Survey: calculation of the characteristics of oral diffusion-controlled release dosage forms related to the drug.

Oral dosage forms with controlled release exhibit various advantages over their immediate release counterparts, but they must be built adequately by dispersing the drug through the well-defined polymer matrix. This study is concerned with diffusion-controlled dosage forms to resolve the problems that appear: in vitro tests generally used for determining the kinetics of drug release do not take into account the nature of the drug. On the contrary, the plasma drug profiles obtained through in vivo tests strongly depend on the nature of the drug, through their typical pharmacokinetic parameters. Moreover, the effect of the stirring rate is difficult to evaluate. Following the demand from the FDA concerned with the in vitro/in vivo correlation, a numerical model was built so as to evaluate the plasma drug profile obtained with any drug delivered from a diffusion-controlled release dosage form. The results are expressed by connecting the half-life times of the drugs obtained either with bolus injection or with the dosage forms, for various values of the parameters of interest: the diffusivity of the matrix polymer and the size of the dosage form. Thus, these diagrams make it possible to promptly determine the characteristics of the dosage forms able to give the desired plasma drug profile for any drug. Of course, for each drug being defined by its pharmacokinetic parameters, the polymer matrix should be selected as a function of its diffusivity. Finally, the evaluation of the plasma drug profile is of effective help to determine quantitatively the effect of the intervariability of the patients as well as the effect of the patient's noncompliance.

Adapting therapy with repeated short-infusions to inter individual variability between patients.

Because of the wide inter individual variability between patients and their marked differences in drug response, one of the major issues that arises is adapting the therapy in question to the particular patient. In hospital, it is possible to vary the conditions of intravenous (i.v.) drug delivery by means of short infusions repeated at certain intervals. In this study, review of this process has been presented, and a therapeutic method described. It essentially consists of two stages. The first concerns the time of the first infusion, and the course of drug elimination: from two analyses of the drug concentrations in the blood made at two different times, the pharmacokinetic parameters of the patient are determined. Stage 2 consists of repeated short infusions and the therapy is adapted to the particular patient by varying the conditions involved. Thus, either the amount of the dose based on the rate of infusion or the time interval between the repeated infusions are varied. In order to reach a general solution, master curves are built by using dimensionless numbers as co-ordinates, such as time expressed in terms of the half-life t0.5 of the drug, and the drug concentration at the peaks defined as a fraction of the first unchanged peak concentration.

Mixed pharmacokinetic population study and diffusion model to describe ciprofloxacin lung concentrations.

The pharmacokinetics of ciprofloxacin in plasma and lung tissue at steady-state (500 mg b.i.d.) were studied in 38 patients subjected to lung surgery for bronchial epithelioma. The mean characteristics of the patient population were: age = 60 years (range: 48-70), weight=70kg (47-95), height=165cm (range 160-170) and serum creatinine=85microM (range 62-168). Plasma samples, two for each patient and lung samples, one for each patient, were obtained and analyzed. Seven groups were made according to the time of sampling after ingestion of the 5th dose. A three-compartment model was used to describe ciprofloxacin kinetics in plasma and lung. The non-linear mixed effect model approach was used to estimate the mean and variance of the pharmacokinetic parameters. The mean +/- SD of the estimates (coefficient of variation of interindividual variability as a percentage) were central volume of distribution, 39.45+/-52.47l(133%); steady-state volume of distribution, 145.86+/-97.51l(60%), clearance of influx into lung tissue, 35.83+/-22.57l/h(63%), extrapolated elimination rate constant, 0.173+/-0.25/h and extrapolated elimination half-life, 4.02+/-0.89h. The mean +/- SD ciprofloxacin concentration versus time curve in plasma and lung at steady state was simulated using pharmacokinetic parameters and lung physiological parameters, another approach was studied to model the transport of ciprofloxacin into the lung tissue by diffusion. Ciprofloxacin concentration-time history was obtained both by experiments or simulations. The ciprofloxacin level in the lung tissue followed the ciprofloxacin plasma level with a lag time resulting from the time necessary for ciprofloxacin to diffuse through the lung.

