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Biomedical subjects

K Mäder

Publications and source records attributed to K Mäder.

At least 37 records · Page 2Linked to original sources
PubMed2000

Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art.

Solid lipid nanoparticles (SLN) introduced in 1991 represent an alternative carrier system to traditional colloidal carriers, such as emulsions, liposomes and polymeric micro- and nanoparticles. SLN combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews the present state of the art regarding production techniques for SLN, drug incorporation, loading capacity and drug release, especially focusing on drug release mechanisms. Relevant issues for the introduction of SLN to the pharmaceutical market, such as status of excipients, toxicity/tolerability aspects and sterilization and long-term stability including industrial large scale production are also discussed. The potential of SLN to be exploited for the different administration routes is highlighted. References of the most relevant literature published by various research groups around the world are provided.

Animals↗
PubMed2000

Investigating the structure and properties of hydrated hydroxypropyl methylcellulose and egg albumin matrices containing carbamazepine: EPR and NMR study.

PURPOSE: The present study was conducted in order to investigate the correlation between the hydration properties of HPMC and EA matrices, gel microstructure and mobility, crystalline changes occurring in the gel and CBZ release kinetics. The influence of HPMC and EA erosion modes on CBZ release kinetics was interpreted in terms of gel microstructures. METHODS: NMR technique was used to determine the T1 and T2 relaxation rates of water in hydrated matrices. PFGSE NMR technique was employed to determine the SDC of water in the gels. EPR technique was used to determine the rotational correlation time of PCA in the hydrated matrices, gel microviscosity, mobile compartment, alpha, beta, gamma parameters and lorentzian/ gaussian ratio. These parameters are indicative of matrix microstructure. RESULTS: CBZ release mechanism from HPMC and EA matrices was markedly different. This behavior was related to the different structures of the polymer and protein. T2 relaxation studies and SDC measurements by NMR revealed higher chain hydration for HPMC compared to EA. Using the EPR technique it has been shown that the microviscosity and mobile compartment of matrices containing HPMC are lower than matrices containing EA. The microviscosity, mobile compartment and S-parameter values of hydrated matrices containing different EA/CBZ ratios were in correlation with the crystallization properties of CBZ in the gels, matrix erosion properties and CBZ release kinetics from the matrices. CONCLUSIONS: Characterization of matrix structures using EPR and NMR techniques supported our hypothesis concerning the mechanism involved in HPMC-CBZ interaction. EA/CBZ matrix microstructure features, analyzed by NMR and EPR techniques, were in correlation with the crystalline changes occurring in the gel and drug release kinetics.

Carbamazepine↗
PubMed1999

Degradation and protein release properties of microspheres prepared from biodegradable poly(lactide-co-glycolide) and ABA triblock copolymers: influence of buffer media on polymer erosion and bovine serum albumin release.

The aim of the present study was to investigate the influence of the chemical insertion of poly(ethylene oxide), PEO, into a poly(lactide-co-glycolide), PLG, backbone on the mechanisms of in vitro degradation and erosion of the polymer. For this purpose microspheres prepared by a modified W/O/W double emulsion technique using ABA triblock copolymers, consisting of PLG A-blocks attached to central PEO B-blocks were compared with microspheres prepared from PLG. Due to their molecular architecture the ABA triblock copolymers differed in their erosion and degradation behavior from PLG. Degradation occurred faster in the ABA polymers by cleavage of ester bonds inside the polymer backbone. Even erosion was shown to start immediately after incubation in different buffer media. By varying pH and ionic strength of the buffer it was found that both mass loss and molecular weight decay were accelerated in alkaline and acidic pH in the case of the ABA triblock copolymers. Although the pH of the medium had a moderate influence on the degradation of PLG, the molecular weight decay was not accompanied by a mass loss during the observation time. In a second set of experiments we prepared bovine serum albumin, BSA, loaded microspheres from both polymers. The release of BSA from ABA microspheres under in vitro conditions parallels the faster swelling and erosion rates. This could be confirmed by electron paramagnetic resonance, EPR, measurements with spin labeled albumin where an influx of buffer medium into the ABA microspheres was already observed within a few minutes. In contrast, PLG microspheres revealed a burst release without any erosion. The current study shows that the environmental conditions affected the degradation and erosion of the pure polymer microspheres in the same way as the release of the model protein. This leads to the conclusion that the more favorable degradation profile of the ABA triblock copolymers was responsible for the improvement of the release profile.

