinct solution properties, thermal properties and morphology. Their unique physical properties are due to the three-dimensional, hyperbranched molecular architecture and influence microsphere fabrication, drug release and degradation profiles. We recently synthesized thermosensitive biodegradable hydrogel consisting of polyethylene oxide and poly(L-lactic acid). Aqueous solution of these copolymers with proper combination of molecular weights exhibit temperature-dependent reversible sol-gel transition. Desired molecular arrangements provide unique behavior that sol (at low temperature) form gel (at body temperature). The use of these two biodegradable polymers have great advantages for sustained injectable drug delivery systems. The formulation is simple, which is totally free of organic solvent. In sol or aqueous solution state of this polymer solubilized hydrophobic drugs prior to form gel matrix.

The controlled porosity osmotic pump

Abstract The zero-order release of water soluble, osmotically active agents from tablets coated with controlled porosity walls has been investigated. The walls were sponge-like in appearance and substantially permeable to both water and dissolved solutes. The rate of release was a function of the wall thickness, level of leachable additives incorporated and permeability of the polymer component of the walls, the total solubility of the core tablet, the drug load, and the osmotic pressure difference across the wall. Release was insensitive to the pH and degree of agitation in the receptor media. Release was primarily due to an osmotic pump mechanism. Steady-state release rates were calculated from basic water and solute permeabilities of the walls and correlated with actual device performance. The concept of osmotically actuated drug delivery on an equivalent mass per unit surface area basis was demonstrated and extended, as well, to multiparticulate dosage forms.

Osmotic flow through controlled porosity films: An approach to delivery of water soluble compounds☆

Abstract The zero-order release of water soluble, osmotically active agents from tablets coated with controlled porosity walls has been investigated. The walls were sponge-like in appearance and substantially permeable to both water and dissolved solutes. Mechanical strengths of the walls were measured. The rate of release was a function of the wall thickness, level of leachable additives incorporated and permeability of the polymer component of the walls, the total solubility of the core tablet, the drug load, and the osmotic pressure difference across the wall. Release was insensitive to the pH and degree of agitation in the receptor media. Release was primarily due to an osmotic pump mechanism. Steady-state release rates were calculated from basic water and solute permeabilities of the walls and correlated with actual device performance. The concept of osmotically actuated drug delivery on an equivalent mass per unit surface area basis was demonstrated and extended, as well, to multiparticulate dosage forms.

The Solubility-Modulated Osmotic Pump: In Vitro/in Vivo Release of Diltiazem Hydrochloride

A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem · HC1 as a model drug. Diltiazem · HC1 has an aqueous solubility >590 mg/ml (37°C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ ml; 37°C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of >80% of an initial diltiazem · HC1 load. Devices were prepared with cores that contained diltiazem · HC1 and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of ∼75% of the initial diltiazem HC1 load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.

Use of Modified Ethylcellulose Lattices for Microporous Coating of Osmotic Tablets

Commercially available lattices are often used to coat nonpareils or beads. Drug release occurs via diffusion through the polymer coating. Adequate release rates may be achieved with small particles because the surface area is large. However, tablets coated with unmodified lattices have exceedingly slow release rates. Therefore, a pore-forming agent, urea, was added to a commercially available ethyl cellulose latex, Aquacoat, to increase the release rate of drugs from coated osmotic tablets. Modified lattices were used to coat KC1 and diltiazem · HC1 tablets. Release of KC1 and diltiazem into water or buffer solutions was determined in a standard U.S.P. dissolution apparatus. Rates varying from 1 to 100% release in 12 hr were obtained by varying the coating thickness, pore-former level, and plasticizer type and concentration. Scanning electron microscopy (SEM) showed that the urea was eluted from the coat in aqueous solution leaving a porous coating. Coat burst strengths were dependent on the coat thickness and the concentrations of pore former and plasticizer. Hence, modified lattices hold potential for use as coatings for controlled release osmotic formulations.

Enhancement of 3-Hydroxy-3-methylglutaryl–Coenzyme A (HMG–CoA) Reductase Inhibitor Efficacy Through Administration of a Controlled-Porosity Osmotic Pump Dosage Form

An extended-release osmotic dosage form was designed for gastrointestinal delivery of the water-soluble tromethamine salt of the β-hydroxyacid form of simvastatin, a potent HMG–CoA reductase inhibitor and cholesterol lowering agent. The cholesterol lowering efficacy and systemic plasma drug levels resulting from peroral administration of this dosage form, relative to a powder-filled capsule oral bolus, were evaluated in dogs. A twofold improvement in cholesterol lowering efficacy was realized with the controlled-release dosage form that was accompanied by a drug AUC and Cmax that were 67 and 16%, respectively, of those achieved with the bolus dosage form. These results suggest that extended-release dosage forms have the potential for a dose-sparing advantage in the administration of HMG–CoA reductase inhibitors for the treatment of hy-percholesterolemia.

Effect of chloride on the release of chlorhexidine salts from methyl methacrylate: 2-hydroxyethyl methacrylate copolymer reservoir devices

Abstract Syntheses of copolymers of methyl methacrylate (MMA) and 2-hydroxyethyl methacrylate (HEMA) were carried out in solution without the addition of external covalent crosslinkers. Devices were formulated as coated matrices: 80% (w/w) chlorhexidine diacetate was incorporated in a core of 50:50 mole ratio HEMA:MMA copolymer and this matrix was then coated with 30:70 mole ratio HEMA:MMA copolymer. Coated devices released chlorhexidine into water for months with zero-order kinetics. In an inorganic saliva simulate, release rates were significantly lower than those observed from devices into water. Release rates were decreased 36% and 85% in 2.2 mM and 10 mM sodium chloride solutions, respectively. Hydration, pH, and osmotic effects were minimal. The effect of external chloride on the release rates was due to the conversion within the core of the acetate salt of chlorhexidine (solubility ~ 23 mg/ml at 37 °C) to the chloride salt (solubility ~ 1 mg/ml at 37 °C) and the consequent lower solubility. Addition of sodium chloride to a core formulation of chlorhexidine diacetate also resulted in lower release rates and presents as a facile method for release rate adjustment. For external chloride to diffuse into the core requires bulk water in the polymers for chloride transport. Differential scanning calorimetric studies indicated that each of the copolymers contained a significant amount of bulk water and hence a pathway for chloride transport from the external environment into the device core.

Highly cited research articles in Journal of Controlled Release: Commentaries and perspectives by authors

Abstract To celebrate the success of the Journal of Controlled Release and the research covered in the journal, here we highlight some of the most cited research articles in the history of the journal. Based on the literature search in Google Scholar in July 2013, we identified ~30 research articles that have received most number of citations. Authors of these articles were invited to provide a commentary on these articles. This compilation of commentaries gives a historical perspective and current status of research covered in these articles.

Ultrasonically mediated solute permeation through polymer barriers.

The effects of ultrasound on the permeation of benzoic acid through polydimethylsiloxane, and hydrocortisone through cellulose was investigated. Ultrasonic irradiation resulted in a 23% increase in the permeability coefficient of hydrocortisone in a cellulose film. A 14% increase in permeability coefficient was observed for benzoic acid in a polydimethylsiloxane film. The effects of ultrasound on stagnant aqueous diffusion layers, membrane‐solution interfacial temperature, membrane integrity, and diffusant stability were investigated. These factors were not responsible for the observed increases in permeability.