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Biomedical subjects

B W Müller

Publications and source records attributed to B W Müller.

15 recordsLinked to original sources
PubMed1992

Complexation of steroid hormones with cyclodextrin derivatives: substituent effects of the guest molecule on solubility and stability in aqueous solution.

The inclusion complexation of homologous derivatives of steroid hormones with cyclodextrins and 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD) was investigated with regard to underlying structure-interaction relationship. The interaction was studied by phase solubility analysis and stabilization effects of complex formation with 2-HP-beta-CD. The solubilizing and stabilizing abilities of 2-HP-beta-CD were generally more effective for testosterone derivatives than for estradiol esters. Within a homologous series of steroid hormones, the steepest linear solubility isotherms were found for 17-methyl and 3-methyl derivatives. The solubilization of steroid esters by 2-HP-beta-CD depended on the structure and length of the ester side chain. The interaction of 2-HP-beta-CD with the steroids was hindered by long-chain fatty acid ester groups. With increasing length of the side chain, a decline of the isotherms occurred and the phase solubility behavior changed from linear to exponential. Contrary to expectations, benzoylation of steroids considerably decreased the guest-host interaction. The observed rates of degradation of the steroid esters were significantly reduced by 2-HP-beta-CD, depending on the chain length, and correlated well with the order found in phase solubility analysis. The degradation showed no deviations from pseudo-first-order kinetics, and the degradation mechanism was not changed because of complexation. The results suggest that interaction of 2-HP-beta-CD with steroid esters involves the ester functions of the prodrugs and is more suitable for unsubstituted guest molecules.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Influence of supersaturation on the pharmacodynamic effect of bupranolol after dermal administration using microemulsions as vehicle.

Transdermal absorption of drugs is limited by the stratum corneum, which serves as a diffusion barrier. This barrier might be overcome by enhancing the thermodynamic activity of the drug vehicle. Thermodynamic activity is particularly high in supersaturated systems because it is directly correlated with the degree of saturation. Since supersaturated systems are not stable, they were formed in situ by application of water-free microemulsion bases. These water-free microemulsion bases saturated with the drug were applied to New Zealand albino rabbits with an occlusive patch. Occlusion leads to water uptake from the skin due to hydratation and changes the microemulsion base into a microemulsion. The microemulsion will become supersaturated as a result of decreasing solubility of the drug with increasing water content. The pharmacodynamic effect of the model drug bupranolol in vivo was investigated over a 10-hr time period. The in vitro solubility of bupranolol was examined with respect to the water content. The solubility vs water content curves were compared to the effect vs time curves. The microemulsions and their individual components were studied, and the effect vs time curves were inversely correlated with the solubility vs water content curves.

Administration, Cutaneous↗
PubMed1992

Optimization of a matrix tablet formulation using a mixture design.

The simplex centroid design was applied to the optimization of a modified release tablet formulation. A base granulation was made with the active ingredient naftidrofuryl. The variables investigated included fractions of the excipients microcrystalline cellulose, lactose and dicalcium phosphate dihydrate. The release rate, crushing strength, friability and weight variation were determined as response parameters. Mathematical models were fitted to the data obtained by the lattice method, described by Scheffé and by means of multiple linear regression. Regression analysis indicated a relatively good fit of the models. On the basis of the regression models, contour plots were constructed. An increase in the amount of dicalcium phosphate caused lower release rate and increased weight variation. An increase in the content of lactose showed lower strength and increased friability, whereas an increase in the amount of microcrystalline cellulose had the opposite effect.

Chemistry, Pharmaceutical↗
PubMed1991

Interaction of prostaglandin E1 with alpha-cyclodextrin in aqueous systems: stability of the inclusion complex.

Prostavasin, an inclusion complex of prostaglandin E1 (PGE1) with alpha-cyclodextrin (alpha-CD), is used in the therapy of thrombosis. Nuclear magnetic resonance measurements have been made to study the interaction of PGE1 with alpha-CD. The observed interaction (chemical shift) and the derived dissociation constant prove that only weak interaction forces are operative and that complete dissociation occurs upon dilution.

Alprostadil↗
PubMed1991

Effect of hydrotropic substances on the complexation of sparingly soluble drugs with cyclodextrin derivatives and the influence of cyclodextrin complexation on the pharmacokinetics of the drugs.