Animals↗
PubMed1999

Tetracycline-HCl-loaded poly(DL-lactide-co-glycolide) microspheres prepared by a spray drying technique: influence of gamma-irradiation on radical formation and polymer degradation.

Tetracycline-HCl (TCH)-loaded microspheres were prepared from poly(lactide-co-glycolide) (PLGA) by spray drying. The drug was incorporated in the polymer matrix either in solid state or as w/o emulsion. The spin probe 4-hydroxy-2,2,6, 6-tetramethyl-piperidine-1-oxyl (TEMPOL) and the spin trap tert-butyl-phenyl-nitrone (PBN) were co-encapsulated into the TCH-loaded and placebo particles. We investigated the effects of gamma-irradiation on the formation of free radicals in polymer and drug and the mechanism of chain scission after sterilization. Gamma-Irradiation was performed at 26.9 and 54.9 kGy using a 60Co source. The microspheres were characterized especially with respect to the formation of radicals and in vitro polymer degradation. Electron paramagnetic resonance (EPR) spectroscopy, gel permeation chromatography (GPC), differential scanning calorimetry (DSC), high-performance liquid chromatography (HPLC), gas chromatography-mass spectroscopy (GC-MS), and scanning electron microscopy (SEM) were used for characterization of the microspheres. Using EPR spectroscopy, we successfully detected gamma-irradiation induced free radicals within the TCH-loaded microspheres, while unloaded PLGA did not contain radicals under the same conditions. The relatively low glass transition temperature of the poly(dl-lactide-co-glycolide) (37-39 degrees C) seems to favor subsequent reactions of free radicals due to the high mobility of the polymeric chains. Because of the high melting point of TCH (214 degrees C), the radicals can only be stabilized in drug loaded microspheres. In order to determine the mechanism of polymer degradation after exposure to gamma-rays, the spin trap PBN and the spin probe TEMPOL were encapsulated in the microspheres. gamma-Irradiation of microspheres containing PBN resulted in the formation of a lipophilic spin adduct, indicating that a polymeric radical was generated by random chain scission. Polymer degradation by an unzipping mechanism would have produced hydrophilic spin adducts of PBN and monomeric radicals of lactic or glycolic acid. These degradation products were not detected by EPR. This result is confirmed by the observation that possible diamagnetic reaction products of low molecular weight, consisting of TEMPOL and lactide or glycolide monomers, could not be detected by GC-MS. While an irradiation dose-dependent decrease in molecular weight of PLGA could be verified in agreement with the literature, TCH content of the microspheres was not affected by the exposure to gamma-rays. It can be concluded that EPR spectroscopy in combination with GPC, DSC, and HPLC allows a detailed characterization of the impact of gamma-sterilization on biodegradable parenteral drug delivery systems.

Anti-Bacterial Agents↗
PubMed1999

pH and osmotic pressure inside biodegradable microspheres during erosion.

PURPOSE: To measure changes in pH as well as osmotic pressure in aqueous pores and cavities inside biodegradable microspheres made from polymers such as poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid -co- glycolic acid) (PLGA). METHODS: The internal osmotic pressure inside eroding PLA microspheres was analyzed with differential scanning calorimetry (DSC) in a temperature range of 10 to--25 degrees C. The osmotic pressure was calculated from the melting peaks of the aqueous phase using purity analysis. For pH determination, PLGA microspheres were loaded with a pH-sensitive spin probe which allowed the determination of pH by electron paramagnetic resonance (EPR). RESULTS: The osmotic pressure in PLA microspheres increased to 600 mOsm within four days and decreased to 400 mOsm after two weeks. The pH in PLGA microspheres in this study was < or =4.7. Basic drugs such as gentamicin free base or buffering additives led to a pH increase. In no case, however, did the internal pH exceed a value of 6 within 13 hours. CONCLUSIONS: DSC and EPR are useful techniques to characterize the chemical microenvironment inside eroding microspheres. This data in combination with detailed information on peptide and protein stability could allow in the future to predict the stability of such compounds within degradable polymers.

