Clinical kinetics on intact cisplatin and some related species.

Plasma concentrations of cisplatin, total platinum, and total filterable platinum were monitored in 24 patients after either 50 or 100 mg/m2 of cisplatin by rapid intravenous injection. Half the patients at each dose were pretreated with mannitol. Total platinum levels declined in a triphasic fashion with a terminal half-life (t1/2)greater than or equal to 24 hr. Both total filterable platinum and cisplatin levels declined in a monophasic manner and exhibited t1/2 of 0.3 to 0.5 hr. The ratio of cisplatin to total filterable platinum in plasma remained constant (0.6 to 0.8) over the time period (2 hr) during which they could be detected, while the ratio of the plasma levels of cisplatin to total platinum decreased continuously from approximately 0.5 at 5 min to approximately 0.10 at 2 hr. Larger doses of cisplatin resulted in higher plasma levels of all three species monitored, and although the increases appeared somewhat less than proportional to dose, terminal plasma slopes were not dose dependent. Neither mannitol nor dose had an effect on the various species ratios, nor did mannitol appear to affect either plasma levels or terminal plasma decline.

Poly(ortho ester) biodegradable polymer systems.

PIP: 1 approach to developing bioerodible drug delivery systems is to prepare hydrolytically labile polymers into which a drug can be physically dispersed under relatively mild conditions and in which release of the drug is controlled by the hydrolytic erosion of the matrix. Focus is on devices in which the hydrolytic erosion process is confined to the surface of a solid device. In such devices, and for a constant rate of polymer hydrolysis, rate of drug release is directly proportional to drug loading, and lifetime of the device is directly proportional to the physical dimensions of the device. Due to the fact that the rate of drug release is directly proportional to the total surface area of the device, as the physical dimensions of the device decrease because of the erosion process, the rate of drug release also will decrease. There are 2 possible approaches to the achievement of controlled surface erosion: the interior of the matrix is stabilized so that only the outer layers can erode; and development of a highly hydrophobic polymer that contains linkages in the polymer backbone whose rates of hydrolysis are pH dependent and to incorporate into the polymer excipients that, in contact with water, produce a pH that induces the desired polymer hydrolysis rate. 1 such polymer system is the poly(ortho esters). This chapter describes some work done on polymer synthesis and the use of various excipients to achieve controlled drug release of various therapeutic agents physically dispersed in these polymers. It contains a review of drug release studies, which covers the use of basic or neutral water-soluble excipients, the use of acidic excipients, the use of calcium lactate, and the use of anhydrides. Poly(ortho ester) bioerodible polymers are suitable materials for the topical administration of a wide variety of therapeutic agents; varying the nature and amounts of excipients physically incorporated into the polymer will vary the erosion rates from a few hours to many months. With this range of control, delivery systems for short-term applications such as oral 12-24 hour tablets, intermediate ophthalmic products lasting 1 week, or implants lasting as long as 1 year can be produced. No extensive toxicological studies have been performed as yet. In vivo release rate experiments performed over many months have not shown any adverse tissue reactions beyond the expected encapsulation.^ieng

Modelling of drug release kinetics from a laminated device having an erodible drug reservoir.

The purpose of this communication is to present a preliminary analysis to demonstrate the effect of laminating a drug-containing erodible polymer matrix with a second barrier membrane. A mathematical model for the diffusive release of the drug from an erodible polymer device undergoing surface erosion has been extended to similar devices with a secondary membrane to allow a comparison of the results. The results indicate that the constant rate of release characteristic of erodible devices is not sacrificed with the addition of the secondary membrane; moreover, the membrane provides additional controllable parameters at the disposal of the device designer.

Drug delivery from catalysed erodible polymeric matrices of poly(ortho ester)s.

The incorporation of small amounts of acid anhydrides into hydrophobic poly(ortho ester)s can facilitate the erosion and drug release from delivery systems. Since the reaction can be controlled by the amount of anhydride employed, the reaction is confined to a small reaction zone near the surface and constant delivery rates can be achieved. The catalytic activity is negatively correlated with the pKa of the corresponding acid of the anhydride.

Quantitative evaluation of topically applied pilocarpine in the precorneal area.

The bioavailability of topically applied pilocarpine is poor due to various loss mechanisms that serve to lessen delivery of the drug to the aqueous humor. Precorneal drainage and other routes of loss have been investigated qualitatively as well as quantitatively. The mechanistic models proposed to date suffer from the drawback of being dependent on our understanding of the mechanism of drug transport through the corneal membrane. This report quantifies the initial disposition of topically applied drugs and their availability for systemic and local absorption. The rate constant for the conjunctival absorption is determined and is independent of the mechanism of transcorneal transport.

