Effects of Sucrose Palmitate on the Physico-Chemical and Mucoadhesive Properties of Buccal Films.

In our current research, sucrose palmitate (SP) was applied as a possible permeation enhancer for buccal use. This route of administration is a novelty as there is no literature on the use of SP in buccal mucoadhesive films. Films containing SP were prepared at different temperatures, with different concentrations of SP and different lengths of hydroxypropyl methylcellulose (HPMC) chains. The mechanical, structural, and in vitro mucoadhesive properties of films containing SP were investigated. Tensile strength and mucoadhesive force were measured with a device and software developed in our Institute. Positron annihilation lifetime spectroscopy (PALS) and X-ray powder diffractometry (XRPD) were applied for the structure analysis of the films. Mucoadhesive work was calculated in two ways: from the measured contact angle and compared with direct mucoadhesive work, which measured mucoadhesive force, which is direct mucoadhesion work. These results correlate linearly with a correlation coefficient of 0.98. It is also novel because it is a new method for the determination of mucoadhesive work.

Preparation and physicochemical characterization of matrix pellets containing APIs with different solubility via extrusion process.

In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points of the process were investigated by means of factorial design. Beside the generally used microcrystalline cellulose, ethylcellulose was used as matrix former to achieve modified drug release ensured by diffusion. The matrix pellets were made by extrusion-spheronization using a twin-screw extruder. Some pellet properties (aspect ratio, 10% interval fraction, hardness, deformation process) were determined. The aim of our study was to investigate how the two different APIs with different solubility and particle size influence the process. The amount of the granulation liquid plays a key role in the pellet shaping. A higher liquid feed rate is preferred in the pelletization process.

Matrix tablets based on a carrageenan with the modified-release of sodium riboflavin 5'-phosphate.

The focus of this work was to produce modified-release monolithic matrix tablets containing sodium riboflavin 5'-phosphate (vitamin B2) as active pharmaceutical ingredient (API). Riboflavin 5'-phosphate is absorbed from the upper gastrointestinal tract by a specific transport mechanism. The aim of this work was the development of modified-release tablets from which most or the entire API can dissolve within 5 h. The dissolution was started in medium pH 1.2 (gastric juice) and finished in medium pH 4.5. The matrix former was iota-carrageenan combined with microcrystalline cellulose (MCC) and lactose in different ratios. Factorial design was used in this work so as to study the effects of the MCC/lactose ratio on the parameters of the tablets, and especially on the dissolution process. The dissolution data were subjected to statistical analysis, and the release profiles were fitted with different models. It was found that the MCC/lactose ratio influenced the quality of the tablets to a high degree. The Korsmeyer-Peppas model proved to characterize the total dissolution profile best, but fitting of the separate sections was also possible with a linear model.

Modified-release capsules containing sodium riboflavin 5'-phosphate.

INTRODUCTION: The focus of this work was to produce delayed-release capsules containing riboflavin (vitamin B2, as API) layered pellets. Riboflavin therapy is indicated in patients with a riboflavin deficiency, which usually occurs in conjunction with malabsorption, alcoholism or a protein-calorie deficiency and rarely as the sole vitamin deficiency. Riboflavin is readily absorbed from the upper gastrointestinal tract by a specific transport mechanism. The dissolution rate of coated capsules was controlled through the coating of the capsules and the thickness of the coating layer. METHODS: The core pellets (Cellet 300) were loaded with a 10% aqueous solution of sodium riboflavin 5'-phosphate by a layering technique in a coating pan. Hard capsules were filled with riboflavin layered pellets and coated with Eudragit NE polymer with different coating layer thicknesses. The dissolution was tested in gastric and intestinal fluids with the half-change method. The dissolution profiles were analyzed with the use of different mathematical models and an attempt was made to predict the optimum coating film thickness that ensures the required degree and rate of dissolution. RESULTS: A new solid dosage form was developed which can enhance the bioavailability of riboflavin. RRSBW distribution and the Chapman-Richards growth function were used to fit the dissolution profiles. Statistical analysis indicated that the best products were described by the Chapman-Richards equation. The results were utilized to create a theoretical model suitable for prediction of the optimum film thickness that ensures the required release of riboflavin.

Development of a Raman method to follow the evolution of coating thickness of pellets.

CONTEXT: Although several methods have been investigated to measure the film thickness of tablets and its correlation with the dissolution behavior, much fewer such investigations exist for pharmaceutical pellets. OBJECTIVE: To study the possibility of measuring the film thickness and predicting the dissolution behavior of pellets produced in different fluid bed equipments with Raman spectroscopy. MATERIALS AND METHODS: Pyridoxine hydrochloride-layered pellets were produced and coated in two different Strea-1 equipments. Raman spectra were collected and analysed to set up a calibration model based on the film thickness data calculated from Camsizer analysis results. Dissolution tests were done according to Ph. Eur. standards. RESULTS: Raman spectroscopy proved to be a good tool in the measurement of film thickness. Polymer weight gain showed a linear correlation with film thickness but was a poor predictor of dissolution results below a threshold value. CONCLUSION: The Raman spectroscopic measurement of a small sample can provide accurate data of the film thickness. The investigation suggests that a threshold value might exist for the film thickness above which it can be used to judge future dissolution results.

