Biomedical subjects

B W Müller

Publications and source records attributed to B W Müller.

At least 37 records · Page 2Linked to original sources

PubMed1999

Physico-chemical characterization of interactions between erythromycin and various film polymers.

In this study the interactions between erythromycin and various polymers (Eudragit L100, shellac, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose acetate phthalate (HPMCP), and hydroxypropyl methylcellulose (HPMC)) were investigated. The polymer films containing drugs were prepared and characterized by the use of infrared spectroscopy, powder X-ray diffraction analysis, thermal analysis, thin layer chromatography, and nuclear magnetic resonance (NMR) spectroscopy. Preliminary studies of pure drug powders recrystallized in various organic solvent systems suggested a mixture of amorphous and crystalline forms whereas those recrystallized in water and organic solvent-water mixture led to the dihydrate form. Erythromycin in drug-polymer mixtures exhibited molecular dispersions in all six polymers studied. The amine salt interaction between the carboxyl group of the acid polymers and N-atom of erythromycin was indicated by the NMR technique. The solid solution of erythromycin in all polymer films studied was physically stable under stress conditions (8 degrees C/3 days and 40 degrees C/3 days for six cycles).

Anti-Bacterial Agents↗

PubMed1999

Critical properties of lactide-co-glycolide polymers for the use in microparticle preparation by the aerosol solvent extraction system.

The Aerosol Solvent Extraction System (ASES) process uses supercritical carbon dioxide for the production of microparticles. Since the critical temperature for this gas is at 304 K, polymers that are used in this process must fulfil certain requirements in crystallinity, and thermal behavior. This can be achieved by the use of blocked copolymers and thus the presence of semicrystalline microdomains in the polymers. However, changing the sequences of the comonomers dilactide and lactide often leads to polymers of low solubility due to long glycolide blocks. In this study, the critical properties of two blocked co-polymers were investigated, such as the blocked structure itself by (1)H-NMR and (13)C-NMR, the thermal behavior by differential scanning calorimetry (DSC), and the crystallinity by powder diffraction. The impact of these properties on microparticles formed by those polymers was also object of these studies. Additionally, two different model drugs, albumin and estriolm were embedded to investigate the impact of different polymer properties on drug content and release.

Aerosols↗

PubMed1999

Physicochemical properties of chitosan-lipid emulsions and their stability during the autoclaving process.

A new positively charged, submicronized fat emulsion with appropriate stability during the autoclaving process was developed. Only the emulsions prepared with a combination of ABA block co-polymer (F68) and chitosan were stable enough to resist the thermic shock induced by autoclaving sterilization. The results indicate that a mixed film consisting of the ABA block co-polymer and chitosan molecules was formed at the o/w interface with an overall positive surface charge. Conversely, a combination between chitosan with phospholipids and/or with a mixture of phospholipids with ABA block co-polymer showed a phase separation during autoclaving. A chitosan type with a low viscosity was used which was intended for a possible use in the ocular and parenteral application. An experimental factorial design 32 was used to investigate the effect of chitosan and F68 concentrations on the physicochemical properties of the system and consequently their influence on the stability of emulsions during autoclaving. Both size and surface charge of emulsions were significantly affected as a function of the chitosan concentration. Formulation with a mean particle size ranging from 125 to 130 nm and with a positive surface charge of 20-23 mV was achieved. Moreover, the chitosan emulsions were autoclaved without a significant change in their particle size. However, increasing the concentration of chitosan needs a higher amount of F68 in order to achieve stable emulsions during autoclaving. This may be due to the interaction between the positively-charged chitosan and the negatively-charged free fatty acids, which are contained in the oil phase (castor oil).

Biocompatible Materials↗

PubMed1999

A rapid and quantitative method for total fatty acid analysis of fungi and other biological samples.

A quantitative method for the one-step esterification and determination of absolute amounts of polyunsaturated fatty acids in biotechnologically produced fungal mycelia is proposed. A system of two internal standards was used to quantify the total fatty acid content of the samples by gas chromatography. The degree of methylation of the analyzed fatty acids was calculated using the internal standards, and subsequently this quotient was used to validate the derivatization and extraction reactions. By utilizing this degree of methylation, the corrected amounts of the various fatty acids in the sample can be calculated.