Modification of in situ gelling behavior of carbopol solutions by hydroxypropyl methylcellulose.

Aqueous solutions of Carbopol [polyacrylic acid (PAA)] are low viscosity acidic solutions that transform into gels upon an increase in the pH and, therefore, may be used as in situ gelling ophthalmic drug delivery systems. However, the amount of PAA required in the solution to form stiff gels upon installation in the eye is not easily neutralized by the buffering action of tear fluid. A reduction in the PAA concentration without comprising the in situ gelling properties as well as the overall rheological behavior of the system can be achieved by adding a suitable viscosity-enhancing polymer. The rheological properties of aqueous solutions containing PAA and hydroxypropyl methylcellulose (HPMC), a viscosity-enhancing polymer, evaluated as a function of temperature and pH, were similar to those of pure PAA solutions; that is, both form low viscosity liquids at pH 4.0 and transform into stiff gels with plastic rheological behavior and comparable viscosities upon increasing the pH to 7.4. In addition, HPMC-PAA gels show slow in vitro release of incorporated timolol maleate. Thus, the HPMC-PAA combination demonstrates properties suitable for formulation as a liquid ophthalmic delivery systems, which upon instillation into the cul-de-sac of the eye can undergo in situ phase transition to form gels capable of sustained drug release.

Mathematical model for cyclocytidine pharmacokinetics.

The pharmacokinetics of the drug cyclocytidine in humans were modeled by using a physiological and anatomical approach. Each pertinent tissue is represented by a single compartment, and these compartments are linked together by the circulatory system. Each compartment is then represented by an ordinary differential equation that represents the rate of change in drug concentration as function of convecting transport, metabolism, and urinary clearance. The models for cyclocytidine and cytarabine are linked together by a hydrolysis term in each equation set. The resulting equation sets are then solved numerically to predict the concentration of both drug species in situ. The models use physiological blood flows, tissue volumes, and clearance parameters. The results of the model show that cyclocytidine can act as a reservoir for cytarabine in vivo over the time studied. This effect is confined to relatively long times and relatively low plasma concentrations.

Preliminary pharmacokinetic model of pilocarpine uptake and distribution in the eye.

A pharmacokinetic model that permits prediction of aqueous humor pilocarpine levels following topical application to rabbit eyes was developed. The model is able to account for changes in both instilled solution volume and drug concentration. The model, although simplified, relies mainly on experimentally verifiable and independently measured parameters. Its utility lies in its ability to account quantitatively for the large drainage loss of instilled drug solutions and its predictive ability regardless of the instilled volume or concentration. The framework established by this model will allow further sophistication as more experimental data become available and should be adaptable to other ophthalmic drugs.

Simultaneous self-association and diffusion of phenol in isooctane.

The impact of self-association on mass transport was studied. The model system chosen was the diffusion of phenol through an immobilized layer of isooctane. In the theoretical development, self-associated phenol contributed to diffusion, with the fluxes being interdependent because of the self-association equilibrium. Predictions from theory were then compared with experimental results. It was shown that self-association can significantly affect flux of diffusing species.

Diffusion of phenol in the presence of a complexing agent, tetrahydrofuran.

The effect of a complexing agent, tetrahydrofuran, on the diffusion of phenol across a stagnant fluid layer has been studied. At a given activity of free phenol, the steady-state flux of phenol appearing in an acceptor phase was greatly enhanced. However, as the fraction of phenol associated with the complexing agent increased, the flux of phenol decreased, since the transport was then controlled by the diffusion of the complex, a larger structure. A mathematical model of simultaneous association and diffusion was derived to determine whether the diffusional behavior of two associating species could be accounted for in terms of the association equilibrium constant and Fick's second law. Experimental results supported the model. It was concluded that the presence of a complexing agent tends to reduce the rate of diffusion, the effect being more pronounced at high concentrations of complexing agent.

Hydrolysis of some poly(ortho-ester)s in homogeneous solutions.

The hydrolysis of poly(ortho-ester)s and a monomeric model compound, 3,9-dibenzyloxy-3,9-diethyl-2,4,8,10-tetraoxaspiro[5,5]un decane, was carried out in dioxane-d8-dioxane and followed by 1H-NMR and HPLC, respectively. Experimental results suggested that the polymer degradation proceeds to a large extent via random scission. The hydrolysis was catalyzed by the acid; the catalytic rate constant increased predictably with decreasing aqueous pKa of the acid. The reaction is first order with respect to the catalyst concentration and the number of ortho-ester linkages present, and it is independent of water in the concentration range studied. Strain at the ortho-ester bond may be a factor influencing the hydrolysis rate.