Algorithms↗
PubMed1998

Monitoring microviscosity and microacidity of the albumin microenvironment inside degrading microparticles from poly(lactide-co-glycolide) (PLG) or ABA-triblock polymers containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethyleneoxide) B blocks.

PURPOSE: The purpose of this study was to monitor the microenvironment of an encapsulated model protein during the release from biodegradable microparticles (MP) made from three different polymers, namely poly(lactide-co-glycolide) (PLG) and ABA-triblock polymers containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethyleneoxide) B blocks with an A:B ratio of 90:10 (ABA1O) and 70:30 (ABA30). METHODS: MP loaded with spin labeled albumin were prepared by a w/o/w technique. The particles were characterized by light scattering and electron microscopy. In vitro release of albumin was determined by size exclusion chromatography. Light microscopic experiments were conducted to visualize water penetration in the matrix. The protein microenvironment inside the degrading microparticles was characterized noninvasively by 2 GHz EPR spectroscopy. RESULTS: Water penetrated rapidly into all MP in the range of few minutes. A burst release was observed for PLG. The release from ABA block-polymers continued for over 14 days despite the rapid solubilization of the protein inside the microparticles. The initial microviscosity of the protein environment inside the ABA particles after exposure to buffer was 2 mm2/s and increased with time. A gradual decrease of the pH to a value of 3.5 was observed within the MP. CONCLUSIONS: The data indicate that the microviscosity and microacidity inside protein loaded microparticles can be studied nondestructively by EPR spectroscopy. Our results clearly demonstrate that ABA-block polymers are superior to PLG allowing a controlled release of proteins from swollen microspheres.

Albumins↗
PubMed1998

pH-sensitive imaging by low-frequency EPR: a model study for biological applications.

The use of pH-sensitive nitroxides, in conjunction with low-frequency EPR, offers a unique opportunity for non-invasive assessment of pH values (in the range 0 to 14) in living animals. In the present study, we have investigated the potential use of pH-sensitive nitroxide free radicals in conjunction with EPR imaging techniques at low and very low frequencies (280 MHz-2.1 GHz). In particular, we have measured the hyperfine splitting (hfs) of a pH-sensitive probe at three different EPR frequencies: 280 MHz, 1.1 GHz and 2.1 GHz. We have also developed EPR imaging experiments with phantoms simulating in vivo conditions, using pH-sensitive probes at 280 MHz (spatial-spatial) and 1.1 GHz (spectral-spatial). Finally, we discuss the actual sensitivity/resolution limits of the EPR imaging techniques at low frequencies. Practical applications of this method in the biomedical field are suggested for the continuous and non-invasive localization of pH in vivo.

Animals↗
PubMed1998

Pharmaceutical applications of in vivo EPR.

The aim of this article is to discuss the applications of in vivo EPR in the field of pharmacy. In addition to direct detection of free radical metabolites and measurement of oxygen, EPR can be used to characterize the mechanisms of drug release from biodegradable polymers. Unique information about drug concentration, the microenvironment (viscosity, polarity, pH) and biodistribution (by localized measurement or EPR Imaging) can be obtained.

Animals↗
PubMed1997

Reduction of carcinogenic chromium(VI) on the skin of living rats.

The reduction of chromate (Cr(VI)) on the skin of living rats was investigated using the technique of in vivo electron paramagnetic resonance (EPR) spectroscopy with a surface coil resonator. Topical application of aqueous solution of Cr(VI) on the skin of rats generated the transient species, Cr(V). Partial removal of the stratum corneum increased the rates of formation and decay of Cr(V), as well as Cr(V) signal intensity. The results demonstrate that skin represents one route for chromium to enter into animals and humans. The generation of reactive Cr(V) species in the reduction of Cr(VI) by the skin may play an important role in the mechanism of Cr(VI)-induced skin cancer. These findings indicate the potential for in vivo EPR spectroscopy for studying the metabolism of paramagnetic reactive species in chemical and biochemical reactions occurring in/on the skin of both small and large animals, and possibly humans.

Animals↗
PubMed1997

Noninvasive in vivo monitoring of drug release and polymer erosion from biodegradable polymers by EPR spectroscopy and NMR imaging.