Chromatography, Gas↗

PubMed1999

Influence of neutron irradiation on Eudragit coated tablets: validation of neutron activation II.

The in vitro characteristics of enteric coated acetylsalicylic acid tablets and cores were compared before and after irradiation with thermal neutrons, 2, 4, 7 or 15 min at 1.1.1013 neutrons cm-2s-I. The irradiation procedure affected the coated formulation to a greater extent than the cores. Drug release from tablets was already affected after 2 min of exposure, whereas the cores showed no significant inhibition of release until after 15 min of irradiation, leading to the conclusion that the effects of irradiation were caused by a combination of changes both in the core and the coating. Both tablets and cores showed an increase in the disintegration time following irradiation. Scanning electron micrographs (SEM) of non-irradiated cores/tablets and cores/tablets irradiated for 15 min, showed clear differences in the structure of the surface. SEM of the tablets irradiated for 15 min, showed that the irradiation had caused the film to loosen from the core in several places. SEM of the cross-sections of both irradiated tablets and cores showed a partially melted surface above stacked layers with reduced porosity.

Acrylic Resins↗

PubMed1999

Influence of the coating thickness and type of oral delivery system (tablets, pellets) on the stability towards degradation by neutron irradiation. Validation of neutron activation III.

Enteric coated dexchlorpheniramine maleate (DCPA) tablets and pellets with varying coating thickness were subjected to several in vitro tests after irradiation by thermal neutrons in a flux of 1. 1 x 10(13) n cm-2 s-1 for 2, 4 or 15 min. The appearance of the tablet formulation changed extensively after exposure of the tablets to pile radiation. The irradiation caused the film to loosen from the surface of the core, indicating the generation of gases during the irradiation process. Already after irradiating the tablets for 2 min the disintegration and dissolution behaviour were significantly changed. The extent of tablet damage increased with increasing time of exposure and increasing thickness of the coating. Compared with the tablet formulation, the cores could resist a larger amount of irradiation since dissolution behaviour of the cores was only affected after 15 min of irradiation. This indicates that the irradiation procedure initially affects the coating of the formulation. Although the dissolution behaviour of the pellet formulations changed significantly after the irradiation procedure, the changes were too small to be attributed exclusively to radiation damage.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

In vitro investigation of the effect of various isotonic substances in parenteral emulsions on human erythrocytes.

The hemolytic behaviour of human erythrocytes in parenteral emulsions containing various isotonizing substances (xylitol, sorbitol and glycerol) was studied. It was found that complete hemolysis of human erythrocytes occurred in parenteral emulsions with isotonic or isosmotic concentration of glycerol after 5 min, whereas emulsions which contained an isotonic concentration of xylitol or sorbitol did not show any hemolysis after 40 min. Conversely, formulations with different concentrations of glycerol in an isotonic solution of sorbitol did not show any hemolytic behaviour after 40 min. It appeared that all the hemolytic phenomena encountered in glycerol were of an isotonic character since hemolysis was totally prevented by the inclusion of an isotonic concentration of sorbitol. According to these in vitro results it seems that glycerol, a commonly used substance in commercial parenteral emulsions, may not be the best isotonizing substance.

Dose-Response Relationship, Drug↗

PubMed1999

Radiolabelling of parenteral O/W emulsions by means of neutron activation.

Parenteral O/W emulsions containing lanthanide fatty acid derivatives were prepared. With regard to enhancing the incorporation efficiency of the neutron activatable excipients, the addition of the non-ionic co-emulsifier Solutol HS 15 proved to be most suitable. Comparing the different chain lengths of the fatty acids, the long chain fatty acid derivative lanthanide(tri)stearate seemed to be superior in strengthening the interfacial layer. After neutron activation, the physical and chemical stability of the irradiated formulations was evaluated. The chemical stability, indicated by the concentration of lyso phosphatidylcholine as the degradation product of the main emulsifier, was shown to be dependent on the irradiation time. By applying a neutron flux of 2.1 x 10(13) neutrons/cm2 per s, the maximum should not rise above 60 s. The physical stability indicated by the particle size distribution was affected by the presence of the non-ionic co-emulsifier. Concerning the amount of radiation necessary for in vivo biodistribution studies the maximum load of Samarium fatty acid derivatives did not yield sufficient radioactivity levels. However, Europium derivatives could be shown to be suitable for in vivo studies.

