Biomedical subjects

Bernd W Müller

Publications and source records attributed to Bernd W Müller.

14 recordsLinked to original sources

PubMed2006

Application of aerosol solvent extraction system (ASES) process for preparation of liposomes in a dry and reconstitutable form.

The aerosol solvent extraction system (ASES) process was applied to prepare liposomes in a dry and reconstitutable form. Dry ASES microparticles containing miconazole (MCZ) as a model drug were prepared by an optimized ASES process with various compositions of spraying solution containing phosphatidylcholine, cholesterol, and Poloxamer 407. The influence of such compositions and the pH of hydration medium on the physico-chemical properties of the produced microparticles were investigated before and after hydration. At optimized conditions, partially crystalline, spherical, and nonporous microparticles associated in aggregates varying from a few microns to 40 microm were produced with the residual content of methylene chloride and methanol lower than 30 and 86 ppm, respectively. The percentage of drug recovered in the produced microparticles was increased with an increase of the drug concentration in the spraying solution. The entrapment efficiency of hydrated MCZ microparticles was improved by increasing the pH of the hydration medium.

Aerosols↗

PubMed2004

Influence of process parameters in the ASES process on particle properties of budesonide for pulmonary delivery.

Budesonide was micronized by precipitation in supercritical carbon dioxide by using the aerosol solvent extraction system at various process conditions. The process is characterised by spraying an organic solution of budesonide into the supercritical fluid (SCF), precipitation of the drug in the SCF and extraction and recovery of the solvent. The micronized budesonide particles were characterized physico-chemically for their morphology, crystallinity, size distribution and for their aerodynamic behaviour. The particle size distribution of the powder products was similar, regardless of the process conditions used for the crystallization. Also, the morphology of the particles did not differ between the batches. However, the aerodynamic properties of the precipitated batches were significantly different between the batches produced and as compared to a jet-milled budesonide powder. In conclusion, the process conditions in the SCF precipitation may influence the aerodynamic properties, although other physico-chemical parameters appear to be similar.

Administration, Inhalation↗

PubMed2004

W/O/W multiple emulsions with diclofenac sodium.

The disperse oil droplets of W/O/W multiple emulsions contain small water droplets, in which drugs could be incorporated, but the structure of these emulsions is also the reason for possible instability. Due to the middle oil phase which acts as a 'semipermeable' membrane the passage of water across the oil phase can take place. However, the emulsions have been produced in a two-step-production process so not only the leakage of encapsulated drug molecules out of the inner water phase during storage but also a production-induced reduction of the encapsulation rate should be considered. The aim of this study was to ascertain how far the production-induced reduction of the encapsulation rate relates to the size of inner water droplets and to evaluate the relevance of multiple emulsions as drug carrier for diclofenac sodium. Therefore multiple emulsions were produced according to a central composite design. During the second production step it was observed that the parameters pressure and temperature have an influence on the size of the oil droplets in the W/O/W multiple emulsions. Further experiments with different W/O emulsions resulted in W/O/W multiple emulsions with different encapsulation rates of diclofenac sodium, due to the different sizes of the inner water droplets, which were obtained in the first production step.

Diclofenac↗

PubMed2004

A method for direct preparation of chitosan with low molecular weight from fungi.

By modifying the common method for the preparation of chitosan from fungi, low molecular weight chitosan with an average MW of 4.5 x 10(4) g/mol and a numerical MW of 1.7 x 10(4) g/mol can be directly extracted from the raw material without the need of thermal or chemical depolymerization. Based on the solubility of low molecular chitosan up to alkaline pH ranges, reprecipitation and washing with ethanol is required to keep the low molecular fraction within the preparation. The use of water for washing between the preparation steps would cause solving and discarding of the low molecular chitosan. The chitosan was analyzed by laser light scattering and 1H-NMR spectroscopy.

Absidia↗

PubMed2004

Micron-size drug particles: common and novel micronization techniques.

