Viscoelasticity of Liposomal Dispersions.

Janus-faced viscoelastic gelling agents-possessing both elastic and viscous characteristics-provide materials with unique features including strengthening ability under stress and a liquid-like character with lower viscosities under relaxed conditions. The mentioned multifunctional character is manifested in several body fluids such as human tears, synovial liquids, skin tissues and mucins, endowing the fluids with a special physical resistance property that can be analyzed by dynamic oscillatory rheology. Therefore, during the development of pharmaceutical or cosmetical formulations-with the intention of mimicking the physiological conditions-rheological studies on viscoelasticity are strongly recommended and the selection of viscoelastic preparations is highlighted. In our study, we aimed to determine the viscoelasticity of various liposomal dispersions. We intended to evaluate the impact of lipid concentration, the presence of cholesterol or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the gelling agents polyvinyl alcohol (PVA) and hydroxyethylcellulose (HEC) on the viscoelasticity of vesicular systems. Furthermore, the effect of two model drugs (phenyl salicylate and caffeine) on the viscoelastic behavior of liposomal systems was studied. Based on our measurements, the oscillation rheological properties of the liposomal formulations were influenced both by the composition and the lamellarity/size of the lipid vesicles.

Determination of the Main Phase Transition Temperature of Phospholipids by Oscillatory Rheology.

Knowledge of the physical and chemical properties of phospholipids, such as phase transition temperatures (Tc), is of great importance in order to reveal the functionalities of biological and artificial membranes. Our research group developed an oscillatory rheological method for the simple and rapid determination of phase transition temperatures (Tc). The phospholipids constructing the membranes undergo conformational changes at their Tc, which cause alterations of viscoelastic properties of the molecules. The oscillatory technique recommended by us proved to be appropriate to reveal the altered molecular properties of phospholipids as tracking the slightest changes in the viscoelasticity. Our study demonstrates the abrupt changes in rheological properties at Tc for the following phospholipids: 1,2-Dimyristoyl-sn-glycero-3-Phosphocholine (DMPC), 1,2-Dipalmitoyl-sn-glycero-3-Phosphatidylcholine (DPPC), and 1,2-Distearoyl-sn-glycero-3-Phosphocholine (DSPC), proving that the applied methodology is adequate for determining the Tc of phospholipids.

Rheological Considerations of Pharmaceutical Formulations: Focus on Viscoelasticity.

Controlling rheological properties offers the opportunity to gain insight into the physical characteristics, structure, stability and drug release rate of formulations. To better understand the physical properties of hydrogels, not only rotational but also oscillatory experiments should be performed. Viscoelastic properties, including elastic and viscous properties, are measured using oscillatory rheology. The gel strength and elasticity of hydrogels are of great importance for pharmaceutical development as the application of viscoelastic preparations has considerably expanded in recent decades. Viscosupplementation, ophthalmic surgery and tissue engineering are just a few examples from the wide range of possible applications of viscoelastic hydrogels. Hyaluronic acid, alginate, gellan gum, pectin and chitosan are remarkable representatives of gelling agents that attract great attention applied in biomedical fields. This review provides a brief summary of rheological properties, highlighting the viscoelasticity of hydrogels with great potential in biomedicine.

Inclusion complexation of the anticancer drug pomalidomide with cyclodextrins: fast dissolution and improved solubility.

Pomalidomide (POM), a potent anticancer thalidomide analogue was characterized in terms of cyclodextrin complexation to improve its aqueous solubility and maintain its anti-angiogenic activity. The most promising cyclodextrin derivatives were selected by phase-solubility studies. From the investigated nine cyclodextrins - differing in cavity size, nature of substituents, degree of substitution and charge - the highest solubility increase was observed with sulfobutylether-ß-cyclodextrin (SBE-ß-CD). The inclusion complexation between POM and SBE-ß-CD was further characterized with a wide variety of state-of-the-art analytical techniques, such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), circular dichroism spectroscopy, fluorescence spectroscopy as well as X-ray powder diffraction method (XRD). Job plot titration by NMR and the AL-type phase-solubility diagram indicated 1:1 stoichiometry in a liquid state. Complementary analytical methods were employed for the determination of the stability constant of the complex; the advantages and disadvantages of the different approaches are also discussed. Inclusion complex formation was also assessed by molecular modelling study. Solid state complexation in a 1:1 M ratio was carried out by lyophilization and investigated by IR and XRD. The complex exhibited fast-dissolution with immediate release of POM, when compared to the pure drug at acidic and neutral pH. Kinetic analysis of POM release from lyophilized complex shows that Korsmeyer-Peppas and Weibull model described the best the dissolution kinetics. The cytotoxicity of the complex was tested against the LP-1 human myeloma cell line which revealed that supramolecular interactions did not significantly affect the anti-cancer activity of the drug. Overall, our results suggest that the inclusion complexation of POM with SBE-ß-CD could be a promising approach for developing more effective POM formulations with increased solubility.

