Biomedical subjects

K Mäder

Publications and source records attributed to K Mäder.

At least 19 recordsLinked to original sources

PubMed2004

Liquid and semisolid SLN dispersions for topical application: rheological characterization.

Aqueous dispersions of solid lipid nanoparticles (SLN) are promising drug carrier systems for topical application. A drawback, however, is the need of incorporating the SLN dispersion in commonly used dermal carriers (creams, gels) to obtain the required semisolid consistency for dermal application. This study describes the production of SLN dispersions having the desired semisolid consistency by a one-step process. Physical characterization of these systems in terms of particle size and rheological properties revealed some interesting features. Despite the high lipid content it was possible to produce colloidal dispersions by high pressure homogenization. Continuous flow measurements revealed systems with yield point, plastic flow and thixotropy. Oscillation measurements proved the viscoelastic microstructure of the SLN dispersions. Higher concentrated SLN dispersions were found to have a prevailing elastic component in contrast to lower concentrated systems. Viscoelastic properties of a 40% SLN dispersion were found to be comparable to standard dermal preparations. Storage stability at room temperature in terms of particle size could be demonstrated over a 6-month period. The development of the gel structure of semisolid SLN dispersions is delayed comparable to commercial O/W creams with non-ionic emulsifiers. Parameters like concentration of the dispersed phase, particle size and particle shape were identified as significant factors influencing the microstructure of these complex semisolid systems.

Administration, Topical↗

PubMed2003

Analysis of the meal-dependent intragastric performance of a gastric-retentive tablet assessed by magnetic resonance imaging.

BACKGROUND: Modern medical imaging modalities can trace labelled oral drug dosage forms in the gastrointestinal tract, and thus represent important tools for the evaluation of their in vivo performance. The application of gastric-retentive drug delivery systems to improve bioavailability and to avoid unwanted plasma peak concentrations of orally administered drugs is of special interest in clinical and pharmaceutical research. AIM: To determine the influence of meal composition and timing of tablet administration on the intragastric performance of a gastric-retentive floating tablet using magnetic resonance imaging in the sitting position. METHODS: A tablet formulation was labelled with iron oxide particles as negative magnetic resonance contrast marker to allow the monitoring of the tablet position in the food-filled human stomach. Labelled tablet was administered, together with three different solid meals, to volunteers seated in a 0.5-T open-configuration magnetic resonance system. Volunteers were followed over a 4-h period. RESULTS: Labelled tablet was detectable in all subjects throughout the entire study. The tablet showed persistent good intragastric floating performance independent of meal composition. Unfavourable timing of tablet administration had a minor effect on the intragastric tablet residence time and floating performance. CONCLUSION: Magnetic resonance imaging can reliably monitor and analyse the in vivo performance of labelled gastric-retentive tablets in the human stomach.

Adult↗

PubMed2002

Semisolid SLN dispersions for topical application: influence of formulation and production parameters on viscoelastic properties.

Aqueous solid lipid nanoparticle (SLN) dispersions with a high lipid content up to 35% and viscous to semisolid consistency were produced by a high pressure homogenization process. Despite their high lipid content and viscosity these dispersions preserved their colloidal size range. The SLN dispersions were compared to nanoemulsions and microparticle dispersions with regard to particle size, viscoelastic properties and formation of a semisolid gel structure. Viscoelastic measurements including oscillation stress sweep tests and oscillation frequency sweep tests demonstrated that the existence of a solid particle matrix with a particle size in the nanometer range is a prerequisite to form a semisolid dispersion having the appropriate consistency for topical application. Striking differences were observed between solid lipid micro- and nanodispersions of the same composition. Particle size reduction resulted in an 80-fold increase of the elastic modulus. Particle size distribution, the physical state of the dispersed lipid phase and the emulsifier concentration have been identified as further key factors for the viscoelastic properties and gel structure of the lipid nanodispersions. By conducting oscillation measurements it was possible to relate the stability of lipid dispersions to specific rheological parameters therefore providing a sensitive tool in stability assessment. Changing the production process from a 40 ml batch to a 2 l batch turned out to have an influence on the colloidal structures of semisolid SLN dispersions. Consistency increased but particle size and ratio of elastic to viscous properties stayed in the same range.