Calculation of the dimensions of dosage forms with release controlled by diffusion for in vivo use.

Using numerical models and data obtained from in vitro experiments, the dimensions of diffusion controlled release dosage forms to achieve desired in vivo levels are predicted. Monolithic polymer-drug devices are considered, the release of the drug being controlled by transient diffusion with constant diffusivity. The dimensions of the devices are calculated for various shapes (e.g. spheres, parallelepipeds, cylinders), so that 85% of the drug is released within 6 or 24 h, respectively. Caffeine, diltiazem HCl, and theophylline are studied in ethylcellulose (EC), plasticized with dibutyl sebacate (DBS) or acetyltributyl citrate (ATBC), respectively. The dosage forms are to be administered orally once a day. The resulting drug levels in the plasma are calculated using a numerical model that takes into account: the kinetics of drug release and the pharmacokinetic data of these dosage forms and drugs. Plasma levels resulting from immediate release dosage forms are also calculated, serving as reference.

Contaminant transfer during the coextrusion of tri-layer polymer films with a recycled layer. Effect of this transfer on the time of protection of the food.

Reusing old polymer packages as new food packages necessitates the coextrusion of tri-layer polymers, the old polymer being located between two virgin polymer layers. As it takes some time for the contaminant initially located in the old polymer, the virgin polymer layer acts upon the food pollution as a functional barrier. With the coextrusion process, the polymer layers are heated up to a high temperature and let cool down in air. During this coextrusion stage, the contaminant diffuses through the package at a fast rate over a short period of time. Then the time of protection of the functional barrier is significantly reduced. The process of the contaminant transfer is especially studied either during the coextrusion stage of the film or in the package-food system at room temperature.

Assessment of blood level with controlled-release dosage forms: effect of the rate constant of elimination of the drug.

Prediction of the drug level in the volume of distribution was made using a numerical model taking into account the following facts: the kinetics of drug release out of the dosage form along the gastrointestinal tract, the kinetics of absorption in the blood compartment and the kinetics of elimination. Various parameters intervene significantly for a given dosage form. Some emphasis was placed upon the rate of elimination of the drug which appears to be the main characteristic for the drug, especially when it is delivered through controlled release dosage forms. The rate of release of the drug out of the dosage form, as well as the dose frequency and the gastrointestinal transit time were also considered. The drug level in the plasma was expressed by the amount of drug as a fraction of the amount of drug initially located in the dosage form.

Problems encountered for food safety with polymer packages: chemical exchange, recycling.

When a polymer is in contact with a liquid, generally some matter transfers take place: the liquid enters the polymer, while some additives leave the polymer. This fact is responsible for a reduction in the properties of the polymer and pollution of the liquid food is obtained. However, it is sure that, on account of their outstanding properties, food packages are becoming more and more based on polymers. The process of mass transfers is controlled by transient diffusion, and these theoretical problems are so complex that only numerical models are able to resolve them. New difficult problems appear with the desire of recycling old food packages made of polymers by reusing them as new food packages. Of course, because of the potential contamination brought with this recycled polymer, the package is made of bi-layer or tri-layer films where the reused polymer is located between two virgin polymer layers. As it takes some time for the contaminant to diffuse through the virgin layer, this latter plays the role of a functional barrier to pollution. The various difficulties in the whole problem are considered in succession: the coextrusion of the films where a contaminant transfer already occurs; and the effect of the liquid food which may enhance the diffusion of the contaminant. Various master curves are drawn by using dimensionless numbers, so as to make the results quite general and of use from a practical point of view.

Calculation of the dimensions of drug-polymer devices based on diffusion parameters.

