Robust Control of Repeated Drug Administration with Variable Doses Based on Uncertain Mathematical Model.

The aim of this paper was to design a repeated drug administration strategy to reach and maintain the requested drug concentration in the body. Conservative designs require an exact knowledge of pharmacokinetic parameters, which is considered an unrealistic demand. The problem is usually resolved using the trial-and-error open-loop approach; yet, this can be considered insufficient due to the parametric uncertainties as the dosing strategy may induce an undesired behavior of the drug concentrations. Therefore, the presented approach is rather based on the paradigms of system and control theory. An algorithm was designed that computes the required doses to be administered based on the blood samples. Since repeated drug dosing is essentially a discrete time process, the entire design considers the discrete time domain. We have also presented the idea of applying this methodology for the stabilization of an unstable model, for instance, a model of tumor growth. The simulation experiments demonstrated that all variants of the proposed control algorithm can reach and maintain the desired drug concentration robustly, i.e., despite the presence of parametric uncertainties, in a way that is superior to that of the traditional open-loop approach. It was shown that the closed-loop control with the integral controller and stabilizing state feedback is robust against large parametric uncertainties.

Using a State-Bounding Observer to Predict the Guaranteed Limits of Drug Amounts in Rats after Oral Administration Based on an Uncertain Pharmacokinetic Model.

In the first part of this paper, the problem of using an uncertain pharmacokinetic model is resolved to determine drug concentrations in rats after the oral administration of drug suspensions with and without added tenside. To this end, a generalized pharmacokinetic model determining the guaranteed limits of drug concentrations was designed. Based on this, the design of the so-called state-bounding observer is described in the second part. Rather than being driven by the output of the pharmacokinetic model, the observer can be driven exclusively by a concentration collected from a suitable part of the body and predict the possible risk of the drug concentration not remaining within the therapeutic range for a sufficiently long time. Specifically, the observer determines the upper and lower limits of the concentrations in all the compartments, especially those that are inaccessible for the collection of samples. The proposed approaches are demonstrated by examples.

In-Vivo Analysis and Model-Based Prediction of Tensides' Influence on Drug Absorption.

Depending on their concentrations the surface-active substances, tensides (surfactants) can positively or negatively influence the drug absorption, which is widely used in the design of the dosage forms with controlled release. A problem is that the (in-vivo) rate of absorption cannot be directly measured and for that reason, it is frequently substituted by evaluation of the (in-vitro) dissolution. On other hand, a suitably designed pharmacokinetic model can directly predict virtually all pharmacokinetic quantities including both the rate of absorption and fraction of the dose reaching the blood circulation. The paper presents a new approach to the analysis of the rate of drug absorption and shows its superiority over traditional in-vivo approaches. Both the in-vivo analysis and model-based prediction of the tenside (monolaurin of sucrose) influence on the rate of absorption of the drug (sulfathiazole) after instantaneous per-oral administration to rats are discussed. It was found that 0.001% solution of tenside can increase the rate of absorption by cca 50% and a two-fold increase in absolute bioavailability can be reached. Attention is also devoted to the formal requirements laid on the model's structure and its identifiability. The systematic design, substantiation and validation of a parsimonious predictive model that confirms in-vivo results are presented. The match between in-vivo observations and model-based predictions is demonstrated. The frequently overlooked metaphysics lying behind the compartmental modelling is briefly explained.

Effect of Molecular Composition of Head Group and Temperature on Micellar Properties of Ionic Surfactants with C12 Alkyl Chain.

The paper analyses influences of the temperature and hydrophilic groups on micellar properties of ionic surfactants with 12-carbonic hydrophobic chains. The aim is to assess the impact of hydrophilic groups and temperature on thermodynamic parameters and micellization. This knowledge is indispensable for the formulation of new dosage forms. The method uses conductometric measurements. The following hydrophilic groups are analyzed: trimethylammonium bromide, trimethylammonium chloride, ethyldimethylammonium bromide, didodecyldimethylammonium bromide, pyridinium chloride, benzyldimethyl-ammonium chloride, methylephedrinium bromide, cis and trans-[(2-benzyloxy)-cyclohexyl-methyl]-N, N-dimethylammonium bromide, sodium sulphate and lithium sulphate. Except for a few cases, there is a good agreement between values of critical micellar concentrations (CMC) and critical vesicle concentration (CVC) obtained here and those which were obtained by other authors and/or by other physicochemical methods. Values of the CMC are compared with respect to the molar masses of hydrophilic groups. It was found that CMC values increased non-linearly with increasing system temperature. The degrees of counterion binding and thermodynamic parameters, like the standard molar Gibbs energy, enthalpy and entropy of micellization are determined and discussed in detail. The results obtained will be incorporated into in silico processes of modeling and design of optimal dosage forms, a current interdisciplinary research focus of the team.