Administration, Topical↗

PubMed2001

Solid lipid nanoparticles: production, characterization and applications.

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.

Capsules↗

PubMed2001

Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles.

Aqueous dispersions of solid lipid nanoparticles (SLN) show some interesting features in topical drug delivery. However, to get a semisolid carrier having the appropriate consistency for topical application, the liquid SLN dispersions have to be incorporated in convenient topical dosage forms like hydrogels or creams. This is a time-consuming production process with several disadvantages. A new one-step production process delivering a semisolid topical formulation including SLN is presented avoiding these disadvantages. The semisolid SLN dispersions were produced by high-pressure homogenization using an APV Lab 40 homogenizer. The resulting dispersions were characterized concerning their particle size and rheological properties. Despite the high lipid content of the SLN dispersions, they retained their colloidal particle size. Viscoelastic measurements proved the existence of a gel-like structure with a prevailing elastic component.

Administration, Topical↗

PubMed2001

Gamma-irradiation stability of saturated and unsaturated aliphatic polyanhydrides--ricinoleic acid based polymers.

The effect of terminal sterilization by gamma-irradiation on several ricinoleic acid based polyanhydrides was investigated. The following polymers were used: poly(ricinoleic acid maleate) [P(RAM)], poly(ricinoleic acid succinate) [P(RAS)], poly(hydroxy stearic acid succinate) [P(HSAS)], poly(hydroxy stearic acid maleate) [P(HSAM)], and their copolymers with sebacic acid. The polymers were irradiated with an absorbed dose of 2.5 or 10 Mrad by means of a 60Co source under dry ice or at room temperature. No differences were found between samples irradiated under dry ice and at room temperature. Polymers prepared from monomers containing maleate residues, which contain double bonds adjusted to the anhydride linkage along the polymer chain, decreased in molecular weight, became insoluble, and showed fast hydrolytic degradation. For example, p(RAM), p(HSAM), and their copolymers with sebacic acid decreased in Mw from about 10,000 to about 2000, and from about 30,000 to about 5000, respectively, while polymers based on RAS and HSAS remained stable. This phenomenon was explained by an anhydride interchange-self-depolymerization process of the unsaturated anhydride bonds induced by gamma-irradiation. This explanation was supported by the depolymerization of another class of polymers having an anhydride bond between two double bonds, fumaric acid anhydride polymers. The anhydride bond that lies between two double bonds was found to be more sensitive to gamma-irradiation. This anhydride bond may be cleaved to form two radicals that further react with aliphatic anhydride bonds along the polymer chain to form inter- and/or intracyclization products.

Anhydrides↗

PubMed2001

Influence of drug treatment on the microacidity in rat and human skin--an in vitro electron spin resonance imaging study.

PURPOSE: The possibilities of the noninvasive examination of microacidity (5) in different depths of the skin in vitro was explored, and the impact of drug treatment on the pH inside the skin was studied. METHODS: Spectral-spatial electron spin resonance imaging (ss-ESRI) and pH-sensitive nitroxides were used to obtain a pH map of rat and human skin in vitro. RESULTS: The dermal application of therapeutically used acids, such as salicylic acid and azelaic acid, caused a plain change of microacidity (pH) inside the skin. Species-linked differences between rat and human skin samples with respect to penetration and microacidity were found. CONCLUSIONS: ESRI has been shown to be a new and completely noninvasive method to monitor microacidity in different skin layers and on the skin surface. This nondestructive method allows serial measurements on skin samples to be performed without any preparatory steps.

Animals↗

PubMed2000

Solid lipid nanoparticles (SLN) based on binary mixtures of liquid and solid lipids: a (1)H-NMR study.