Biodegradable polymers have attracted much attention as implantable drug delivery systems. Uncertainty in extrapolating in vitro results to in vivo systems due to the difficulties of appropriate characterization in vivo, however, is a significant issue in the development of these systems. To circumvent this limitation, noninvasive magnetic resonance techniques, electron paramagnetic resonance (EPR) and magnetic resonance imaging (MRI), were applied to characterize drug release and polymer degradation in vitro and in vivo. MRI makes it possible to monitor water content, tablet shape, and response of the biological system such as edema and encapsulation. The results of the MRI experiments give the first direct proof in vivo of postulated mechanisms of polymer erosion. Using nitroxide radicals as model drug releasing compounds, information on the mechanism of drug release and microviscosity inside the implant can be obtained by means of 1.2 GHz EPR spectroscopy. To be able to attribute nitroxide mobility to a particular layer of the implant, sandwich-like tablets were manufactured, taking advantage of the distinct spectral features of nitroxides containing different isotopes of nitrogen (15N vs 14N). The use of both noninvasive methods to monitor processes in vivo leads to new insights in understanding the mechanisms of drug release and polymer degradation.

Biodegradation, Environmental↗
PubMed1997

In vitro/in vivo comparison of drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides--a noninvasive approach by the combined use of electron paramagnetic resonance spectroscopy and nuclear magnetic resonance imaging.

PURPOSE: The purpose of this study was to compare drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides in vitro and in vivo in real time and with minimal disturbance of the investigated system. METHODS: P(FAD-SA) 20:80 and P(FAD-SA) 50:50 polymer tablets were loaded with the spin probe 3-carboxy-2,2,5,5-tetramethyl-pyrrollidine-1-oxyl (PCA) and implanted subcutaneously in the neck of rats or placed in 0.1 M phosphate buffer. 1.1 GHz EPR spectroscopy experiments and 7T MRI studies (T1 and T2 weighted) were performed. RESULTS: A front of water penetration was visible by MRI in vitro in the case of P(FAD-SA) 20:80, but not for P(FAD-SA) 50:50. For both polymers, the thickness of the tablets decreased with time and a insoluble, easy deformable residue remained. Important processes such as edema, deformation of the implant, encapsulation and bioresorption were observable by MRI in vivo. P(FAD-SA) 50:50 was almost entirely absorbed by day 44, whereas an encapsulated residue was found for P(FAD-SA) 20:80 after 65 days. The EPR studies gave direct evidence of a water penetration induced changes of the microenvironment inside the tablet. EPR signals were still detectable in P(FAD-SA) 20:80 implants after 65 days, while the nitroxide was released in vitro within 16 days. CONCLUSIONS: Important parameters and processes such as edema, deformation of the tablet, microviscosity inside the tablet and encapsulation can be monitored in real time by the combined use of the noninvasive techniques MRI and EPR leading to better understanding of the differences between the in vitro and in vivo situation.

Animals↗
PubMed1996

Nitric oxide oxidises a ferrous mammalian lipoxygenase to a pre-activated ferric species.

Nitric oxide is known as an inhibitor of soybean lipoxygenase-1. Investigating the interaction of a mammalian 15-lipoxygenase with nitric oxide, we found that this enzyme is also inhibited reversibly when incubated with nitric oxide for a short time period (5 s) under anaerobic conditions. This inhibition may be due to the formation of a dissociable lipoxygenase-nitric oxide complex. With longer incubation periods the ferrous lipoxygenase is oxidised to a ferric form. This oxidation renders the enzyme more susceptible to peroxide activation, causing a time-dependent shortening of the kinetic lag phase.

Animals↗
PubMed1996

Noninvasive measurement of the pH inside the gut by using pH-sensitive nitroxides. An in vivo EPR study.

The use of pH-sensitive probes permits the measurement of the proton activity in biological systems by EPR spectroscopy. To illustrate the potential of this technique for in vivo purposes, the authors took advantage of the oral administration of nitroxides to monitor the pH value inside the stomach of mice after administration of different antacidics. The results indicate that EPR can be a valuable tool to characterize the pH in vivo in a continuous and noninvasive way.