Emulsions↗

PubMed1999

Determination of liposome partitioning of ionizable drugs by titration.

Drug partitioning to liposomes has been suggested as a model for partitioning to biomembranes but has been lacking a rapid analytical assay useful for drug screening. A fast pH-metric titration method for the determination of liposome partitioning of ionizable drugs using small unilamellar phosphatidylcholine vesicles prepared by sonic homogenization has been successfully developed, enabling the use of high lipid-to-drug ratios. Liposome-water partition coefficients of diclofenac and propranolol were determined to study the impact of varying titration parameters, temperature, equilibration time, lipid, and liposome types on the partitioning. To validate this method, the results were compared to literature values generated with different techniques and to pH-metric titration results with large unilamellar vesicles. The rapid pH-metric assay gave liposome partitioning data for the two model compounds which were consistent with other analytical techniques and liposome types.

Chemical Phenomena↗

PubMed1999

Drug liposome partitioning as a tool for the prediction of human passive intestinal absorption.

PURPOSE: Appropriate physicochemical parameters are desired for the prediction of passive intestinal drug absorption during lead compound selection and drug development. METHODS: Liposome distribution coefficients measured titrimetrically and solubility data at pH 6.8 were used to characterize 21 structurally diverse ionizable drugs covering a range from <5% to almost complete absorption. RESULTS: A sigmoidal relationship was found between the percentage of human passive intestinal absorption and a new absorption potential parameter calculated from liposome distribution data and the solubility-dose ratio. In contrast, the human absorption data did not correlate with an octanol-based absorption potential or partitioning data alone. Poor correlations were found between liposome and octanol partitioning of ionic species or nonionic bases indicating the profound differences of the partitioning systems. CONCLUSIONS: Liposome distribution coefficients of ionizable drugs derived by a pH-metric titration were successfully used to calculate a parameter that correlates with the percentage of passive intestinal absorption in humans. Profound differences between liposome and octanol partitioning were found for a highly diverse set of species. This titration technique may serve to generate liposome partitioning data for the selection and optimization of lead compounds and in drug development.

Humans↗

PubMed1999

Solubility and stability of lorazepam in bile salt/soya phosphatidylcholine-mixed micelles.

In the present study, the solubility and stability of the drug lorazepam, which was solubilized in bile salt/soya phosphatidylcholine-mixed micelles (BS/SPC-MMs), were investigated. The solubility of lorazepam could be enhanced substantially in different bile salts and also in sugar ether, whereas the solubility in Pluronic F68 (Pl.F68) was of lower order. Moreover, the addition of SPC to different BS solutions greatly enhanced their solubilizing capacities toward lorazepam; this could be correlated with the ability of the formed MM to reduce the surface tension. The stability study showed that lorazepam degradation followed apparent first-order degradation kinetics in phosphate buffer, as well as in the BS/SPC-MM, with highly enhanced stability in the latter system. The stabilizing effect of BS/SPC-MM was higher in the case of trihydroxy BS than for dihydroxy BS. From an Arrhenius plot with degradation constants in a temperature range from 30 degrees C to 60 degrees C, a shelf stability of about 10 months could be calculated for BS/SPC-MM at 5 degrees C. The solubility studies in BS/SPC-MM showed a recrystallization and a polymorphic transition from modification II to I.

Anticonvulsants↗

PubMed1999

Importance of the fraction of microcrystalline cellulose and spheronization speed on the properties of extruded pellets made from binary mixtures.