SLN with improved payloads and enhanced storage stability were investigated. Based on the experiences with solid lipid nanoparticles, a new type of solid lipid nanoparticle has been developed by incorporating triglyceride containing oils in the solid shell of the particle. The structure and mixing behaviour of these particles was characterised by DSC and (1)H-NMR. DSC yields information on the melting and crystallisation behaviour of the solid and liquid constituents of the particles. NMR is especially suited for the characterisation of the liquid oil domains inside the SLN. In this study a medium chain triglyceride oil was successfully incorporated in a matrix of a solid long chain glyceride (glyceryl behenate). The resulting particles were solid but the oil inside the particle remained in a liquid state. The relation between oil supplementation and melting point depression of glyceryl behenate proved to be linear. Mobility of the oil molecules inside the particles was considerably reduced compared to the emulsified oil. Moreover, two different chemical shifts for each of the lipid signals were observed indicating two different chemical environments. The experimental data is in line with a model describing uniform distribution of the oil molecules in the glyceryl behenate for low oil loads. However, at higher oil loads our data indicate the formation of oil clusters within the solid nanoparticle.

Capsules↗

PubMed2000

Structure and hydration properties of hydroxypropyl methylcellulose matrices containing naproxen and naproxen sodium.

The present study was conducted to obtain a deeper insight into the mechanism of drug release from HPMC matrices. The microstructure, mobility, internal pH and the state of water within the gel layer of hydrated HPMC matrices (having different molecular weights) containing naproxen sodium (NS) and naproxen (N) were studied using Electron Paramagnetic Resonance (EPR), Nuclear Magnetic Resonance (NMR) and Differential Scanning Calorimetry (DSC) techniques. The study show that matrices composed of various viscosity grades of HPMC are characterized by similar microviscosity values in spite of the difference in their molecular weight. The NMR and DSC results led to the conclusion that higher molecular weights of HPMC are characterized by higher water absorption capacity and higher swelling. Analysis of non-freezable water in HPMC(K4M)-NS system revealed that addition of NS to solution increased the fraction of water bound to K4M+NS compared with the equivalent solutions without NS. The results suggest that the drug is participating in the crystallization of water and leads to the formation of a three dimensional network structure that decreases the freedom of water in K4M+NS samples. Calculation of the number of hydration shells showed that up to 2.2 layers are involved in HPMC-NS hydration compared to 1.5 layers for HPMC gel without NS. This was explained based on the different water ordering in the gel induced by NS as results of its absorption to polymer surface. Microviscosity values measured by EPR for K4M/N and K4M/NS hydrated matrices were found to be higher for K4M/N matrices, especially at initial stage of hydration. Mobile compartment calculations showed lower values for K4M/N compared with K4M/NS matrices. pH measurements by EPR revealed that incorporation of N to HPMC matrix led to lower internal pH value inside the hydrated tablet compared with NS. This behavior led to lower solubility of N which dictates its surface erosion mechanism, compared with NS matrix that was characterized by higher internal pH value and higher drug solubility. These properties of HPMC/NS increased chain hydration and stability, and led to drug release by the diffusion mechanism.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Heavy metal contamination of nanosuspensions produced by high-pressure homogenisation.

High pressure homogenisation is a method for the production of nanosuspensions. In this process crystalline drug particles are pressed with high pressure through a narrow homogenisation gap. Due to the conditions in the gap it seems possible that metal erosion can occur. In this study the heavy metal (Fe) contamination of nanosuspensions produced by high pressure homogenisation was determined. Therefore nanosuspensions were analysed by atom absorption spectroscopy concerning their load of iron which is chosen as reference metal. The results show that the erosion of metal is below 1 ppm and will not cause any toxicological problems.

Calibration↗

PubMed2000

Influence of high pressure homogenisation equipment on nanodispersions characteristics.

