Valentino J. Stella

Directed Drug Delivery

Drug response triggered by receptor activation arises from a chain of events that are regulated by many factors. Molecular changes associated with drug sensitization or tolerance are currently being elucidated on the molecular level, e.g. for adenylate cyclase coupled systems. Despite the complexity of the drug-response mechanism, simple empirical pharmaco-dynamic models on the basis of the law of mass action are widely applicable to describe drug-effect relationships. In combination with a pharmacokinetic model and suitable delay functions, such models are capable of simulating the complete time course of drug action in vivo. The predictive potential of the pharmacokinetic-pharmacodynamic models should prove useful in evaluating pharmaceutical formulations with controlled drug delivery.

Mechanisms of drug release from cyclodextrin complexes

This review addresses the issue of the mechanisms of drug release from cyclodextrin complexes. More specifically, it attempts to answer the question whether drug release from aqueous formulations is slow or incomplete? A critique of the literature, our own work, and various simulations suggests that drug release from cyclodextrin complexes is rapid and quantitative in most cases. In aqueous solution, drug/cyclodextrin complexes are continually forming and dissociating with lifetimes in the range of milliseconds or less. Although the stronger the binding, the slower the relative kinetics of dissociation, the rates are still fast and essentially instantaneous. After parenteral administration, the major driving force for dissociation of weakly to moderately bound drugs appears to be simple dilution. For strongly bound drugs, binding constants of 10(-4)M(-)(1) or higher, or for those cases where dilution is minimal, contributions from competitive displacement by endogenous materials, drug binding to plasma and tissue components, drug uptake into tissues not available to the complex or the cyclodextrin, rapid elimination of the cyclodextrin and possibly pH and temperature effects, may also be important. After parenteral administration, it does appear that cyclodextrins might cause some alterations in the fraction of free drug eliminated in the urine during that time frame where the cyclodextrin is itself undergoing substantial renal clearance.

Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules

This paper concerns itself with the importance of lipid solubility in a vehicle such as peanut oil (as well as partition coefficient) as an important criteriom for estimating the potential for intestinal lymphatic transport of orally ingested drugs and xenobiotics. Absorbability, and metabolic stability in the lumen and mucosal cells of the molecule, are other important criteria. The intestinal lymphatic system provides a potential route for drug molecules to enter systemic circulation subsequent to oral administration. The physiology of the intestinal lymphatic system is such that drugs transported from the intestinal lumen by the intestinal lymph gain access directly to the general circulation of the body at the junction of the left internal jugular and left subclavian veins, thereby avoiding initial liver contact (Youmans, 1962). Therefore, the promotion of the intestinal absorption of drug molecules which are susceptible to first-pass liver metabolism may offer a means of circumventing this initial clearance of the drug. In addition, intestinal

The Interaction of Charged and Uncharged Drugs with Neutral (HP-β-CD) and Anionically Charged (SBE7-β-CD) β-Cyclodextrins

AbstractPurpose. The objective of this work was to determine the role that charge might play in the interaction of charged and uncharged drugs with neutral (2-hydroxypropyl-β-cyclodextrin, HP-β-CD) and anionically charged (SBE7-β-CD) modified β-cyclodextrins. SBE7-β-CD is a sulfobutyl ether, sodium salt, derivative variably substituted on the 2-, 3- and the 6-positions of β-cyclodextrin. The number seven refers to the average degree of substitution. Methods. The binding of the acidic drugs, indomethacin, naproxen and warfarin and the basic drugs, papaverine, thiabendazole, miconazole and cinnarizine with the two cyclodextrins was determined at 25°C as a function of pH and cyclodextrin concentration by the phase-solubility method. Results. Except for miconazole and cinnarizine (AP-type diagrams), all other materials studied displayed AL-type diagrams. By comparing the binding constants of both the charged and uncharged forms of the same drugs to both HP-β-CD and SBE7-β-CD, the following conclusions could be drawn. The binding constants for the neutral forms of the drugs were always greater with SBE7-β-CD than with HP-β-CD. For the anionic agents, the binding constants between SBE7-β-CD and HP-β-CD were similar while the binding constants for the cationic agents with SBE7-β-CD were superior to those of HP-β-CD, especially when compared with the neutral form of the same drug. Conclusions. A clear charge effect on complexation, attraction in the case of cationic drugs and perhaps inhibition in the case of anionic drugs, was seen with the SBE7-β-CD.

Prodrugs of phosphates, phosphonates, and phosphinates

Abstract The objective of this paper is to review the literature on the use of prodrugs to overcome the drug delivery obstacles associated with phosphate, phosphonate and phosphinate functional group-containing drugs. This is an important area of research because, although we have been successful at identifying numerous phosphate and phosphonate functional group-containing drugs as antiviral and anticancer agents, as well as for other uses, our ability to orally deliver these drugs and to target them to desired sites has led to limited success. Various acyloxymethyl- and aryl-ester prodrugs have shown promise. Alternative and imaginative approaches may be necessary before complete success is realized. It is our hope that this review will stimulate further innovative prodrug research into overcoming the barriers to the delivery of these important drugs.