The release kinetics of a polymeric-controlled release device are determined by its geometry and dimensions. A method to calculate the required size and shape of diffusion-controlled dosage forms to achieve a particular release profile is presented. The diffusion parameters are determined for various drugs (theophylline, diltiazem hydrochloride and caffeine) with thin ethyl cellulose (EC) films, containing different plasticizers [dibutyl sebacate (DBS) and acetyl tributyl citrate (ATBC)]. Computer simulations are then used to predict the drug release kinetics from various dosage forms (e.g. microparticles and cylinders). The practical benefit of these simulations is to optimize the geometry and dimensions of a controlled release device without the need of experimental studies. To verify the theoretical predictions, the release kinetics of theophylline from EC/ATBC microparticles of different size have also been determined experimentally. Good agreement is found between theory and experiment, proving the validity of the presented method.

Calculation of the antibiotic level in the lung tissue and bronchial secretion with an oral controlled-release dosage form.

The drug level-time history in plasma and lung tissue was calculated with an antibiotic orally delivered in either an immediate-release or a controlled-release dosage form. The drug profiles were compared with experiment results given in the literature. In the same way, the drug level was evaluated in the bronchial secretion in contact with lung tissue. A numerical model, based on finite differences taking all the known facts into account was built and tested with the data found in the literature. Transport of the drug was looked at, including a stage of diffusion through the thickness of the lung tissue and a stage of convection into the bronchial secretion. A few parameters were thus considered, including the thickness of the lung tissue and the diffusivity of the antiobiotic through the tissue, the thickness of the bronchial secretion and the coefficient of convective transport into the sputum which characterizes its viscosity. Two partition factors were also introduced for the drug: between the tissue and the serum and between the lung tissue and the bronchial secretion.

Food and packaging interactions: determination of the kinetic parameters of olive oil diffusion in polypropylene using concentration profiles.

The penetration of olive oil into polypropylene was studied in order to allow a complete modellization of food and packaging interactions. Oil concentration profiles through polypropylene food trays were determined by FTIR-microscopy measurements along the thickness at various times. Calculations of the relevant parameters characterizing Fickian diffusion, namely constant diffusivity, coefficient of convective mass transport on the surface and concentration at equilibrium were carried out. This way of working has proven to be considerably shorter and more accurate than the method consisting of recording the global absorbance of the substance absorbed, especially when the amount of diffusing fat is low. Major conclusions are: that absorption of olive oil is strongly influenced by convection; the diffusion coefficient of olive oil in polypropylene is constant. Possible consequences to simplify global migration testing are discussed.

Modelling transport between a monolayer and a bi-layer polymeric package and food.

There is considerable interest in the recycling of food packaging, but also the potential for problems. Any chemical component initially located in the re-used food packaging may be responsible for contamination of the food. The kinetics of this transfer can be established whether the food is liquid or solid. The process is controlled by diffusion in the packaging and by convection in the liquid food or by diffusion in the solid food. A bi-layer package made of a re-used polymer layer and a virgin polymer layer exhibits quite different kinetics for the contamination of the food. The role of the virgin polymer layer or so-called functional barrier can be established either by the kinetics of contaminant transfer or by the profiles of concentration developed through the packaging-food system. Dimensionless numbers are used in order to be of help to anyone in need of precise information on the length of time this functional barrier offers protection of the food.

Prediction of worst case migration from packaging to food using mathematical models.

Prediction of migration from packaging to food is often made using equations which are not always designed specifically for the problem. At least, these equations should overestimate migration, in order to be on the safe side. Integration of Fick's equation under the assumption of 'infinite packaging' provides an equation which is very practical since it requires only a few experimental data. It is shown here that, unfortunately, the use of this equation leads to a systematic underestimation of the diffusivity, by the square of the percentage of migration at steady state. In contrast to widely accepted opinion, this model is not conservative. A conservative approach requires that the diffusivity is determined under 'finite packaging' assumptions, associated with very large volumes of food and with long term experiments. These equations are applied to the migration of a phenolic antioxidant from polypropylene.