In this study a comparison of the influence of the homogenising equipment supplied by different manufacturers on the quality of the lipid nanodispersions is given. An Avestin EmulsiFlex-B3 (B3) and APV Micron Lab 40 (LAB 40) were used for high pressure homogenisation. Particle size and particle size distribution were chosen as quality parameters. The influence of different process parameters was evaluated. The two homogenisers were compared in their quality of nanoparticles-production by hot and cold homogenisation technique and in processing nanoemulsions. Working with the B3 appeared as useful for preformulation studies and processing of expensive or rare drugs and excipients. This first scaling up within laboratory scale is evaluated and the problems and remarkable aspects working with the B3 are pointed out.

Chemistry, Pharmaceutical↗

PubMed2000

Influence of different parameters on reconstitution of lyophilized SLN.

Drug-loaded solid lipid nanoparticles (SLN) suitable for parenteral administration were freeze-dried. The lipid matrix Imwitor 900 (concentration, 2.5%) was stabilized with Lipoid E 80 and sodium glycocholate. The influence of different parameters of lyophilization like the protective effect of cryoprotectants, freezing velocity, and thermal treatment was investigated. The results of this study demonstrate that, by optimizing critical process parameters, i.v.-injectable SLN-dispersions can be freeze-dried, preserving their small particle size.

Drug Carriers↗

PubMed2000

Investigation on the viscoelastic properties of lipid based colloidal drug carriers.

The rheological behaviour of solid lipid nanoparticle dispersions (SLN) prepared by high pressure homogenization was investigated using a Haake RS-100 rheometer. Four preparations differing in their lipid content and macroscopic consistency were tested by continuous shear rheometry and oscillatory testing. Rheological data from continuous shear measurement reveal plastic flow for systems with low lipid content as well as for systems with high lipid content. By using oscillatory testing more detailed information concerning the structure could be achieved. Rheological measurements of 40% lipid dispersions show viscoelastic properties comparable to the data from standard dermal preparations. Therefore high concentrated lipid dispersions might constitute a promising vehicle for topical administration.

Colloids↗

PubMed2000

Interactions of nanoparticles with body proteins--improvement of 2D-PAGE-analysis by internal standard.

Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) is the method of choice to investigate protein adsorption of blood proteins (opsonization) onto nanoparticular drug carriers. In general the reproducibility of the obtained adsorption patterns is satisfying. However, direct comparison between the amounts of single protein spots from gels obtained in different runs is difficult, because 2D-PAGE is a multistep procedure. A possible solution of the problem is to establish a protein as internal standard. Therefore, selected proteins (Bio-rad) were under investigation. Due to its molecular weight and isoelectric point, soybean trypsin inhibitor (TI) does not interfere with plasma components. Therefore, a method was established to use TI as an internal standard protein to improve comparability between the 2D-PAGE gels obtained in different analytical runs.

Animals↗

PubMed2000

Nanoparticles with decreasing surface hydrophobicities: influence on plasma protein adsorption.

The rapid uptake of i.v. injected nanoparticles by cells of the mononuclear phagocytic system (MPS) is a major obstacle for a long blood circulation time and a drug targeting to sites other than the MPS. The adsorption of proteins on the particles surface after i.v. administration depends on their surface characteristics and is regarded as key factor for the in vivo organ distribution. The objective of this study is to investigate changes in the plasma protein adsorption patterns in the course of surface hydrophobicity variation. Latex particles with decreasing surface hydrophobicity were synthesized as model colloidal carriers. Physicochemical characterization had been performed and considerable differences in the protein adsorption patterns on the particles could be detected by using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Correlations between physicochemical characteristics and the protein adsorption patterns have been found and are discussed.

Adsorption↗

PubMed2000

Correlation between drug release kinetics from proteineous matrix and matrix structure: EPR and NMR study.