Animals↗
PubMed1995

In vivo detection of anthralin-derived free radicals in the skin of hairless mice by low-frequency electron paramagnetic resonance spectroscopy.

Free radicals were directly detected in vivo in the skin of hairless mice by low-frequency electron paramagnetic resonance spectroscopy after topical application of anthralin under pertinent therapeutic conditions. The electron paramagnetic resonance signal intensity increased steadily, reaching a maximum after about 1 d and decreased slowly in the following days, probably because of desquamation of the skin. We conclude from the spectroscopic features (single line with a line width of 6 gauss; g = 2.0036) and from the pharmacokinetic pattern that the observed signal arises from the final products of anthralin metabolism (ether-insoluble polymeric structures--"anthralin brown"). Two potential antioxidants, vitamin E and the spin trap tert-butylphenylnitrone, decreased the amount of the anthralin-derived radical that was formed. Neither vitamin E radicals nor tert-butylphenylnitrone spin adducts were observed. We suggest that electron paramagnetic resonance is a valuable tool for the noninvasive and direct in vivo monitoring of drug-induced radical formation in the skin under therapeutic conditions.

Animals↗
PubMed1993

Comparison of malondialdehyde and hydrogen peroxide modified CuZnSOD by EPR spectroscopy.

CuZn superoxide dismutase (CuZnSOD) contributes to the regulation of the steady-state concentration of reactive oxygen species in cells and minimizes pathological consequences induced by these reactive oxygen species. During the exaggerated formation of reactive oxygen species, often resulting from an activation of phagocytotic cells, CuZnSOD is administered with a therapeutic purpose. But inhibition of the endogeneous or administered CuZnSOD by products generated during the process of formation of reactive oxygen species (H2O2, HOCl, .OH, products of lipid peroxidation) might intensify cell damage. In this study, we compared the influence of malondialdehyde (MDA, high reactive molecule formed in lipid peroxidation) and H2O2 (known to inhibit the CuZnSOD) on bovine CuZnSOD. MDA reacted with CuZnSOD. The reaction was found to be both time- and concentration-dependent, which was demonstrated by the formation of fluorophors. EPR spectroscopy revealed that this reaction had no influence on the activity of CuZnSOD since the catalytic centre of the CuZnSOD was not effected by MDA. In contrast, H2O2 modified the catalytic centre which caused an activity decrease.

Animals↗
PubMed1993

Detection of free radicals in living mice after inhalation of DTBN by X-band ESR.

A new application of X-band electron spin resonance (ESR) is demonstrated for in vivo investigations on living mice. It is the first report on in vivo detection, identification, and localization of a free radical after uptake in the body of a living mammal by inhalation. The volatile di-tert-butyl-nitroxyl (DTBN) has been used as a suitable spin probe. After inhalation of DTBN, a superimposed ESR spectrum consisting of a polar (g = 2.0057; a = 1.65 mT) and a nonpolar paramagnetic species (g = 2.0061; a = 1.51 mT) was detected in mice tails. Collected blood exhibits only the polar spectrum. The decay of signals after removing of the DTBN-soaked swab follows first-order kinetics with k = 0.08 min-1.

Administration, Inhalation↗
PubMedDate not supplied

Gamma-sterilization-induced radicals in biodegradable drug delivery systems.

Electron paramagnetic resonance (EPR) spectroscopy (1.2 and 9.25 GHz, 25 degrees C) was used to characterize free radicals in gamma-ray sterilized biodegradable polymers of the type which are in clinical use. Free radicals were detected in all irradiated polymer samples. The temperature of irradiation (25 degrees C vs dry ice temperature) had only a minor influence on the yield of radicals and the shape of the EPR spectra. In contrast, the composition of the polymers and the drugs incorporated in them did strongly influence the amount of radiation-induced free radicals and their reactivity. In general, polymers with high melting points and crystallinity had the highest yields of radicals observable at room temperature. We were able to use the free radicals induced by the usual sterilization procedures to follow the penetration of water and the degradation of the polymers in vitro and in vivo. The ability of in vivo EPR to follow drug delivery noninvasively and continuously in vivo, using the free radicals induced in the usual sterilization process indicates that this approach could be applied immediately for the characterization of these drug delivery systems in experimental animals and in the near future should be able to be used in human subjects.

Animals↗