Association, Distribution, Liberation, and Rheological Balances of Alkyldimethylbenzylammonium Chlorides (C12-C16).

It is known that cationic surfactants have an antimicrobial effect and act as enhancers. This paper studies three cationic surfactants from the group of alkyldimethylbenzylammonium chlorides (dodecyl-, tetradecyl-, and hexadecyl). Interest is focused on the association of the surfactants with respect to temperature, partition balances and their influence on drug release, rheological properties, and the pH of hydrogels. The critical micelle concentrations (CMC) of the surfactants were estimated from dependencies of conductivity, density, spectrofluorimetry, and UV-VIS spectrophotometry on molarity in the temperature range of 25-50 °C. It was found that the temperature dependence of a CMC is U-shaped, with its minimum at 30 °C, and the CMC value decreases as the length of the chain increases. The pseudo-phase separation model was used for the calculation of various thermodynamic parameters, such as the Gibbs free energies (spontaneous process), enthalpies (exothermic process), and entropies of the micelles' formation, CMCs, and the degree of counterion binding. All thermodynamic parameters, as functions of the temperature, were estimated. It was found that partition coefficients increase as the length of the alkyl chain and the pH = (5.0-7.0) increase. The influences of surfactants, below and above the CMC, on drug (chlorhexidine dihydrochloride) release from hydrogels, rheological properties, and pH at 30 °C were studied. Also, the amounts of the released drug increase as the alkyl chains of the surfactants prolongate. The amounts of the released drug with the surfactant below the CMC are greater than that above the CMC. All hydrogels (regardless of the length of the alkyl chain) exhibit a non-Newtonian pseudo-plastic flow. The results obtained will be used in the formulation of the drug and surfactants into dosage forms.

Simultaneous formulation of terbinafine and salvia monoterpenes into chitosan hydrogel with testing biological activity of corresponding dialysates against C. albicans yeast.

This work was aimed at a progressive formulation of drugs into chitosan hydrogels. It was taken into consideration that a therapeutic effect of the drugs could be enhanced by a combination of natural compounds with chemical (synthetic) drugs. In this work, sage essential oil (SEO) bicyclic monoterpenes with antiflogistic, antiseptic, and antimycotic properties were combined with terbinafine (TB) having a strong antimycotic activity. Detail optimization of the hydrogel-drugs composition (SEO monoterpenes, TB, chitosan, and polysorbate 80 concentrations), based on permeation experiment and UV absorption/GC-MS analysis of permeated species (eucalyptol, camphor, borneol, thujone, TB) in dialysates, was made. Concerning the active drugs formulation, an optimum concentration of TB was set at the level providing maximum release of the SEO monoterpenes. In vitro activity of the dialysates from the optimized hydrogel was tested against Candida albicans showing that a minimum inhibition concentration was significantly exceeded. The experimental results revealed that the chitosan hydrogel was suitable for the simultaneous formulation of the natural drugs (SEO) with chemical drug (TB) resulting in the preparation with acceptable stability, required gel properties, and significant biological activity. Such preparation should be effective in an antimycotic dermal use.

Formulation of sage essential oil (Salvia officinalis, L.) monoterpenes into chitosan hydrogels and permeation study with GC-MS analysis.

This study deals with the formulation of natural drugs into hydrogels. For the first time, compounds from the sage essential oil were formulated into chitosan hydrogels. A sample preparation procedure for hydrophobic volatile analytes present in a hydrophilic water matrix along with an analytical method based on the gas chromatography coupled with the mass spectrometry (GC-MS) was developed and applied for the evaluation of the identity and quantity of essential oil components in the hydrogels and saline samples. The experimental results revealed that the chitosan hydrogels are suitable for the formulation of sage essential oil. The monoterpene release can be effectively controlled by both chitosan and caffeine concentration in the hydrogels. Permeation experiment, based on a hydrogel with the optimized composition [3.5% (w/w) sage essential oil, 2.0% (w/w) caffeine, 2.5% (w/w) chitosan and 0.1% (w/w) Tween-80] in donor compartment, saline solution in acceptor compartment, and semi-permeable cellophane membrane, demonstrated the useful permeation selectivity. Here, (according to lipophilicity) an enhanced permeation of the bicyclic monoterpenes with antiflogistic and antiseptic properties (eucalyptol, camphor and borneol) and, at the same time, suppressed permeation of toxic thujone (not exceeding its permitted applicable concentration) was observed. These properties highlight the pharmaceutical importance of the developed chitosan hydrogel formulating sage essential oil in the dermal applications.

