Exogenic production of bioactive filamentous biopolymer by monogonant rotifers.

The chemical ecology of rotifers has been little studied. A yet unknown property is presented within some monogonant rotifers, namely the ability to produce an exogenic filamentous biopolymer, named 'Rotimer'. This rotifer-specific viscoelastic fiber was observed in six different freshwater monogonants (Euchlanis dilatata, Lecane bulla, Lepadella patella, Itura aurita, Colurella adriatica and Trichocerca iernis) in exception of four species. Induction of Rotimer secretion can only be achieved by mechanically irritating rotifer ciliate with administering different types (yeast cell skeleton, denatured BSA, epoxy, Carmine or urea crystals and micro-cellulose) and sizes (approx. from 2.5 to 50 µm diameter) of inert particles, as inductors or visualization by adhering particles. The thickness of this Rotimer is 33 ± 3 nm, detected by scanning electron microscope. This material has two structural formations (fiber or gluelike) in nano dimension. The existence of the novel adherent natural product becomes visible by forming a 'Rotimer-Inductor Conglomerate' (RIC) web structure within a few minutes. The RIC-producing capacity of animals, depends on viability, is significantly modified according to physiological- (depletion), drug- (toxin or stimulator) and environmental (temperature, salt content and pH) effects. The E. dilatata-produced RIC is affected by protein disruptors but is resistant to several chemical influences and its Rotimer component has an overwhelming cell (algae, yeast and human neuroblastoma) motility inhibitory effect, associated with low toxicity. This biopolymer-secretion-capacity is protective of rotifers against human-type beta-amyloid aggregates.

Synthesis and Statistical Optimization of Poly (Lactic-Co-Glycolic Acid) Nanoparticles Encapsulating GLP1 Analog Designed for Oral Delivery.

PURPOSE: To design and stabilize Liraglutide loaded poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) proper for oral administration. METHODS: PLGA NPs were prepared by means of double emulsion solvent evaporation method and optimized by applying 7-factor 2-level Plackett-Burman screening design. RESULTS: Spherical shaped NPs with homogeneous distribution, 188.95 nm particle size and 51.81% encapsulation efficiency were obtained. Liraglutide was successfully entrapped in the NPs while maintaining its native amorphous nature, and its structural integrity as well. CONCLUSION: Lira-PLGA NPs with the required Critical Quality Attributes (CQAs) were successfully designed by implementing a 7-factor 8-run Plackett Burman design into the extended Quality by Design (QbD) model, to elucidate the effect of formulation and process variables on the particle size, size-distribution, encapsulation efficiency and surface charge. As the developed nanoparticles maintained the native structure of the active pharmaceutical ingredient (API), they are promising compositions for the further development for the oral delivery of Lira. Graphical Abstract.

High-shear granulation of high-molecular weight hypromellose: effects of scale-up and process parameters on flow and compaction properties.

CONTEXT: Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation. OBJECTIVE: The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer. METHODS: The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the 'out-of-die' Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High-shear granulation was performed at different scales: 4 L, 300 L, and 600 L. RESULTS AND CONCLUSION: The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction.

Development and Characterisation of Modified Release Hard Gelatin Capsules, Based on In Situ Lipid Matrix Formation.

A new technology was developed to form extended release hard gelatin capsules, based on the lipid matrix formation of Gelucire 50/13 and cetostearyl alcohol. Matrices were formed in situ by filling pulverised lipids, ethylcellulose and active ingredients such as diclofenac sodium, acetaminophen and metronidazol into capsules and heating at 63°C for 11 min. Effects of heating were investigated also on the brittleness of capsule shells. Inhibition of the evaporation of water reduced capsule damage. Dissolution tests and texture analysis were performed to discover the release and mechanical profiles of the matrices. Tests were repeated after 1 month storage and results were compared. Gelucire 50/13 alone prolonged drug release but cetostearyl alcohol slowed drug liberation even further. Drug release from all compositions was found to follow first-order kinetic. Significant softening of the matrices was detected during storage in composition containing only Gelucire 50/13, ethylcellulose and diclofenac sodium. Thermal analysis and IR tests were also performed to discover physicochemical interactions between active pharmaceutical ingredients and excipients. Thermal analysis confirmed a notable interaction between diclofenac sodium and Gelucire 50/13 which could be the cause of the observed softening. In conclusion, modified release hard gelatin capsules were developed by a simple and fast monolithic lipid matrix formation method.

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.

[Titanate nanotubes in the therapy]. / Titanát nanocsövek a gyógyászatban.

The demand for revealing the medical advantages offered by nanotechnology is increasing more and more. Titanate nanotubes deserve consideration in many aspects. Their production is easy, cost-effective and environmentally friendly. Due to their special physico-chemical properties, titanate nanotubes can play an important role in different fields of therapy, such as medical diagnostics, implantology, or even as cancer treatment. The aim of our work is to present the titanate nanotubes and give an overview on their medical applicability through the results of previous researches.