Preparing of pellets by extrusion/spheronization using different types of equipment and process conditions.

INTRODUCTION: The focus of this work was to produce matrix pellets made by extrusion/ spheronization using two types of equipment. The aim was to accomplish the laboratory-scale I process that has been already optimized and accepted with another type of equipment (laboratory-scale II). METHODS: A matrix pellet formulation consisting of MCC, Eudragit NE 30D and diclofenac sodium was used in the two types of equipment. Physico-chemical parameters and the dissolution profiles of the pellets in phosphate buffer pH 6.8 were compared. RESULTS: Pellets from both processes were similar in shape and tensile strength. They differed in particle size and dissolution profile. This may be contributed to different spheronization conditions.

Investigation of the cytotoxic effects of titanate nanotubes on Caco-2 cells.

Titanate nanotubes can be used as drug delivery systems, but limited information is available on their interactions with intestinal cells. In this study, we investigated the cytotoxicity and cellular uptake of titanate nanotubes on Caco-2 monolayers and found that up to 5 mg/ml concentration, these nanotubes are not cytotoxic and not able to permeate through the intestinal cell layer. Transmission electron microscopic experiments showed that titanate nanotubes are not taken up by cells, only caused a high-density granulation on the surface of the endoplasmic reticulum. According to these results, titanate nanotubes are suitable systems for intestinal drug delivery.

[Influence of physico-chemical properties of materials on the postcompressional parameters of tablets]. / Az anyagok fizikai-kémiai tulajdonságainak befolyása a tabletták posztkompressziós paramétereire.

The number of tablets marketed with a score line to aid divisibility is increasing. The subdivision of scored tablets in order to ensure dose flexibility may be an easier and cheaper solution from the aspect of production. However, to ensure the appropriate mechanical properties and divisibility of tablets so as to guarantee consequent dosing is a difficult problem, which is influenced by many properties of the applied materials, such as the physicochemical behaviour, the plasticity, the degree of elasticity, the mechanism of compression, etc. These exert a significant influence on the postcompressional properties of tablets, and hence on the subdivision of tablets. Despite the considerable difficulties, the increasing importance in paediatrics and the ever stricter requirements of the drug authorities, the subdivision of scored tablets is a poorly studied field. This paper deals with the influence of physico-chemical properties of materials on the postcompressional parameters of tablets, and especially on the subdivision of tablets. For measurement of the force required to break tablets into halves, a laboratory-constructed hardness tester was utilized.

[Application of biosensors from the point of drug research]. / Bioszenzorok alkalmazhatósága a gyógyszerkutatás szemszögébol.

With the increasing number of protein active agents produced by the biotechnological route, the suitable analytical methods will also be important. The detection of small changes of protein and the monitoring of the processes of the biotechnological procedure are important. Biosensors can be applied for the detection of very low concentrations with nearly 100% selectivity. The aims of our work are to give basic information about biosensors, about their grouping and potential field of application.

Effects of pharmaceutical processing on pepsin activity during the formulation of solid dosage forms.

The main aim of this study was to investigate the effects of pharmaceutical technological methods on pepsin activity during the formulation of solid dosage forms. The circumstances of direct compression and wet granulation were modeled. During direct compression, the heat and the compression force must be taken into consideration. The effects of these parameters were investigated in three materials (pure pepsin, and 1:1 (w/w) pepsin-tartaric acid and 1:1 (w/w) pepsin-citric acid powder mixtures). It was concluded that direct compression is appropriate for the formulation of solid dosage forms containing pepsin through application without acids or with acids at low compression force. The effects of wet granulation were investigated with a factorial design for the same three materials. The factors were time, temperature and moisture content. There was no significant effect of the factors when acids were not applied. Temperature was a significant factor when acids were applied. The negative effect was significantly higher for citric acid than for tartaric acid. It was found that wet granulation can be utilized for the processing of pepsin into solid dosage forms under well-controlled circumstances. The application of citric acid is not recommended during the formulation of solid dosage forms through wet granulation. A mathematically based optimization may be necessary for preformulation studies of the preparation of dosage forms containing sensitive enzymes.

Application of physicochemical properties and process parameters in the development of a neural network model for prediction of tablet characteristics.