[Formulation of benzethonium chloride into gels]. / Formulácia benzetóniumchloridu do gélov.

This study is focused on the preparation of gels with antimicrobial effects. A quaternary ammonium salt, benzethonium chloride, in a concentration of 0.01-0.5% (w/w) was employed as the drug. The humectant employed was propylene glycol in concentrations of 5% and 10% (w/w). Two types of polymers, chitosan and hydroxyethyl cellulose, in the same concentrations of 2.5% (w/w), were used for gel preparation. Finally the flow properties, rheological parameters and pH values of the gels were evaluated. Based on the obtained results, the samples of the gels prepared on the basis of chitosan and hydroxyethyl cellulose, which have the following optimum composition shown below, were found: 2,5% (w/w) CHIT + 0,5% (w/w) BZCl + 10% (w/w) PG; 2,5% (w/w) HEC + 0,5% (w/w) BZCl + 5% (w/w) PG.

[Influence of excipients on caffeine permeation from gels]. / Vplyv pomocných látok na permeáciu kofeínu z gélov.

UNLABELLED: The subject of this paper is a study of the influence of excipients on caffeine permeation from dermal semisolids drugs. Due to its advantageous properties, caffeine can be successfully used in dermal hydrogels. The choice of excipients from the group of humectants and cationic surfactants also plays an important role. The excipients should ensure long-term stability of hydrogels and the best permeation of the drug from gels. In particular, the influence of various excipients on caffeine permeation from gels and at the same time their influence on rheological properties of hydrogels were investigated. Based on the obtained results, the following optimal composition of caffeine gel was determined: 2.5 % chitosan + 0.1 % caffeine + 10 % propylenglycol + 0.1 % benzyldimethylhexadecylammonium chloride. KEYWORDS: caffeine hydrogels permeation rheological parameters.

[Influence of temperature and concentration of a surfactant on pharmaceutical availability]. / Vplyv teploty a koncentrácie tenzidu na farmaceutickú dostupnost lieciva.

This study aimed to analyze the influence of surfactant concentration and temperature on drug liberation from hydrogels and their flow properties. The surfactant benzethonium chloride (BZCl) was used in concentrations of 0.01, 0.1 and 0.5 % (w/w), while the drug chlorhexidine dihydrochloride (CHX) was used in a concentration of 0.1 % (w/w). Chitosan (CHIT) in 2.5 % (w/w) concentration was used as a gel-creating substance. The drug and surfactant liberation were evaluated within the temperature range of 25-40 °C. The largest amounts of both of them were liberated at the temperature of 40 °C. Through the concentration changes it was possible to obtain statistically significant differences (P < 0.05) between the liberation of CHX and BZCl. An analysis of the flow properties revealed that the character of the plastic system was not influenced by the changing concentration of the surfactant. The experimental results led to the conclusion that the optimum composition of the gel was as follows: 2.5 % (w/w) CHIT + 0.1 % (w/w) CHX + 0.01 % (w/w) BZCl.

[Evaluation of liberation of caffeine from dermal semisolids drugs]. / Hodnotenie liberácie kofeínu z dermálnych polotuhých liekov.

The paper deals with formulation of caffeine into dermal semisolid dosage forms - hydrogels. Caffeine was chosen as a model drug because its properties can be successfully used just in hydrogels. Protective and tranquilization effects can be used in the preparations for sunbathing, and its lipolytic and regenerative effect can be used for the treatment of androgenic alopecia or cellular bioprotection. The aim of the study was to investigate the influence of different concentrations of chitosan and caffeine on the liberation of gels. Besides, stability of the prepared samples was evaluated by means of the evaluation of their rheological parameters. Based on the obtained results, there was determined the optimal drug concentration - caffeine 0.2% (w/w) and also the gel forming substance - chitosan 2.3% (w/w).