The aim of the study was to prove the importance of the binary mixture composition and spheronization speed on pellet properties. Extrudates from different binary mixtures of microcrystalline cellulose (MCC) and dicalcium phosphate dihydrate were prepared with a power-consumption-controlled extruder and spheronized at different speeds. The water content of the extrudate for the production of spherical pellets was evaluated. The pellets were characterized in terms of size, shape, porosity, mechanical properties, and disintegration. The fraction of MCC in the binary mixtures had the highest impact on the pellet properties. With an increasing fraction of MCC more water was required for successful pelletization, size and porosity of the pellets decreased, and the surface tensile stress increased. These observations were evaluated using the "sponge" and the "crystallite--gel" models for MCC. The latter led to the conception that an extrudate consists of two phases: a percolating crystallite--gel phase formed by MCC and water during extrusion and a filler phase formed by the second component of the binary mixture. This two-phase concept provides explanations for the extent of shrinking during drying and for the disintegration behavior. The spheronization speed had an influence on the size but not on porosity or surface tensile stress of the pellets. The best results were obtained at intermediate spheronization velocities of 10 and 13.4 m/sec. Fundamental properties of extrudates and pellets can be described by applying a two-phase concept of the crystallite--gel model.

Algorithms↗

PubMed1998

Solubility and stability of tetrazepam in mixed micelles.

The solubility and stability of the chemically unstable drug tetrazepam which has poor water solubility have been studied in bile salts-phosphatidylcholine-mixed micelles (BS-PC-MM). The solubilization potential of BS-PC-MM was much higher than that of BS alone. The use of soya-PC (SPC) instead of egg-PC (EPC) increased the solubilization capacity of MM. The results of the stability studies indicated first order degradation kinetics in most cases under aerobic conditions. An Arrhenius plot could be constructed in a temperature range from 30 to 60 degrees C in sodium deoxycholate-SPC-MM (SDC-SPC-MM) as well as in phosphate buffer at pH 7.4. Sodium glycocholate-SPC-MM (SGC-SPC-MM) interfered with the degradation kinetics and displayed better stabilizing effects under both aerobic and anaerobic conditions. The addition of ascorbic acid (AA) protected tetrazepam to some extent, whereas Na2SO3 or Na2S2O5 were incompatible with it. Formulating tetrazepam in SGC-SPC-MM containing 0.1% AA resulted in a shelf stability of more than 1 year under anaerobic conditions.

Anti-Anxiety Agents↗

PubMed1998

Metered-dose inhaler formulations with beclomethasone-17,21-dipropionate using the ozone friendly propellant R 134a.

Metered-dose inhalers (MDI) are the most widely prescribed devices in the treatment of lung diseases but the continued use of chlorofluorocarbons (CFC) as propellants has made them unpopular due to their influence on the stratospheric ozone layer. The purpose of this study was to show possibilities of formulating beclomethasone-17,21-dipropionate (BDP) with the alternative propellant R 134a as a solution or as a suspension-type metered-dose inhaler. Influencing factors such as surfactant concentration, cosolvent content and actuator tube design were investigated. Metered-dose inhaler formulations were manufactured using a pressure filling technique. The resulting formulations were characterized with regard to their emitted fine particle fraction using the two-stage impinger, BP 93. Fine particle fraction was found to be independent on the surfactant concentration but highly dependent on the cosolvent content and the actuator tube design. In vitro fine particle fractions of 50% were obtained with solution phase MDIs. Formulating BDP as a suspension resulted in unstable dispersions in most cases because of the partial solubility of the drug in the liquified propellant. Stable suspension formulations gave an in vitro fine particle fraction of about 30%. A comparison with established marketed BDP suspension formulations which were found to emit a fine particle fraction in the range 10-50% showed the equivalence of the new CFC-free formulations.

Aerosol Propellants↗

PubMed1998

Size controlled production of biodegradable microparticles with supercritical gases.