The present study was conducted in order to probe the microstructure, microviscosity, and hydration properties of matrices containing two model drugs, naproxen sodium (NS) and naproxen (N), and egg albumin (EA) as matrix carrier. The results suggested that N release from EA matrix was controlled by a bulk erosion mechanism in combination with additional processes (crystal dissolution/crystallization rate) compared with NS matrix, which behaved as a non-erodible matrix and drug release occurred by diffusion through the gel. Using EPR technique it has been shown that incorporating NS into EA matrix strongly influences the microstructure of the protein gel, and hence the transport of the penetrant within the matrix, compared with matrices containing N. The presence of NS increased the protein chain mobility and hydration which supports our previous results showing that NS cause unfolding of EA. In contrast, N caused only marginal effect on EA chain mobility. The gel formed in EA/NS matrices was more porous compared with EA/N matrices as revealed by the lower rotational correlation time of PCA (lower microviscosity) in EA/NS matrices compared with EA/N. However, EA/N gelled matrices were more heterogeneous, i.e., containing a higher number of components having different mobility. The T(1) and T(2) relaxation studies by NMR provided an additional support for the higher chain hydration in EA/NS matrices compared with EA/N as indicated by the higher relaxation rates in the gelled matrices. Internal pH measurements by EPR revealed that the micro-pH inside 100% EA and 50/50 EA/N matrices were lower than 50/50 EA/NS matrices and in all cases lower than the penetrating buffer pH. The lower pH compartment formed in N matrices affected N solubility and crystal dissolution rate, which can explain its lower release rate compared with EA, from the same formulation. The EPR and NMR data supports our findings that NS caused unfolding of the protein, affected matrix structure, and converted it to a hydrophobic non-erodible matrix compared with EA/N matrix in which the native properties of EA were mainly retained.

Diffusion↗

PubMed2000

The degradation, swelling and erosion properties of biodegradable implants prepared by extrusion or compression moulding of poly(lactide-co-glycolide) and ABA triblock copolymers.

In the design of parenteral delivery systems the modulation of the biodegradation of a polymer matrix represents a promising strategy to control drug release. We have investigated the degradation of ABA triblock copolymers, consisting of poly(lactide-co-glycolide) A-blocks and poly(oxyethylene) B-blocks, and PLG, poly(lactide-co-glycolide), with respect to swelling behaviour, molecular weight loss and polymer erosion. Implants were prepared by either compression moulding or extrusion using a laboratory ram extruder. Insertion of an elastoplastic B-block did not lower the processing temperature, but the entanglement of the polymer chains was significantly reduced as can be seen from the diameters of the extruded rods. The swelling of the rods showed a volume extension of 130% for an ABA containing 50% PEO and 20% for an ABA containing 20% PEO. Using 1H-NMR it was found that protons in the B-blocks of the swollen ABA copolymers were mobile, while the A-blocks remained rigid during incubation. The analysis of the pH inside ABA rods using electron paramagnetic resonance, EPR, gave a pH of 5.2 after incubation with a subsequent increase to pH 6.0 during the first day, approaching the pH of the medium after nearly 33 d. Acidic degradation products did not accumulate inside the ABA rods. Degradation and erosion started immediately upon incubation. By contrast, PLG rods showed the typical profile of degradation and erosion. In this case, the influence of the geometry of the device was insignificant. Consequently, ABA triblock copolymers may widen the spectrum of parenteral drug delivery with regard to release of pH-sensitive drugs as well as erosion-controlled release kinetics.

Biodegradation, Environmental↗

PubMed2000

Accurate and sensitive measurements of pO(2) in vivo using low frequency EPR spectroscopy: how to confer biocompatibility to the oxygen sensors.

Within the last few years, there has been a significant amount of progress using EPR oximetry, which has resulted in the availability of instrumentation and paramagnetic materials capable of measuring pO(2) in tissues with an accuracy and sensitivity comparable to or greater than that available by any other method. While the results obtained with EPR so far indicate that criteria for the measurements of pO(2)-such as accuracy, sensitivity, repeatability, and noninvasiveness-can be met, some of the paramagnetic materials with optimum spectroscopic properties (i.e., strong simple signals which are appropriately responsive to changes in pO(2)) may have some undesirable interactions with tissues, causing reactions with and/or losing responsiveness to oxygen. In this paper, several approaches are discussed, such as encapsulation procedures, which can result in the availability of oxygen-sensitive materials in a suitable configuration for long-term studies (absence of toxicity and preservation of the responsiveness to oxygen).

Animals↗