The influence of hydrotropic compounds on complex formation by 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD) was investigated with methyltestosterone (MeT). Various representatives of the lyotropic series were used for this purpose. Additive hydrotropic effects were observed for nicotinamide and urea, which disrupt the water structure, while structure formers such as sorbitol exerted negative effects. The effects of hydrotropic substances on the phase solubility relationship of MeT showed that inclusion complex formation with 2-HP-beta-CD depends on the degree of ordering of the solvent and is apparently subject to entropy effects. Combined systems comprising 2-HP-beta-CD and auxiliary substances with various underlying solubilizing principles were also investigated. Combination of 2-HP-beta-CD with conventional solubilizers, such as 1,2-propylene glycol or sodium deoxycholate, reduced the solubilization capacity of 2-HP-beta-CD. Competitive displacement of the inclusion molecule from its 2-HP-beta-CD complex by sodium deoxycholate suggested that cholesterol participates in the release mechanism of the inclusion molecule under in vivo conditions. The spontaneous release of complexed drug molecules could indirectly be shown on the basis of the spontaneous action of a complexed dihydropyridine derivative after iv administration in rats. The bioavailability of an investigational drug in cynomolgus monkeys could be enhanced sevenfold by inclusion complexation with 2-HP-beta-CD.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

Investigations into the pharmacodynamic effects of dermally administered microemulsions containing beta-blockers.

Water uptake from the skin changes dermally applied near-saturated solutions of beta-blockers in microemulsion-bases into supersaturated microemulsions. Due to an enhanced thermodynamic activity, high absorption rates are expected from these preparations. The pharmacodynamic effect after dermal administration of such preparations has been evaluated using rabbits as a suitable in-vivo model. The dose dependency, influence of lipophilicity and of the thermodynamic activity of the drug is described. Assessment of dermal doses which were therapeutically equivalent to i.v. doses as, for example, shown with carazolol is possible. Although not all observed pharmacodynamic effects were due to these influences but rather due to the numerous other skin-vehicle-drug interactions which could not be explained with this model, the presented in-vivo model is helpful in evaluation of beta-blockers which were suitable candidates for transdermal administration.

Administration, Cutaneous↗
PubMed1991

Pharmacodynamic effects of transdermal bupranolol and timolol in vivo: comparison of microemulsions and matrix patches as vehicle.

Transdermal administration of drugs possesses several advantages in therapy, but is limited by generally poor penetration through the skin. The aim of this study was to assess whether in vivo transdermal absorption could be enhanced by using microemulsions (ME) as vehicles. Water uptake from the occluded skin changes the water-free microemulsion base (MEB) into a ME. The increasing content of water decreases the solubility of apolar drugs. This leads to in situ formation of a super-saturated ME that possesses a particularly high absorption rate due to the enhanced diffusion pressure of the drug. A saturated solution of the model drugs bupranolol (B) and timolol (T) in a water-free microemulsion base was applied to an clipped area of the dorsal skin of rabbits with an occlusive patch. Evaluations were made in comparison to matrix patches (M) containing 1.2 mg/cm2 B or 2.0 mg/cm2 T. The beta-blocker dose applied was 2.0 mg/kg body weight throughout the study. The measured parameter of the pharmacodynamic effect was the maximal heart rate (HR) after an i.v. bolus injection of a standard dose of isoproterenol. Observations were made in different intervals over a 10-h time period after application of the patches. The response to isoproterenol was calculated as beta-blocker effect. Faster increasing effects and higher maxima for both drugs was found after application in MEB compared to M. After administration of B and T in MEB the effects were found to be identical, with a maximum (85-90%) after 2 h. Application in M showed B to be less effective (34%, 10h no plateau) than T (74%, 10h). Therefore microemulsions represent an improved vehicle for transdermal administration of test drugs.

Administration, Cutaneous↗
PubMed1990

Effect of cyclodextrin derivatives on indomethacin stability in aqueous solution.