Characterization of sulphoalkyl ether derivatives of β-cyclodextrin by capillary electrophoresis with indirect UV detection

A capillary electrophoresis method which characterizes the degrees of substitution of heterogeneous sulphoalkyl ether beta-cyclodextrin derivatives is described. The separation is based on the different electrophoretic mobilities observed from changes in the overall charge of the molecule as a result of substitution. Individual peaks of the electropherogram then provide a measure of each degree of substitution of the present beta-cyclodextrin. Detection of these beta-cyclodextrin derivatives is performed by indirect UV detection.

Gellan-based systems for ophthalmic sustained delivery of methylprednisolone

Abstract Gellan is an anionic exocellular polysaccharide of microbial origin, having a characteristic property of cation-induced gellation. In the current study, gellan was evaluated for applications in ocular sustained release devices. A methylprednisolone (MP) ester of gellan (gellan-MP) was synthesized. Sustained release dosage forms evaluated were gellan-MP films, gellan films with physically incorporated MP and eye drops of MP suspended in a 0.6% w/w/ gellan dispersion in water. The control dosage form was a suspension of MP in normal saline. In vitro release ofMP from the test dosage forms was determined in a pH 7.4 phosphate buffer at 32 °C using a rotating bottle apparatus. MP concentrations in the tear fluid of New Zealand white rabbits were measured after ocular application of the dosage forms. In vitro, the gellan-MP films released covalently bound MP in an approximate zero-order pattern, whereas the release of physically incorporated MP from the gellan eye drops and films followed a square root of time relationship and anomalous kinetics, respectively. Compared with the MP suspension control, the gellan-MP films yielded an approximately 4-fold higher area under tear fluid concentration vs time curve, AUC0–8h, but exhibited a tendency to slip out of the eye due to a high degree of swelling. The in vivo release from films containing physically incorporated MP showed higher variability and provided mean AUC0–8h values approximately equal to the control values. The gellan eye drops containing MP yielded 2.6-fold higher AUC0–8h values than the control and also provided ease of administration. Gellan solutions might thus provide a versatile vehicle for ocular sustained release of drugs. The results also show that the gellan-MP ester can be used to increase the residence time of methylprednisolone in the tear fluid of rabbits.

Application of benzyl hyaluronate membranes as potential wound dressings: evaluation of water vapour and gas permeabilities

Membranes of 75% and 100% benzyl hyaluronate esters (percentage of total carboxylate groups esterified) were prepared and their water vapour, oxygen and carbon dioxide transmission rates determined. The values of these properties were compared with the values obtained for several commercial wound dressings under the same conditions. The benzyl hyaluronate membranes showed water vapour transmission rates (2157-2327 gm-2 per day) comparable to those from commercial skin dressings (426-2047 gm-2 per day). In the dry state, the benzyl hyaluronate membranes showed lower oxygen and carbon dioxide transmission rates. Taking into account the biocompatibility of the hyaluronic acid esters, and the possibility that therapeutic agents could be incorporated into these membranes, the results indicate that the benzyl hyaluronate membranes have potential wound dressing applications.

Prodrugs: Some thoughts and current issues

The prodrug approach to resolving formulation, delivery, and toxicity limitations on problematic drugs has had its proponents and detractors. Over the last 10 years or so, about 20% of all new small molecule NCEs have been prodrugs-a number that will surprise some. As chemists begin to explore new chemical spaces, larger and more complex molecules present greater drug delivery challenges. Prodrugs provide a means of solving these challenges, but also have their limitations. Prodrugs are becoming an integral part of the drug discovery paradigm in some large pharma companies, and a number of small biotech companies have been built around the design and application of prodrugs to improve drug candidates. Some issues facing the area of prodrug research and the commercialization of prodrugs are discussed.

Systemic bioavailability of penclomedine (NSC-338720) from oil-in-water emulsions administered intraduodenally to rats

Abstract Penclomedine (NSC-338720) is a low melting point, poorly water-soluble cytotoxic agent with good solubility in triglycerides and a high octanol/water partition coefficient. Its pharmacokinetics in anesthetized rats was studied after i.v. bolus injection of a soybean oil emulsion. Penclomedine displayed biexponential behavior with an apparent t 1 2 (± SE ) of 1.9 ± 0.3 h and a clearance of 3.3 ± 0.1 ml/min per kg. After intraduodenal administration to anesthetized rats as either a 10% o/w emulsion of tributyrin, trioctanoin, triolein, soybean oil or mineral oil, or as a suspension, the rank order of absolute bioavailability was trioctanoin > soybean oil ≈ triolein > mineral oil > tributyrin > suspension. The results were rationalized by assuming that drug release from the emulsions was by a combination of vehicle metabolism and diffusional drug release. The poor bioavailability from tributyrin was rationalized by the rapid release of penclomedine resulting in its possible precipitation and subsequent need to redissolve.