The importance of in silico modeling in the pharmaceutical industry is continuously increasing. The aim of the present study was the development of a neural network model for prediction of the postcompressional properties of scored tablets based on the application of existing data sets from our previous studies. Some important process parameters and physicochemical characteristics of the powder mixtures were used as training factors to achieve the best applicability in a wide range of possible compositions. The results demonstrated that, after some pre-processing of the factors, an appropriate prediction performance could be achieved. However, because of the poor extrapolation capacity, broadening of the training data range appears necessary.

Study of the influence of alkalizing components on matrix pellets prepared by extrusion/spheronization.

The aim of this study was to investigate the effects of alkalizing components and the nature of the wetting liquid on the properties of matrix pellets prepared by extrusion and spheronization. Atenolol was used as an active pharmaceutical ingredient, ethylcellulose as a matrix former, microcrystalline cellulose as a filler and disodium phosphate anhydrous and trisodium phosphate dodecahydrate as alkalizing materials. Water and a water-ethanol mixture served as granulation liquids. Pellet formation was evaluated via mechanical, dissolution and morphological studies. In order to enhance the dissolution of Atenolol from the pellets, alkalizing components were used and the influence of these components on the pH was tested. Investigations of the breaking hardness, the morphology and the dissolution revealed that the pellets containing trisodium phosphate dodecahydrate and prepared with a higher amount of water as binding liquid displayed the best physico-chemical parameters and uniform dissolution. In in vitro experiments, the dissolution release complied with the texture of the pellets and the effect of pH. The pellets have suitable shape and very good hardness for the coating process and are appropriate for subsequent in vivo experiments.

Effects of processing on the release profiles of matrix systems containing 5-aminosalicylic acid.

The aim of this study was to investigate the influence of different processing methods on the profiles of 5-aminosalicylic acid dissolution from controlled-release matrix systems based on Eudragit® RL and Eudragit® RS water-insoluble polymers. The pure polymers and their mixtures were studied as matrix formers using different processing methods, i.e., direct compression, wet granulation of the active ingredient with the addition of polymer(s) to the external phase, wet granulation with water, and wet granulation with aqueous dispersions. In comparison with the directly compressed tablets, tablets made by wet granulation with water demonstrated a 6-19% increase in final drug dissolution, whereas when polymers were applied in the external phase during compression, a 0-13% decrease was observed in the amount of drug released. Wet granulation with aqueous polymer dispersions delayed the release of the drug; this was especially marked (a 54-56% decrease in drug release) in compositions, which contained a high amount of Eudragit RL 30D. The release profiles were mostly described by the Korsmeyer-Peppas model or the Hopfenberg model.

Predicting Drug Release Rate of Implantable Matrices and Better Understanding of the Underlying Mechanisms through Experimental Design and Artificial Neural Network-Based Modelling.

There is a growing interest in implantable drug delivery systems (DDS) in pharmaceutical science. The aim of the present study is to investigate whether it is possible to customize drug release from implantable DDSs through drug-carrier interactions. Therefore, a series of chemically similar active ingredients (APIs) was mixed with different matrix-forming materials and was then compressed directly. Compression and dissolution interactions were examined by FT-IR spectroscopy. Regarding the effect of the interactions on drug release kinetics, a custom-made dissolution device designed for implantable systems was used. The data obtained were used to construct models based on artificial neural networks (ANNs) to predict drug dissolution. FT-IR studies confirmed the presence of H-bond-based solid-state interactions that intensified during dissolution. These results confirmed our hypothesis that interactions could significantly affect both the release rate and the amount of the released drug. The efficiencies of the kinetic parameter-based and point-to-point ANN models were also compared, where the results showed that the point-to-point models better handled predictive inaccuracies and provided better overall predictive efficiency.

Investigation of Surface Properties and Free Volumes of Chitosan-Based Buccal Mucoadhesive Drug Delivery Films Containing Ascorbic Acid.

Nowadays, the buccal administration of mucoadhesive films is very promising. Our aim was to prepare ascorbic acid-containing chitosan films to study the properties and structures important for applicability and optimize the composition. During the formulation of mucoadhesive films, chitosan as the polymer basis of the film was used. Ascorbic acid, which provided the acidic pH, was used in different concentrations (2-5%). The films were formulated by the solvent casting method. The properties of films important for applicability were investigated, such as physical parameters, mucoadhesive force, surface free energy, and breaking strength. The fine structure of the films was analyzed by atomic force microscopy, and the free volume was analyzed by PALS, which can be important for drug release kinetics and the location of the drug in the film. The applicability of the optimized composition was also tested with two different types of active ingredients. The structure of the films was also analyzed by XRPD and FTIR. Ascorbic acid can be used well in chitosan films, where it can function as a permeation enhancer when reacting to chitosan, it is biodegradable, and can be applied in 2% of our studies.