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.

[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.

Aspects and Implementation of Pharmaceutical Quality by Design.

The introduction of the Quality by Design concept in 2004 has brought a paradigm shift in the pharmaceutical industry as well as a new era in pharmaceutical research and development [...].

An Overview of Hydrothermally Synthesized Titanate Nanotubes: The Factors Affecting Preparation and Their Promising Pharmaceutical Applications.

Recently, titanate nanotubes (TNTs) have been receiving more attention and becoming an attractive candidate for use in several disciplines. With their promising results and outstanding performance, they bring added value to any field using them, such as green chemistry, engineering, and medicine. Their good biocompatibility, high resistance, and special physicochemical properties also provide a wide spectrum of advantages that could be of crucial importance for investment in different platforms, especially medical and pharmaceutical ones. Hydrothermal treatment is one of the most popular methods for TNT preparation because it is a simple, cost-effective, and environmentally friendly water-based procedure. It is also considered as a strong candidate for large-scale production intended for biomedical application because of its high yield and the special properties of the resulting nanotubes, especially their small diameters, which are more appropriate for drug delivery and long circulation. TNTs' properties highly differ according to the preparation conditions, which would later affect their subsequent application field. The aim of this review is to discuss the factors that could possibly affect their synthesis and determine the transformations that could happen according to the variation of factors. To fulfil this aim, relevant scientific databases (Web of Science, Scopus, PubMed, etc.) were searched using the keywords titanate nanotubes, hydrothermal treatment, synthesis, temperature, time, alkaline medium, post treatment, acid washing, calcination, pharmaceutical applications, drug delivery, etc. The articles discussing TNTs preparation by hydrothermal synthesis were selected, and papers discussing other preparation methods were excluded; then, the results were evaluated based on a careful reading of the selected articles. This investigation and comprehensive review of different parameters could be the answer to several problems concerning establishing a producible method of TNTs production, and it might also help to optimize their characteristics and then extend their application limits to further domains that are not yet totally revealed, especially the pharmaceutical industry and drug delivery.

QbD Approach-Based Preparation and Optimization of Hydrophobic Ion-Pairing Complex of Lysozyme with Sodium Dodecyl Sulphate to Enhance Stability in Lipid-Based Carriers.

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods.

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.

Quality by Design-Based Development of Solid Self-Emulsifying Drug Delivery System (SEDDS) as a Potential Carrier for Oral Delivery of Lysozyme.

For many years, researchers have been making efforts to find a manufacturing technique, as well as a drug delivery system, that will allow for oral delivery of biopharmaceuticals to their target site of action without impairing their biological activity. Due to the positive in vivo outcomes of this formulation strategy, self-emulsifying drug delivery systems (SEDDSs) have been intensively studied in the last few years as a way of overcoming the different challenges associated with the oral delivery of macromolecules. The purpose of the present study was to examine the possibility of developing solid SEDDSs as potential carriers for the oral delivery of lysozyme (LYS) using the Quality by Design (QbD) concept. LYS was successfully ion paired with anionic surfactant, sodium dodecyl sulphate (SDS), and this complex was incorporated into a previously developed and optimized liquid SEDDS formulation comprising medium-chain triglycerides, polysorbate 80, and PEG 400. The final formulation of a liquid SEDDS carrying the LYS:SDS complex showed satisfactory in vitro characteristics as well as self-emulsifying properties (droplet size: 13.02 nm, PDI: 0.245, and zeta potential: -4.85 mV). The obtained nanoemulsions were robust to dilution in the different media and highly stable after 7 days, with a minor increase in droplet size (13.84 nm) and constant negative zeta potential (-0.49 mV). An optimized liquid SEDDS loaded with the LYS:SDS complex was further solidified into powders by adsorption onto a chosen solid carrier, followed by direct compression into self-emulsifying tablets. Solid SEDDS formulations also exhibited acceptable in vitro characteristics, while LYS preserved its therapeutic activity in all phases of the development process. On the basis of the results gathered, loading the hydrophobic ion pairs of therapeutic proteins and peptides to solid SEDDS may serve as a potential method for delivering biopharmaceuticals orally.

Quality by Design-Guided Systematic Development and Optimization of Mucoadhesive Buccal Films.