Drug powders containing micron-size drug particles are used in several pharmaceutical dosage forms. Many drugs, especially newly developed substances, are poorly water soluble, which limits their oral bioavailability. The dissolution rate can be enhanced by using micronized drugs. Small drug particles are also required in administration forms, which require the drug in micron-size size due to geometric reasons in the organ to be targeted (e.g., drugs for pulmonary use). The common technique for the preparation of micron-size drugs is the mechanical comminution (e.g., by crushing, grinding, and milling) of previously formed larger particles. In spite of the widespread use of this technique, the milling process does not represent the ideal way for the production of small particles because drug substance properties and surface properties are altered in a mainly uncontrolled manner. Thus, techniques that prepare the drug directly in the required particle size are of interest. Because physicochemical drug powder properties are decisive for the manufacturing of a dosage form and for therapeutic success, the characterization of the particle surface and powder properties plays an important role. This article summarizes common and novel techniques for the production of a drug in small particle size. The properties of the resulting products that are obtained by different techniques are characterized and compared.

Animals↗

PubMed2003

In vitro characterization of jet-milled and in-situ-micronized fluticasone-17-propionate.

Particle properties are decisive for therapeutic efficiency of an inhaled pulmonary drug. Jet-milling as the common way for micronization of inhaled powder drugs shows several disadvantages such as a non-homogeneous particle size distribution and unnatural, thermodynamically-activated particle surfaces causing a high agglomeration behavior. For pulmonary use in a dry powder inhaler (DPI) beside a small particle size, a good de-agglomeration activity is required. In this study, fluticasone-17-propionate (FP) is in-situ prepared in a respirable particle size by a controlled crystallization technique. First, the drug is dissolved in acetone and precipitated by a solvent change method in the presence of a cellulose ether (HPMC) as stabilizing hydrocolloid. By rapidly pouring the drug solution into the polymer-rich water phase, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth simultaneously by the presence of the hydrophilic polymer. This dispersion was then spray-dried. The mean particle size of the drug was around 2 microm and consequently in the respirable range. The physico-chemical properties of the in-situ-micronized drug were compared to those of an unmilled and a jet-milled quality. Differences in the X-ray patterns and amorphous parts could be detected for the jet-milled but not for the in-situ-micronized drug. In addition, the aerodynamic behavior of the engineered and the jet-milled FP was analyzed using the FlowCaps inhaler as delivery device and compared to the commercial product Flutide Diskus. The fine particle fraction (FPF) (<5 microm) was increased four-fold from approximately 9% for the jet-milled drug to approximately 40% for the in-situ-micronized drug when the pure drug powder was dispersed with the FlowCaps device.

Androstadienes↗

PubMed2003

Microcrystals for dissolution rate enhancement of poorly water-soluble drugs.

Slight dissolution rates related to poor water-solubility are one of the well-known difficulties to be covered during the development of new drug substances. The poorly water-soluble drug ECU-01, a low molecular enzyme-inhibitor with anti-inflammatory properties for oral administration, shows a poor dissolution rate. This study is intended to enhance the drug dissolution rate by using microcrystals. The common way for micronization is the milling of previously formed larger crystals. However, milling shows several disadvantages as the newly created surfaces are thermodynamically activated due to the high energy input and not naturally grown. In this study microcrystals were not produced using any cutting up techniques, but only by association. Naturally grown microcrystals were prepared by a precipitation method in the presence of stabilizing agents (e.g. gelatin, chitosan, different types of cellulose ethers) followed by spray-drying of the formed dispersion. First the drug was dissolved in acetone and then precipitated by rapid pouring an aqueous solution of the stabilizer into the drug solution. Particularly, cellulose ethers were able to form stable and homogeneous dispersions of microcrystals (mean particle size = 1 microm) showing a tight particle size distribution. By spray-drying, the drug powder was obtained. The dissolution rate is significantly enhanced (common drug: 4% after 20 min/microcrystals 93% after 20 min) due to the large surface, which is hydrophilized by adsorbed stabilizers as shown by the decreased contact angle (65 and 30 degrees, respectively).