Assessment of antibiotic levels in lung tissue with erosion-controlled dosage forms.

The concentration-time curve of ciprofloxacin has been assessed in the blood compartment and in the lung tissue following oral administration of the drug. Immediate release and erosion-controlled dosage forms have been examined. A numerical model based on finite differences and taking into account all relevant data has been built: the kinetics of drug release in the gastrointestinal tract, drug absorption in the blood compartment and elimination, and the transient diffusion of the drug through the lung tissue. A partition coefficient for the drug at the tissue-blood interface has been considered to express the drug concentration at the tissue surface. The effect of dose frequency and erosion rate on the antibiotic versus time curves in the plasma and the lung tissue has been studied in detail.

Comparative pharmacokinetics of Aspegic 1000 mg i.v. versus 1000 mg i.m. thrice daily.

The comparative pharmacokinetics of Aspegic, the lysine salt of acetylsalicylic acid, administered in multi doses either through i.v. or i.m. route was studied. 1 g of drug was injected each time with a frequency of 3 times a day. The pharmacokinetic parameters were determined using the experimental data in the literature. From these results, three categories of patients were considered, depending on their response to the drug. A numerical model was established in order to evaluate the following results: the drug level in the blood compartment obtained with the i.v. or i.m. administration, as well as the area under the curve for the first day and the third day when the so-called stationary state was obtained. Approximately similar values for AUC were obtained for each route of administration, for a given category of patients. The effect of the inter-variability of the patients characterised by their response to the drug was found to be of prime importance.

Theoretical treatment of pollutant transfer in a finite volume of food from a polymer packaging made of a recycled film and a functional barrier.

The problem of pollutant transfer in food from a polymer packaging made of a recycled film and a functional barrier is studied from a theoretical point of view. In the present case, the process is controlled by Fickian diffusion through the two films of the polymer packaging in perfect contact and by convection into the food. A numerical model is built, taking all the facts into account: the diffusion of the pollutant through the two polymer films, a convective coefficient of mass transfer on the surface, a partition factor, the volume of the liquid and the thicknesses of the polymer films. The results are expressed by using dimensionless numbers so that they can be used for various cases, viz the kinetics of pollutant transferred into the food and the profiles of concentration of the pollutant through the packaging.

Prediction of in-vivo blood level with controlled-release dosage forms. Effect of the gastrointestinal tract time.

The process of in-vivo drug transfer is very complex in the case of oral dosage forms with controlled release. A numerical model taking all the known facts into account, including the release of the drug controlled by diffusion through the dosage form along the gastrointestinal tract, the kinetics of absorption in the blood compartment and the kinetics of elimination was constructed. Various parameters intervene in an important manner for a given drug: the size of the dosage form which is associated with the rate of release of the drug, and the dose frequency in multidosing. Some emphasis is placed upon the gastrointestinal tract time which appears to be the main and first parameter to be considered in preparing a dosage form.

Adaptive control of therapeutic drug regimens relations between clinical situations: outcomes and simulations using nonlinear dynamic models.

With Bayesian modeling and adaptive control of drug dosage regimens, serum and peripheral drug concentrations can be predicted in clinical situations using linear pharmacokinetic compartmental models (PK). Recently, several pathophysiologic and pharmacodynamic nonlinear models (PD) have been developed. The present report illustrates both their utility and limits for the computation of effects in clinical situations in the setting of actual routine and acute patient care. Patients who received therapy with aminoglycosides or/and vancomycin were selected. For each patient, after estimation of individual pharmacokinetic parameters, the computed outputs of the linear compartmental pharmacokinetic model were used as inputs for 2 different a priori nonlinear dynamic models: 1) the EFFECT modeling program, using a Hill model, and 2) the BACTCIDE program, which is a combination of a simple growth model for the organism and a Hill effect model considering both the microorganism, the antibiotic, and the patient's minimal inhibitory concentration (MIC). The programs (1) and (2) can use as inputs the computed concentrations from any of three compartments: central, peripheral, or a spherical diffusion compartment to compute drug diffusion into endocardial vegetations or abscesses. The EFFECT program can be used alone for the evaluation of drug effects. The BACTCIDE program illustrates differences in activity between concentration-dependent and time-dependent antibiotics. Such nonlinear programs are very sensitive to the MIC values.