Mucoadhesive buccal films have found increased popularity in pharmaceutical drug delivery due to the several advantages that they possess. The present study strives to develop and optimize chitosan-based mucoadhesive buccal films by relying on quality-by-design (QbD) principles. Previous knowledge and experience were employed to firstly identify the critical quality attributes (CQAs), followed by a thorough risk assessment, which led to the selection of seven critical material attributes and process parameters, namely, the polymer grade and concentration, the plasticizer type and concentration, the citric acid (CA) concentration, the amount of the casted solution, and the drying condition. Their effects on the breaking hardness and mucoadhesivity, selected as CQAs, were investigated in three steps by three designs of the experiment (DoE). The medium molecular weight of chitosan (CH) was the preferred choice in the optimized formulation, and its concentration was the most important factor affecting the CQAs, thickness, and moisture content of the films. It was found that 0.364 g/cm2 was the suitable amount of the casting solution, and its optimum drying conditions were presented in the form of a design space. Glycerol (Gly) was the best choice as a plasticizer, and a design space representing several combinations of CH and CA concentrations that produce films with the required quality was constructed at a fixed concentration of 35% Gly. A formula from this design space was selected and employed to load with two model drugs to test its drug-carrying properties for drugs with different physicochemical characteristics. Uniform drug distribution with an immediate release profile was achieved in both drugs, although one of the CQAs was outside of the specifications in the case of lidocaine-containing film. To summarize, the obtention of the optimum mucoadhesive buccal film based on CH was efficiently facilitated by the rational application of QbD principles and the DoE approach.

Surface Modification of Titanate Nanotubes with a Carboxylic Arm for Further Functionalization Intended to Pharmaceutical Applications.

Nanotechnology is playing a significant role in modern life with tremendous potential and promising results in almost every domain, especially the pharmaceutical one. The impressive performance of nanomaterials is shaping the future of science and revolutionizing the traditional concepts of industry and research. Titanate nanotubes (TNTs) are one of these novel entities that became an appropriate choice to apply in several platforms due to their remarkable properties such as preparation simplicity, high stability, good biocompatibility, affordability and low toxicity. Surface modification of these nanotubes is also promoting their superior characters and contributing more to the enhancement of their performance. In this research work, an attempt was made to functionalize the surface of titanate nanotubes with carboxylic groups to increase their surface reactivity and widen the possibility of bonding different molecules that could not be bonded directly. Three carboxylic acids were investigated (trichloroacetic acid, citric acid and acrylic acid), and the prepared composites were examined using FT-IR and Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS). The toxicity of these functionalized TNTs was also investigated using adherent cancer cell lines and fibroblasts to determine their safety profile and to draw the basic lines for their intended future application. Based on the experimental results, acrylic acid could be the suitable choice for permanent surface modification with multiple carboxylic groups due to its possibility to be polymerized, thus presenting the opportunity to link additional molecules of interest such as polyethylene glycol (PEG) and/or other molecules at the same time.

[Comparative study of crystallization processes in case of glycine crystallization]. / Kristályosítási eljárások összehasonlító vizsgálata glicin kristályosításánál.

In our work, the effect of crystallization methods and their parameters on the particle size, particle size-distribution and roundness were investigated in case of glycine crystallization. Three types of crystallization methods were applied according to the solubility results of the substance. In case of cooling crystallization, the effect of cooling and stirring rates were investigated. The feeding and stirring rates were changed in the feeding crystallization. In the antisolvent technique, the effect of cycle and amplitude of the sonification were studied on the particle size. A 3(2) full factorial design was applied for investigation of the effect of crystallization parameters. The results were analyzed by statistical software. The particle size distribution and roundness were measured by laser diffraction and light microscopic image analysis systems. The polymorph type of products was investigated by XRPD. The crystallized product morphology was examined using scanning electron microscopy. We found that the crystallization methods and certain parameters have significant effect on the particle size, particle size distribution. In spite of the modified particle size, morphology, roundness, the polymorph type of the product was the same with the original material.

Development and evaluation of bioadhesive buccal films based on sodium alginate for allergy therapy.

Buccal drug administration is a less explored area, therefore researchers and companies focus on its research because of its innovative potential and opportunities. Buccal polymer films (patches) are considered to be an innovative form and have a great number of advantageous properties. Firstly, patients who suffer from swallowing problems and children can also apply them. The active pharmaceutical ingredient enters the systemic circulation directly without degradation and transformation. The aim of this study was to formulate buccal films with sodium alginate (SA) because it is a rarely used, innovative polymer for the formulation of buccal films. The mechanical, chemical properties and dosage forms of the prepared films were investigated with different methods. To formulate the films, cetirizine dihydrochloride (CTZ) was used as model drug, and glycerol (GLY) was added to make the films more elastic. The samples were prepared and stored at room temperature. As a result, it can be seen that the mechanical properties of all film compositions show good results, especially breaking hardness. The films with high SA concentration containing CTZ had appropriate mucoadhesion forces, so these samples are suitable for application on the buccal mucosa. The results of dissolution confirmed this finding. Finally, it can be said we formulated fast dissolving films and it can be concluded that the films prepared with 3% SA concentration containing 1% and 3% GLY can be recommended for buccal application.

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.