[Influence of quaternary ammonium salt on liberation of drug with antiseptic effect]. / Vplyv kvartérnej amóniovej soli na liberáciu lieciva s antiseptickým úcinkom.

The paper evaluates the influence of three surfactants (carbetopendecinium halogenides) on the liberation of the drug chlorhexidine dihydrochloride (CHX) in 0.1% (w/w) from the dosage form-gel and also the flow properties of gels. The following tensides were evaluated: carbetopendecinium bromide (SB), carbetopendecinium chloride (SC), and carbetopendecinium iodide (SI). The tenside concentration was set under the critical micelle concentration. The biopolymer - chitosan (CHIT) in 2.5% (w/w) concentration was used as a gel creating substance. Based on the flow properties of the studied gels, it was found that the employed tensides exhibited no influence on the character of the system. The gels exhibited the character of plastic systems with time-independent flow. The drug liberation was evaluated at the temperatures of 20, 30 and 40 °C. Between the types of the tensides, the statistically significant differences (P < 0.05) were found as to the amount of the liberated CHX, which was reflected by the increased amount of the liberated drug. Based on the obtained results, it can be concluded that the most suitable was the SI tenside. From the gel with this tenside the greatest amount of CHX was liberated, which had the highest value of the liberation rate constant.

[Formulation of salvia-containing gels]. / Formulácia gélov s obsahom salvie lekárskej.

The trend during the past years is to prefer natural drugs to synthetically prepared medicines. Due to its important antiphlogistic, antiseptic and antihidrotic effects, Salvia officinalis L. has a wide use in medicine, pharmacy and cosmetics in various dosage forms. The aim of this research was the formulation of Salvia officinalis L. in the form of a tincture to hydrogels. Gels were parallelly prepared on the basis of the natural polymer chitosan and the synthetic polymer Carbopol 940. The evaluation was focused on the influence of the anionic polymer and the cationic polymer in different concentrations on hydrogel flow properties. Glycerol functioning as a humectant was used in various percentage ratios. On the basis of the determination of rheological parameters and flow curves lapses the most suitable hydrogel from the application point of view was selected.

Study of local anaesthetics--Part 196 formulation of the local anaesthetic heptacaine into hydrogel on the basis of chitosan.

The study aimed to formulate the local anaesthetic heptacaine into hydrogels on the basis of chitosan. The gel-creating compounds used included natural polymers --three different types of chitosan, namely those of a medium molecular weight, from the shells of shrimp, and from the bumblebees species Bombus terrestris. The prepared hydrogels were evaluated on the basis of their rheological properties and drug liberation. From the point of drug liberation and flow properties, the optimal gel composition was as follows: 0.1% heptacaine + 2% chitosan (medium molecular weight) + 0.2% carbaethopendecinium bromide.

[Study of local anaesthetics - part 200 choice of the optimal type of chitosan for the formulation of local anaesthetics of the carbamate type into hydrogels]. / Stúdium lokálnych anestetík - cast 200* Výber optimálneho typu chitosanu pre formuláciu lokálnych anestetík karbamátového typu do hydrogélov.

The aim of this examination was a study of hydrogels on the base of various types of the natural polymer chitosan with an assay of local anaesthetics of the carbamate type. The concentration of the gel-creating compound in hydrogels was 2.5%. The study included heptacainiumchloride (HEP), pentacainiumchloride (PEN) and carbisocainiumchloride (CAR). Evaluation was focused on the flow properties of prepared gels and the liberation of drugs from them. Based on the achieved results, the optimal type of biopolymer was determined: PEN - CHIT B, for CAR - CHIT C, while in the case of HEP it was found that chitosan is not suitable as a gel-creating base.

[Influence of membranes on alaptide permeation from hydrogels]. / Vplyv membrán na permeáciu alaptidu z hydrogélov.