Dissolution kinetics of carboxylic acids I: effect of pH under unbuffered conditions.

The dissolution behavior of benzoic acid, 2-naphthoic acid, and indomethacin from rotating compressed disks into aqueous solutions of constant ionic strength (mu = 0.5 with potassium chloride) at 25 degrees was investigated. The pH of the bulk aqueous medium was maintained during dissolution by means of a pH-stat apparatus. A model for the initial steady-state dissolution rate of a monoprotic carboxylic acid was derived from Fick's second law of diffusion. This model assumed that diffusion-controlled mass transport and simple, instantaneously established reaction equilibria existed across a postulated diffusion layer. Using previously determined intrinsic solubilities, pKa values, and diffusion coefficients, the model was found to predict the dissolution rates of these acids accurately as a function of the bulk solution pH. Hydroxide ion and water were the only reactive base species present in the bulk solution. The concentration profiles of all of the species across the diffusion layer were generated for a given bulk pH. Furthermore, the model generated values for the pH profile within the microclimate of the diffusion layer and the pH at the solid-solution boundary.

Dissolution kinetics of carboxylic acids II: effect of buffers.

The dissolution behavior of 2-naphthoic acid from rotating compressed disks into aqueous buffered solutions of constant ionic strength (mu = 0.5 with potassium chloride) at 25 degrees was investigated. A model was developed for the flux of a solid monoprotic carboxylic acid in aqueous buffered solutions as a function of the solution pH and the physicochemical properties of the buffer. The model assumes a diffusion layer-controlled mass transport process and simple, instantaneously established reaction equilibrium between all reactive species (acids and bases) across the diffusion layer. Using intrinsic solubilities, pKa values, and diffusion coefficients, the model accurately predicts the dissolution of 2-naphthoic acid as a function of the bulk solution composition. The concentration profiles of all species across the diffusion layer are generated for each buffer concentration and bulk solution pH, including the pH profile within the microclimate of the diffusion layer and the pH at the solid-solution boundary.

Dissolution kinetics of phenylbutazone.

This study investigated the possible effects of simultaneous, noninstantaneous, reversible chemical ionization of carbon acids on the dissolution of a typical pharmaceutical carbon acid, phenylbutazone, and its deutero analog. The dissolution rate versus pH profile for phenylbutazone was consistent with phenylbutazone acting as if it were an acid where the ionization can be considered instantaneous. In view of the dissolution behavior of phenylbutazone under various conditions, it is unlikely that the noninstantaneous ionization kinetics demonstrated for this compound play a major role in determining the dissolution rate, either in vitro or in vivo, since the average residence time in a typical aqueous diffusion layer for phenylbutazone dissolution is longer than the reaction time for its ionization. Slowing the reaction time with a primary isotope effect by deuterium substitution for the ionizable proton caused significant deviation from classical behavior for d-phenylbutazone.

Dissolution of carboxylic acids. III: The effect of polyionizable buffers.

The dissolution behavior of three carboxylic acids of variable aqueous solubility but with approximately equal pKa values into aqueous buffered solutions has been studied as a function of pH and of buffer properties. The dissolution from constant-surface-area compressed disks of benzoic acid, 2-naphthoic acid, and indomethacin into solutions of constant ionic strength (mu = 0.5 with potassium chloride) and constant pH (maintained by pH stat) at 25 degrees C using a rotating disk apparatus was evaluated. Models for dissolution of these weak acids into diprotic and triprotic buffering media are developed to predict the flux of the acid as a function of bulk solution pH and the physical and chemical properties of the buffer and acid. The models assume that mass transfer can be represented by a single second order diffusive term and that instantaneous equilibrium between all reactive species exists. Values of flux and pH at the solid-liquid interface are calculated and the fluxes compared to experimentally determined values. Reasonable correlation was found between values predicted by the models and experimental flux values. Major influences on model accuracy are the Ka and physical properties of the buffer.

Determination of steady state generation time distributions from labelled mitosis experimental data.

The proper application of detailed deterministic cell kinetic models depends on the way in which cells are assigned their generation times. A method is presented for the determination of population generation time distributions from labelled mitoses experiments. The model assumes that the generation time of each new cell is a function of both the steady-state generation time distribution function of the population, and also the generation time frequency-function of the previous generation of cells. This approach is applied to two different cell types to successfully simulate extended labelled mitoses curves using a population balance model with constant maturation rates.