Configuration-Controlled Crystal and/or Gel Formation of Protected d-Glucosamines Supported by Promiscuous Interaction Surfaces and a Conformationally Heterogeneous Solution State.

The configuration-dependent self-association mode of the two anomers of O-Ac,N-Fmoc-d-glucosamine, a foldamer building block, leading to gel and/or single crystal formation is described. The ß-anomer of the sugar amino acid (2) forms a gel from various solvents (confirmed by SEM, rheology measurements, NMR, and ECD spectroscopy), whereas the α-anomer (1) does not form a gel with any solvent tested. Transition from the solution state to a gel is coupled to a concurrent shift of the Fmoc-groups: from a freely rotating (almost symmetrical) to a specific, asymmetric orientation. Whereas the crystal structure of the α-anomer is built as an evenly packed 3D system, the ß-anomer forms a looser superstructure of well-packed 2D layers. Modeling indicates that in the lowest energy, but scarcely sampled conformer of the ß-anomer, the Fmoc-group bends above the sugar moiety, stabilized by intramolecular CH↔π interactions between the aromatic rings. It is concluded that possessing an extended and promiscuous interaction surface and a conformationally heterogeneous solution state are among the basic requirements of gel formation for a candidate molecule.

Liposomes for topical use: a physico-chemical comparison of vesicles prepared from egg or soy lecithin.

Developments in nanotechnology and in the formulation of liposomal systems provide the opportunity for cosmetic dermatology to design novel delivery systems. Determination of their physico-chemical parameters has importance when developing a nano-delivery system. The present study highlights some technological aspects/characteristics of liposomes formulated from egg or soy lecithins for topical use. Alterations in the pH, viscosity, surface tension, and microscopic/macroscopic appearance of these vesicular systems were investigated. The chemical composition of the two types of lecithin was checked by mass spectrometry. Caffeine, as a model molecule, was encapsulated into multilamellar vesicles prepared from the two types of lecithin: then zeta potential, membrane fluidity, and encapsulation efficiency were compared. According to our observations, samples prepared from the two lecithins altered the pH in opposite directions: egg lecithin increased it while soy lecithin decreased it with increased lipid concentration. Our EPR spectroscopic results showed that the binding of caffeine did not change the membrane fluidity in the temperature range of possible topical use (measured between 2 and 50 °C). Combining our results on encapsulation efficiency for caffeine (about 30% for both lecithins) with those on membrane fluidity data, we concluded that the interaction of caffeine with the liposomal membrane does not change the rotational motion of the lipid molecules close to the head group region. In conclusion, topical use of egg lecithin for liposomal formulations can be preferred if there are no differences in the physico-chemical properties due to the encapsulated drugs, because the physiological effects of egg lecithin vesicles on skin are significantly better than that of soy lecithin liposomes.

Optimization of liposomal encapsulation for ceftazidime for developing a potential eye drop formulation.

Ceftazidime is a broad spectrum third generation cephalosporin antibiotic which is effective mainly against Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter and Enterobacteriaceae, the pathogens which most often cause ophthalmological infections. Unlike other commonly used beta lactam antibiotics, ceftazidime is resistant to several types of beta lactamases (e.g., TEM, SHV and PSE-1). Because of these advantages, ceftazidime is used in the treatment of eye infections. However, ceftazidime undergoes rapid degradation in aqueous solutions therefore eye drops containing ceftazidime in aqueous solutions are not commercially manufactured. In the present study, liposomal encapsulations of ceftazidime with various lipid compositions, hydrating solutions and pH-values have been studied in order to optimize liposomal composition for a potential eye drop formulation.

Natural oils and waxes: studies on stick bases.

The objective of the present article was to examine the role of origin and quantity of selected natural oils and waxes in the determination of the thermal properties and hardness of stick bases. The natural oils and waxes selected for the study were sunflower, castor, jojoba, and coconut oils. The selected waxes were yellow beeswax, candelilla wax, and carnauba wax. The hardness of the formulations is a critical parameter from the aspect of their application. Hardness was characterized by the measurement of compression strength along with the softening point, the drop point, and differential scanning calorimetry (DSC). It can be concluded that coconut oil, jojoba oil, and carnauba wax have the greatest influence on the thermal parameters of stick bases.

Nanoencapsulated and microencapsulated enzymes in drug antidotal therapy.