The effect of various cyclodextrins (CD) and cyclodextrin derivatives on indomethacin stability in phosphate buffer, pH 7.4, was investigated. The influence of CD-ring size, type of substituent, degree of substitution, substitution pattern, and influence of CD concentration were monitored. The indomethacin complex in solution was studied by 1H-NMR spectroscopy to develop a molecular inclusion model. The most favorable ring size for the stabilization of indomethacin was the beta-CD. The beta-CD derivatives inhibited the hydrolysis of indomethacin more effectively than the parent CD. Among the studied CD derivatives, those with lipophilic substituents, such as ethyl or methyl, were superior to those with hydrophilic substitutents. The more hydroxyl groups of the glucose moiety are substituted, the better is the stabilizing effect. Further, the p-chlorobenzoic part of the indomethacin molecule is included in the CD channel.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1990

Stability of gonadorelin and triptorelin in aqueous solution.

The influence of pH, temperature, various buffer species at different concentrations, and ionic strength on the stability of gonadorelin and triptorelin in aqueous solution has been studied using stability-indicating high-performance liquid chromatographic methods. The degradation behavior of both peptides is similar. The maximum stability of both peptides was shown to be at an approximate pH of 5.0. Acetate has the most favorable effect on stability, while phosphate causes higher degradation. Varying the concentration of acetate buffer does not affect the degradation behavior of the peptides. A higher phosphate concentration in buffer solutions causes higher degradation, however. The ionic strength of buffer solutions has no significant influence on stability. Solutions of gonadorelin and triptorelin, respectively, buffered with acetate (0.1 M, pH 5.0) with 3% (w/v) mannitol as an additive show a predicted t90% of 9.0 years and 7.7 years at 20 degrees C, respectively.

Acetates↗
PubMed1986

Hydroxypropyl-beta-cyclodextrin derivatives: influence of average degree of substitution on complexing ability and surface activity.

The average degree of substitution of mixtures of hydroxypropyl-beta-cyclodextrin derivatives has a large influence on the complexing abilities and physiochemical properties of the derivatives. A low degree of substitution is preferable, since these derivatives show the best complexing properties and, at the same time, low surface activities.

Chemistry, Pharmaceutical↗
PubMed1984

Particle size analysis of latex suspensions and microemulsions by photon correlation spectroscopy.

The particle size in microemulsions and other highly dispersed systems was determined by means of photon correlation spectroscopy (PCS). As PCS cannot be applied to highly concentrated dispersed phases, the measurement accuracy was tested for its dependence on the particle concentration using latex suspensions. The data obtained by clipping and scaling were compared. The particle size determination was expected to provide information about the influence of the structure of the surfactant system on microemulsions, using a homologous alcohol series as cosurfactant and potassium oleate as surfactant. In this system the region of solubilization is characteristically divided from the region of microemulsification by a zone of instability. Furthermore, there are distinct differences in mean particle sizes between microemulsions (9-30 nm) and micellar solutions (4-6 nm).

Alcohols↗
PubMed1984

Particle size distributions and particle size alterations in microemulsions.

Several component diagrams for different alcohols as cosurfactants and potassium oleate as the surfactant were investigated. Between the regions of the water-in-oil microemulsion and the micellar solution (reverse micelles), and diagrams showed a zone of instability which was determined by particle size analysis by means of photon correlation spectroscopy (PCS). The polydispersity of the internal phase was determined at the instant of microemulsion formation and after fixed intervals of storage. At the edge of the microemulsion region, a rapid increase in particle size due to coalescence followed by breaking was observed. If a slow transition toward the region of solubilization could be seen by a slow decrease of the droplet size, coalescence was observed after storage. In the middle of the microemulsion region, the particle radius, however, was almost constant for a long interval. The velocity of the microemulsion formation depended on the alcohol used. In some cases a very fast formation (milliseconds) was observed; in others, macroemulsions were formed which became transparent within a few hours or days. PCS was used to follow the dynamic process of formation and breaking of such systems with droplet diameters of 5-200 nm by obtaining the mean hydrodynamic diameters. Distribution curves were calculated by the Laplace transform of the correlation function. The practicability of the method was demonstrated with mono- and polydispersed latex suspensions and microemulsions.

Emulsions↗
PubMed1979

Semisynthetic bicyclomycin derivatives: preparation and antibacterial evaluation.

A number of semisynthetic bicyclomycin derivatives have been prepared by modifications at various sites of the molecule. The preparation, characterization and antimicrobial evaluation of the new compounds is described. In contrast to bicyclomycin itself, the new derivatives 48 and 58 are also active against Proteus species. Otherwise, the antibacterial potency of the bicyclomycin molecule was found to be very sensitive to structural changes.

Animals↗