The paper evaluates the liberation of alaptide from gels through various types of permeable membranes. The gels were prepared on the basis of three different polymers (3% chitosan; 2.5% hydroxypropyl cellulose; 3% hydroxyethyl cellulose) in different concentrations with additions of humectants (5 %; 15% propylene glycol and 10% glycerol) and the preserving agent, 0.3% Sepicide HBR with 1% alaptide, and finally without the drug. The permeation of the drug from gels into the acceptor solution was evaluated with the use of the following membranes: the hydrophilic membrane from Chemosvit, the chicken skin, the stripped snakeskin, and the wall of the small intestine. The measurements showed that the highest percentage of the drug penetrated through the small intestine, a smaller percentage through the chicken skin, and the smallest amount through the snakeskin. Rheological properties of the prepared hydrogels were evaluated as well. The pseudoplastic flow was only confirmed for the hydrogel prepared on the basis of hydroxypropyl cellulose. An utterly opposite situation was with the hydrogels prepared on the basis of chitosan and hydroxyethyl cellulose. They showed a significant thixotropic character and the degree of thixotropy increased with time. Based on the results of the pH measurement, the samples prepared on the basis of chitosan and hydroxypropyl cellulose have been shown to be inconvenient because they reached a lower pH and had a potential of causing skin irritation. The hydroxyethyl cellulose hydrogel matched the physiological values of skin pH even after 14 days since its preparation.

[Study of local anaesthetics--Part 194. Evaluation of carbopol hydrogels with lidocaine]. / Stúdium lokálnych anestetík--6ast' 194. Hodnotenie karbopolových hydrogélov s lidokaínom.

The objective of this article is to describe the formulation and evaluation of dermal semisolid drugs--carbopol hydrogels containing the solution of Bukofit, zinc chloride and the local anaesthetic lidocaine. The hydrogels were evaluated after 2, 7, 14 and 28 days after their preparation and stored at the temperature of 5 degrees C +/- 0.2 degrees C. All prepared hydrogels were found to be stable with respect to pH values and rheological parameters. It follows from the found rheological parameters and flow curves that all evaluated hydrogels belong to non-Newtonian thixotropic systems. The extensometric analyses revealed increased deformation values, indicating that the gels can be easily spread out over the mucous membrane which results in the increased ability of the drug to diffuse into it. Based on the results obtained, it can be concluded that the prepared hydrogels have appropriate technological parameters and therefore in the future they may become potential drugs for the treatment of various inflammations in the oral cavity.

Alternative and generalized approach to in vitro-in vivo correlation.

Evaluation of in vitro-in vivo correlation (IVIVC) plays important role in securing therapeutic effect if a dosage form undergoes technological modifications. Similarity (closeness) of dissolution profiles of the original and modified dosage forms has been traditionally considered to be sufficient for similar in vivo responses. This may be true if the IVIVC model (dependence between the dissolution and corresponding absorption profiles) is given by a linear straight line with the unit slope. The paper presents an alternative and generalized approach to IVIVC evaluation. Influences of pre-systemic processes (disintegration, dissolution, absorption) on the system response (concentration time profile C(t), bioavailability BD and other) are analyzed and evaluated. Both the magnitude and sign of IVIVC are then derived from the magnitudes and signs of these influences. The underlining idea is that pre-systemic processes do not correlate with the system response, (e.g., plasmatic concentration) if small modifications of the former do not induce significant changes of the later. If this is so, the therapeutic effects of the modified and original dosage forms may be considered equal or at least similar. In this way the problem of IVIVC is not only exactly mathematically founded but modifications of pre-systemic processes are directly projected to the system output-- the time profile of plasmatic concentration. Moreover, the approach is applicable to virtually any dosage form. Its feasibility was validated in vivo.

Evaluation of aqueous preparations from herbal drugs.

The paper presents results obtained within analysis of aqueous preparations obtained from the herbal drugs, (APHD) which are available in pharmacy as mass produced drugs. In particular, the following drugs were analyzed: CYNAROFIT, L'ALIAFIT, Tinctura belladonnae, Tinctura gentianae, Tinctura chinae a Tinctura valerianae made by Calendula, j.s.c.--Slovakia and Tinctura valerianae made by IVAX-Czech republic. Tictura valerianae magistraliter was prepared in a laboratory. The APHDs were analyzed under the following aspects: amount of dry matter, density, index of refraction, pH value, content of ethanol, influence of the light on these parameters as well as the global appearance of samples. In parallel to that, the stability of samples Tinctura valerianae prepared by two different manufacturers and the samples of magistraliter preparations were compared. It was found that storing samples delivered by Calendula j.s.c. does not significantly influenced their stability neither in the light nor in the dark, kept at the temperature of 20-25 degrees C over the time interval of 6 months. All samples were in agreement with the norms of companies as well as with both Czechoslovak (CSL 4) and Slovak (SL 1) pharmacopoeias. Besides, the results obtained show that a kind of extraction methods (percolation, maceration) does not influence neither quality nor stability of the samples Tinctura valerianae.