Joseph Kost

Responsive polymeric delivery systems

This paper discusses the state of the art in a relatively new approach in the field of controlled drug delivery-responsive polymeric drug delivery systems. Such systems are capable of adjusting drug release rates in response to a physiological need. The fundamental principles of externally and self-regulated delivery systems are examined. Special attention is paid to specific clinical settings such as diabetes, presenting the advantages and disadvantages of different approaches.

Handbook of Biodegradable Polymers

Polyglycolide and Polylactide. Poly (p-dioxanone) and its Copolymers. Polycaprolactone. Polyhydroxyalkanoates. Poly (propylene fumarate). Poly (ortho esters). Other Polyesters. Polyanhydrides. Biodegradable Polyphosphazenes for Biomedical Applications. Poly (alklcyanoacrylates). Degradable Hydrogels. The Poloxamers: Their Chemistry and Medical Applications. Degradable Polymers Derived from the Amino Acid L-tyrosine. Natural Modified Polysaccharides. Oxidized Cellulose: Chemistry, Processing and Medical Applications. Gelatin. Collagen: Characterization, Processing and Medical Applications. Fibrinogen and Fibrin: Characterization, Processing and Medical Applications. Transductional Elastic and Plastic Protein-based Polymers as Potential Medical Devices. Genetically Engineered Protein Polymers. Surface Characterization of Bioerodible Polymers Using XPS, SIMS and AFM. Mechanisms of Polymer Degradation and Elimination. Non-medical Biodegradable Polymers: Environmentally Degradable Polymers.

Pectin-based systems for colon-specific drug delivery via oral route

Pectin-derived matrices are now being examined and tested for controlled drug delivery. Pectin is intact in the upper gastrointestinal tract and degraded by colonic microflora. The composition of this microflora remains relatively consistent across a diverse human population. Thus, pectin-derived drug carriers provide promising potential for colon-specific drug delivery. This paper reviews recent developments in pectin-derived formulations. Subjects reviewed include gelation of pectin, calcium cross-linked pectinate, composites of pectin and other polymers, technologies to fabricate pectin into useful drug delivery vehicles, and methods to evaluate release kinetics of incorporated drugs. This article discusses advantages, limitations, and possible future developments in pectin-based formulations with particular emphasis on the field of colon-specific drug delivery.

Ultrasound, liposomes, and drug delivery: principles for using ultrasound to control the release of drugs from liposomes.

Ultrasound is used in many medical applications, such as imaging, blood flow analysis, dentistry, liposuction, tumor and fibroid ablation, and kidney stone disruption. In the past, low frequency ultrasound (LFUS) was the main method to downsize multilamellar (micron range) vesicles into small (nano scale) unilamellar vesicles. Recently, the ability of ultrasound to induce localized and controlled drug release from liposomes, utilizing thermal and/or mechanical effects, has been shown. This review, deals with the interaction of ultrasound with liposomes, focusing mainly on the mechanical mechanism of drug release from liposomes using LFUS. The effects of liposome lipid composition and physicochemical properties, on one hand, and of LFUS parameters, on the other, on liposomal drug release, are addressed. Acoustic cavitation, in which gas bubbles oscillate and collapse in the medium, thereby introducing intense mechanical strains, increases release substantially. We suggest that the mechanism of release may involve formation and collapse of small gas nuclei in the hydrophobic region of the lipid bilayer during exposure to LFUS, thereby inducing the formation of transient pores through which drugs are released. Introducing PEG-lipopolymers to the liposome bilayer enhances responsivity to LFUS, most likely due to absorption of ultrasonic energy by the highly hydrated PEG headgroups. The presence of amphiphiles, such as phospholipids with unsaturated acyl chains, which destabilize the lipid bilayer, also increases liposome susceptibility to LFUS. Application of these principles to design highly LFUS-responsive liposomes is discussed.

Transdermal monitoring of glucose and other analytes using ultrasound

1, including implantable sensors 2‐4 , minimally invasive skin microporation approaches involving laser or miniaturized lancets 5 and noninvasive technologies such as near-infrared spectroscopy 5 , transdermal permeation enhancers 6 or reverse iontophoresis 7,8 . However, none are used in routine clinical practice 5 . One of the fundamental problems in noninvasive transdermal diagnostics is obtaining sufficient quantities of analyte for detection. Ultrasound, particularly at low frequencies, enhances transdermal delivery of drugs (sonophoresis) 9‐11 . Here, we sought to determine whether such ultrasound facilitates the outward transport of analytes present in the interstitial fluid, thereby allowing noninvasive extraction of clinically useful analytes 12

Characterization of glucose-sensitive insulin release systems in simulated in vivo conditions