Polymer microparticles were produced by means of the aerosol solvent extraction system. A solution of 3% w/w poly(L-lactic acid) in dichloromethane was sprayed into supercritical or near critical carbon dioxide gas phase. The mean particle size by volume moderately depended on the nozzle diameter and the spraying pressure used. When the polymer solution was saturated with carbon dioxide up to 5.0 MPa, the particle size and morphology of the particles were unchanged and the product was less agglomerated. Microparticles with mean diameters from 6 to 50 microns were achieved by decreasing the carbon dioxide density from 690 to 250 kg/m3. The surface structure of the particles sprayed in low density carbon dioxide showed cracks and holes. All other particles were non-porous with a smooth surface.

Biodegradation, Environmental↗

PubMed1998

Mixture experiments with the oil phase of parenteral emulsions.

The effects of the oil phase as a mixture (binary, ternary) on the emulsion droplet size were investigated. The binary trials were performed with the aid of simplex lattice design with constraints. Droplet diameter was evaluated in terms of the oil phase viscosity and the interfacial tension between oil phase and the aqueous phase. As a result it could be shown that increasing the oil phase viscosity as a function of castor oil concentration led to a greater increase in particle size. At the same time, decreasing the interfacial tension of the oil phase as a function of oleic acid or oleic alcohol was shown to have a negligible effect on the particle size of the dispersed phase. A further aim was to find out a formulation by using a ternary oil phase resulting in a stable emulsion which could pass the autoclaving process. It was ascertained that oleic acid as a part of the oil phase led to proper formulation showing a satisfactory stability.

Castor Oil↗

PubMed1998

Increasing drug solubility by means of bile salt-phosphatidylcholine-based mixed micelles.

Study of the solubilization of commercial grades of soya phosphatidylcholine (SPC) with different purities by bile salts (BS) indicated that only highly pure grades of SPC are suitable for the preparation of clear solutions of BS/SPC-mixed micelles (BS/SPC-MM). The solubilizing capacity of different BS towards SPC increased in the following order; Sodium cholate (SC) < sodium deoxycholate (SDC) < sodium glycocholate (SGC). Moreover, egg phosphatidylcholine (EPC) was solubilized to a higher extent than SPC. Furthermore, the solubility study of different drugs in the prepared MM showed substantial enhancement of solubility, the extent of which is essentially affected by the chemical nature of the drug and the composition of MM. Benzodiazepine drugs such as clonazepam, tetrazepam, diazepam, and lorazepam displayed higher affinity for MM compared with BS alone, whereas steroidal drugs, such as estradiol, prednisolone and progesterone, compared with benzodiazepines, displayed relatively higher affinity for BS alone. The solubilizing capacity of MM for the different drugs was increased to different degrees by the addition of benzyl alcohol which was comparable to the solubility of the drug in pure benzyl alcohol. The interaction between benzyl alcohol and the drug in MM could be proved by NMR.

Benzyl Alcohol↗

PubMed1998

Metered-dose inhaler add-on devices: an in vitro evaluation of the BronchoAir inhaler and several spacer devices.

Spacer devices minimize the drug deposition in the oropharyngeal region as they retain between 30% and 50% of the nominal drug dose. Additionally, they should increase the fine particle fraction of the emitted aerosol. A new effort to increase the lung deposition was the design of a new actuator, the BronchoAir inhaler, (BronchoAir Medizintechnik GmbH, Munich, Germany). This study was carried out to evaluate the usefulness of this new actuator device by comparing its fine particle fraction with that emitted with the standard actuators and with spacer devices. The fine particle fraction's of commercially available metered dose inhalers (MDIs) marketed with specific spacers were determined using a multistage liquid impinger (MSLI). The effect of the BronchoAir inhaler on fine particle fractions was quite dependent on the formulation causing a decrease as great as 43% with Beclomet forte (beclomethasone-17, 21-dipropionate [BDP]) and an increase as great as 35% with Arubendol (salbutamol) but causing a difference of less than 20% with the other six tested formulations. Deposition in the upper stages of the impinger was sometimes higher than it was for the standard actuator. Spacer devices decreased the deposition in the upper stages of the impinger significantly, and in some cases, the fine particle fractions were also decreased. Varying the spacer design showed the superiority of large-volume open spacers compared with spacers with other designs.

Bronchodilator Agents↗