A catalytic bioscavenger for the therapeutic and prophylactic defense against recognized chemical threat agents has been a long-standing objective of civilian and military research. Among the toxic agents, organophosphate molecules and cyanide have been widely studied. In order to overcome the limitations of traditional antidotal therapies, isolated, purified, recombinant enzymes with bacterial origin possessing fast catalytic activity were used in in vitro and in vivo experiments. However, the fast degradation, excretion and adverse immunologic reaction against enzymes limit their in vivo use. Development of biodegradable, nontoxic carrier systems, microparticles, and nanoparticles-offering advantageous pharmacokinetic parameters was suggested. Present work deals with the perspectives of carrier systems, such as resealed and annealed erythrocytes and sterically stabilized liposomes. Dendritic polymers and polymer-conjugated enzymes, being in the focus of extensive research efforts nowadays, are also discussed.

[Importance of the HLB-value in drug technology]. / A HLB-érték jelentosége a gyógyszertechnológiában.

Surface active agents can be classified 60 years ago with the introduction of the HLB system. The characterization of emulgents allowed their common use in the practice. The objective of the review is to summarize the research in the field of surface active agents and HLB-value. The basic principles and relationships related to HLB are detailed such as the predicting and experimental methods for the determination, as well as the achievements of development and applications of surface active agents.

Investigation of genetic variants of alpha-1 acid glycoprotein by ultra-performance liquid chromatography-mass spectrometry.

Genetic variants of human plasma alpha-1 acid glycoprotein (AGP) have been studied in cancer, compared with a group of healthy control. AGP has four genetic variants: AGP F1, F2, and S variants correspond to the ORM1 gene whereas AGP A corresponds to the ORM2 gene. The proportion of ORM1 and ORM2 variants were studied in plasma using a novel UPLC-MS method. Plasma total AGP level was 0.5 +/- 0.2 g L(-1) and the proportions of the ORM1 and ORM2 variants were 76.3 +/- 8.2% and 23.7 +/- 8.2%, respectively. In cancer plasma AGP levels increased fourfold and the proportion of ORM1 variants increased to 88.7 +/- 6.8%. Changes in the proportion of genetic variants due to cancer were clearly significant, as shown by statistical analysis. Three different cancer types have been studied, lymphoma, melanoma, and ovarian cancer. The results did not show any difference depending on cancer type. The results indicate that, in accordance with prior expectations, the ORM1 variant is predominantly responsible for the acute-phase property of AGP.

[Methods to increase the encapsulation efficiency for liposomal drugs]. / A bezárási hatásfok növelésének lehetoségei liposzómába zárt lomefloxacinnál.

Liposomes as drug delivery systems--in comparison to the traditional dosage forms--offer the advantage of the targeted drug delivery and as a consequence, reduction of the side effects. In case of fluoroquinolone antibiotics, such as lomefloxacin, the liposomal encapsulation of the active ingredient can result in an enhancement of its therapeutic efficacy against intracellular bacteria. The aim to improve the liposomal encapsulation efficiency of drugs--which is one of the main factors influencing the therapeutic effect of vesicular dosage forms--is one of the important challenges in the field of pharmaceutical technology. In our experiments we prepared lomefloxacin containing multilamellar vesicles from various lipids using different hydrating solutions. We intended to study the effect of lipid composition, cholesterol content and surface charge of liposomes on the encapsulation efficiency of lomefloxacin. Our results can contribute to the rational design of fluoroquinolone containing liposomal drugs.

Analysis of complex oligosaccharides using graphitized carbon liquid chromatography/mass spectrometry.

The sugar fraction of alpha-1 acid glycoprotein (AGP) was studied using porous graphitized carbon (PGC) chromatography coupled to mass spectrometry. Electrospray ionization provides efficient control over fragmentation; at low collision energy only molecular species were observed, allowing accurate oligosaccharide profiling. PGC chromatography was useful separating 18 sugars differing in monosaccharide composition. Most of these were separated into several isomeric forms; altogether 49 different oligosaccharides were found in AGP.

Gels and liposomes in optimized ocular drug delivery: studies on ciprofloxacin formulations.

Ciprofloxacin (CPFX) containing therapeutic systems were developed using gel- and liposome-based formulations to minimize tear-driven dilution in the conjunctival sac, a long-pursued objective in ophthalmology. Physicochemical properties (pH, osmolarity, viscosity, expansivity, membrane fluidity and in vitro CPFX release rate) of the preparations were studied by the appropriate methods. For gel preparation, the bio-adhesive poly(vinyl alcohol) and polymethacrylic acid derivatives were applied in various concentrations. In our liposome-supported carrier systems, multilamellar vesicles from lecithin and alpha-L-dipalmithoyl-phosphatidylcholine provided the encapsulating agent. Electron paramagnetic resonance (EPR) spectroscopy was applied to study the molecular interactions in the ophthalmic formulations. The polymer hydrogels used in our preparations ensured a steady and prolonged active ingredient release. In addition, encapsulation of the CPFX into liposomes prolonged the in vitro release of the antibacterial agent depending on the lipid composition of the vesicles.