We studied the glucose-responsive insulin controlled release system based on the hydrogel poly(2-hydroxyethyl methacrylate-co-N,N-dimethylaminoethyl methacrylate), also called poly(HEMA-co-DMAEMA), with entrapped glucose oxidase, catalase and insulin. When exposed to physiological fluids, glucose diffuses into the hydrogel, glucose oxidase catalyzes the glucose conversion to gluconic acid, causing swelling of the pH-sensitive hydrogel and subsequently increased insulin release. The higher the glucose concentration in the medium, the higher and faster the swelling and release rates. The effects of polymer morphology and oxygen availability on hydrogel swelling and on insulin release kinetics were tested. Polymer morphology was modified by changing the crosslinking agent (tetraethylene glycol dimethacrylate) concentration (0-0.95 vol%). Oxygen availability was modified by changing the immobilized catalase concentration (0-15 units catalase per unit glucose oxidase) and by bubbling oxygen through the medium. The results indicated that: (i) Hydrogels without crosslinking agent were found to be stable in water, and their sensitivity to pH and glucose was higher than the chemically crosslinked hydrogels. (ii) Immobilization of catalase in addition to glucose oxidase in hydrogels prepared without crosslinking agent, resulted in enhanced swelling kinetic. In addition, we carried out primary in vivo experiments on rats, which demonstrated that at least some of the entrapped insulin retains its active form and is effective in reducing blood glucose levels. Moreover, no tissue encapsulation was observed around matrices implanted in the peritoneum. In conclusion, the pH-sensitive hydrogel poly(HEMA-co-DMAEMA) can be manipulated to produce glucose-responsive insulin release system that is effective in reducing blood glucose levels.

Ultrasound and transdermal drug delivery

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Application of ultrasound to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin. This review presents the main findings in the field of sonophoresis, namely transdermal drug delivery and transdermal monitoring. Particular attention is paid to proposed enhancement mechanisms and future trends in the field of cutaneous vaccination and gene delivery.

Characterization of a polymeric PLGA-injectable implant delivery system for the controlled release of proteins.

Physico-chemical properties of injectable polymeric implant systems, based on the principle that a water-insoluble polymer dissolved in a biocompatible solvent will precipitate upon contact with water, were studied and utilized to predict the release of proteins from these systems. Polylactide-co-glycolide copolymer (PLGA) and glycofurol were chosen since they both have pharmaceutical precedence. Changes in polymer composition, its weight percent in solution, molecular weight, and protein loading level were assessed to provide formulations with the desired release rates and duration of release.

Effect of ultrasound on transdermal drug delivery to rats and guinea pigs.

The effect of therapeutic range ultrasound (1 MHz) on skin permeation of D-mannitol, a highly polar sugar alcohol, inulin, a high molecular weight polysaccharide and physostigmine, a lipophilic anticholinesterase drug was studied in rats and guinea pigs. D-Mannitol and inulin are totally and rapidly excreted, once they have penetrated through the skin into the blood stream, permitting direct in vivo monitoring. For evaluating skin penetration of physostigmine the decrease of whole blood cholinesterase was measured. Ultrasound nearly completely eliminated the lag time usually associated with transdermal delivery of drugs. 3-5 min of ultrasound irradiation (1.5 W/cm2 continuous wave or 3 W/cm2 pulsed wave) increased the transdermal permeation of inulin and mannitol in rats by 5-20-fold within 1-2 h following ultrasound application. Ultrasound treatment also significantly increased (P less than 0.05) the inhibition of cholinesterase during the first hour after application in both physostigmine treated rats and guinea pigs: while in control guinea pigs no significant inhibition of cholinesterase could be detected during the first 2 h after application of physostigmine, the ultrasound treated group showed a 15 +/- 5% (mean +/- SEM) decrease in blood cholinesterase 1 h after ultrasound application. For physostigmine-treated rats the level of cholinesterase inhibition 1 h after ultrasound application was 53 +/- 5% in the ultrasound-treated group and 35 +/- 5% in the controls.

Determination of threshold energy dose for ultrasound-induced transdermal drug transport

Low-frequency (20 kHz) ultrasound has been shown to enhance transdermal transport of drugs, a phenomenon referred to as sonophoresis. In this paper, we report the threshold energy dose for ultrasound-induced transdermal drug transport. The threshold was determined by in vitro measurements of the dependence of sonophoretic enhancement on ultrasound parameters, including intensity, duty cycle, and exposure time. While the enhancement varies linearly with ultrasound intensity and exposure times, it is independent of the duty cycle in the range of parameters studied. The enhancement is also directly proportional to the ultrasound energy density once the threshold value is crossed. For full thickness pig skin, the threshold value is about 222 J/cm(2). The overall dependence of transport enhancement on ultrasound parameters is similar to that of cavitation measured in a model system, pitting of aluminum foil. Specifically, the extent of pitting is proportional to ultrasound intensity and exposure time and is independent of duty cycle. Furthermore, the extent of pitting is also proportional to the ultrasound energy density. The similarity between the parametric dependence of transport enhancement and cavitation is consistent with previous findings that cavitation plays the dominant role in sonophoresis.