Numerical models for calculating the blood level of a drug with oral controlled release forms.

Controlled release dosage forms offer advantages over conventional dosage forms and a more constant and prolonged therapeutic effect. These new dosage forms are tested by using in-vitro tests or in-vivo tests; however, a great problem appears with the establishment of correlations between these tests. A new way of working is able to resolve the problem. It consists of coupling either experiments or models based on numerical analysis and computerization. In-vitro tests performed at various pH are used to determine the kinetics of release and the parameters characterizing diffusion or erosion. From the knowledge of the certain data (the gastrointestinal tract-time history, the kinetics of release of the drug out of the dosage form, the rate constants of absorption and elimination, and the plasmatic volume), it is possible to obtain, by calculation, the kinetics of the drug in the plasmatic volume, as well as other pieces of information. Not only is the model able to predict the pharmacokinetics of a drug from a controlled release dosage form, but it also optimizes the characteristics of the dosage form. The validity of the model is successfully tested by comparing the blood level of Theophylline, obtained either by in-vivo tests or calculation.

Intravegetation antimicrobial distribution in endocarditis: a numerical model and establishment of the conditions for an in-vitro test.

Two problems appear when it is desired to get good knowledge concerning transfer of matter through a material, and especially the penetration of antibiotics into vegetations on heart valves. One is to build a numerical model to describe and simulate the process and thus to gain a fuller insight into the nature of the transfer. The other is to develop an in vitro test to represent the in vivo process, with simple operational conditions and accurate measurements. The in vitro test must enable one to measure the parameters of interest, i.e. the diffusivity of antibiotic through the vegetation, or rather through the blood located in the vegetation. Experiments and calculations are made in order to build a numerical model describing the process and to develop an in vitro test capable of determining the diffusivity. A simulation is made with a polymer bead made of Ethylene vinyl acetate saturated by a liquid such as n-heptane with a slight amount of benzene. The release of benzene from the polymer bead into n-heptane free from benzene is the best way for measuring the diffusivity of the benzene (simulating the antibiotic) through the liquid located in the polymer.

Computation of drug concentrations in endocardial vegetations in patients during antibiotic therapy.

The treatment of endocarditis often requires prolonged antibiotic therapy. Individualized drug dosage regimens have made such therapy possible even in patients with impaired renal function. However, the problem of efficacy remains. Especially for aminoglycosides, it would be a useful guide to have at least an approximate idea of the concentration of an antibiotic within an endocardial vegetation. This study was designed to develop software to model the drug concentrations at different layers within spherical vegetations to provide a guide during clinical therapy of patients with endocarditis. A general model describing the diffusion of antibiotics in spheres has now been developed and interfaced with the USC*PACK PC Clinical Programs in order to compute and plot concentrations, within the vegetation, based on the regimen given to the patient and the diffusitivity of the antibiotic into the vegetation. Some preliminary results of this research, which are still in progress, are presented. Diffusion into simulated spherical vegetations has been computed for different treatment regimens for endocarditis: amikacin or netilmicin and vancomycin were given to three elderly patients (3 women, 74, 75 and 92 years old, with initial estimated creatinine clearances of 51, 36, and 31 ml/min/1.73 m2, respectively). Although Amikacin has a low diffusivity, the concentrations, even in the center of the vegetation, appear to be effective. The effects of various regimens, including a 'once-a-day' aminoglycoside regimen, are presented.