Effect of lubricant on spreading of coating liquid on surface of tablets containing pancreatin.

The objective of this study was to evaluate the spreading of the coating liquid on different tablets containing pancreatin and microcrystalline cellulose. The effects of the ratio of the components, the presence of magnesium stearate and the blending circumstances were investigated. The contact angle of the liquids on the different tablets did not change linearly. For the mixture containing 50% pancreatin, the deviation of the measured value from the predicted one was more than 25%. This deterioration was also detected for mixtures containing 1% lubricant, but the extent was lower and was not modified by change of the mixing circumstances. This phenomenon was explained by the special microstructure of the surface of the tablet. This was predicted from the spreading coefficient, calculated from the surface free energy. The enrichment of pancreatin on the surface was preferred in binary mixtures. The spreading of magnesium stearate was most preferred for the powder mixture, and thus prediction of the properties of the tablet was easier for these mixtures. The extent of the effect of this excipient on the surface properties was very wide-ranging. The change in the spreading of the coating liquid was significant; however, the change in the work of friction was negligible.

The compressibility and compactibility of different types of lactose.

OBJECTIVE: The purpose of this study was to investigate and quantify flow properties, compressibility, and compactibility of various pharmaceutical lactose powders found on the market today (DCL-11, DCL-21, M-200, Flowlac-100, and Tablettose 70, 80, and 100). METHODS: Flow properties were estimated by measuring flow time, angle of repose, and the Hausner ratio. Particle rearrangement was studied using Kawakita's linear model. Compressibility was studied using two 'out-of-die' methods: (i) the Heckel model and (ii) a modified Walker model. Compactibility was quantified using two methods: (i) the tensile strength profile (Cp) and (ii) the compactibility factor (Pr). Statistical approach was used to analyze the results. RESULTS: Flow properties of all materials were passable or better, except for M-200, which has very poor flowability. Compressibility results demonstrated that the most compressible lactose is spray-dried grade of lactose (Flowlac-100) and the least compressible is milled lactose (M-200). Compactibility studies showed that beta-lactose (DCL-21) forms tablets with superior tensile strength in comparison with alpha-lactose. CONCLUSION: Results of the compressibility study showed that the discriminative power of modified Walker model is greater in comparison with Heckel model. Compactibility methods yield similar and comparable results.

Formulation of intelligent tablets with an antacid effect.

Matrix systems with a local antacid effect were produced in this study. Aluminium hydroxide and magnesium trisilicate in constant concentrations were used as active agents. Eudragit E PO was applied as a matrix former and sodium bicarbonate as a disintegrant (third antacid component), in different ratios. Their effects on the properties of the tablets were studied. Such formulated systems must be insoluble if the pH of the stomach is less acidic, but a rapid disintegration must occur if necessary. It can be concluded that Eudragit E PO in appropriate composition can ensure tablets with pH-dependent disintegration. Its binding effect allows tablet making from the elastic active component. The liberation of antacid materials from this system is controlled. If the pH reached 2.5, the erosion of the tablet was reduced. In contrast with expectations, the application of poorly compressible and effervescent sodium bicarbonate increased the time for disintegration of the tablets, because of its extended alkalizing effect around the tablet. This system with this acrylic component is appropriate to produce a controlled-release local antacid preparation.

[Evaluation of phenomena detected on the surface of stirred coating liquid]. / Felületen lejátszódó jelenségek szerepének vizsgálata a bevonó folyadékok eloállítása során.

The main objective of this work was to study the effect of conditions of coating fluids through the properties of the coating fluid, film and coated product. With a more accurate understanding of the process the effects of the factors can be defined and by means of this the optimal composition can be determined and problem-free coating can be carried out. In this work the evaporation was studied. The effects of different operational factors on evaporation were studied through fluids of different compositions. In case of fluids containing ethanol a significant loss can be detected after a short period of time and this fact cannot be changed by the use of an antifoaming agent. The highest difference in effect of a given factor was detected for the stirring rate. The effect of the operational factors changed depending on the Composition. Stirring rate showed the highest sensitivity to the presence of the volatile component. These results can help to determine the critical control points and the optimal stirring circumstances.

Standpoint on the priority of TNTs and CNTs as targeted drug delivery systems.

Conventional drug delivery systems have limitations according to their toxicity and poor solubility, bioavailability, stability, and pharmacokinetics (PK). Here, we highlight the importance of functionalized titanate nanotubes (TNTs) as targeted drug delivery systems. We discuss the differences in the physicochemical properties of TNTs and carbon nanotubes (CNTs) and focus on the use of functionalization to improve their characteristics. TNTs are promising materials for drug delivery systems because of their superb properties compared with CNTs, such as their processability, wettability, and biocompatibility. Functionalization improves nanoparticles (NPs) via their surface modification and enables them to achieve the targeted therapy.