Anti-Inflammatory Agents↗

PubMed2003

Micronization of anti-inflammatory drugs for pulmonary delivery by a controlled crystallization process.

Jet-milling as the common way for micronization of drugs shows several disadvantages. Drug powder properties are decisive for pulmonary use because, besides a small particle size, a good deagglomeration behavior is required. In this study, several anti-inflammatory drugs [beclomethasone-17,21-dipropionate (BDP), betamethasone-17-valerate (BV), triamcinolone acetonide, ECU-R2, budesonide, and prednisolone] were micronized by controlled crystallization without any milling processes. First the drug is dissolved in an organic solvent (BDP/BV: 4%; ECU-R2: 1% in acetone) and precipitated by a solvent change method in the presence of a cellulose ether (hydroxypropylmethylcellulose) as stabilizing hydrocolloid. By rapid pouring the solution of hydroxypropylmethylcellulose in water (BDP/BV: 0.005%; ECU-R2: 0.025%) into the drug solution under stirring in a relationship (v/v) of 1:16 (BDP/BV), 1:4 (ECU-R2), the previously molecularly dispersed drug was associated to small particles and stabilized against crystal growth simultaneously. This dispersion was spray-dried, resulting in a drug powder with a uniform particle-size distribution and a drug load of up to 98% (BDP, BV). The mean particle size of the drug was lower than 5 microm in most cases and consequently in the respirable range. Whereas the fine particle fraction (<5 microm, measured without excipients and without an inhalation device) of jet-milled drugs is 9.5 (BDP) or 13.1 (ECU-R2), fine particle fractions of 25.6% (BDP) resp. 78.2% (ECU-R2) are obtained with the spray-dried powders. As the formation of the small crystals requires a rapid solvent change process, the affinity of the hydrocolloid, and a high difference between the solubility in the solvent and nonsolvent, the drug's partition coefficient limits the method as drugs which are more hydrophilic form larger particles.

Administration, Inhalation↗

PubMed2003

In-situ-micronization of disodium cromoglycate for pulmonary delivery.

Drug particle properties are critical for the therapeutic efficiency of a drug delivered to the lung. Jet-milling, a commonly used technique for micronization of drugs, has several disadvantages such as a non-homogeneous particle size distribution, and unnatural, thermodynamically activated particle surfaces causing high agglomeration. For pulmonary use in a dry powder inhaler, in addition to a small particle size, good de-agglomeration behaviour is required. In this study disodium cromoglycate is prepared in situ in a respirable particle size by a controlled crystallization technique. First the drug is dissolved in water (4%) and precipitated by a solvent change method in the presence of a cellulose ether (hydroxypropylmethylcellulose) as a stabilizing hydrocolloid. By rapidly pouring isopropyl alcohol into the drug solution in a 1:8 (v/v) ratio, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth in the presence of the hydrophilic polymer. This dispersion was spray-dried. The mean particle size of the drug was around 3.5 microm and consequently was in the respirable range. The in-situ-micronized drug powder was tested for its aerodynamic behaviour and compared with jet-milled drug powder and with commercial products using the Spinhaler, the Cyclohaler, and the FlowCaps-Inhaler as model devices. The fine particle fraction (FPF) (<5 microm) was increased from 7% for the jet-milled drug to approximately 75% for the in-situ-micronized drug when the pure drug powder was dispersed without any device. Delivery of the engineered particles via the Spinhaler, the FlowCaps-Inhaler and the Cyclohaler increased the FPF from 11 to 46%, 19 to 51%, and 8 to 40%, respectively.

Administration, Inhalation↗

PubMed2002

Ibuprofen crystals with optimized properties.

The common analgesic drug ibuprofen shows bad dissolution and tableting behavior due to its hydrophobic structure. Additionally its high cohaesivity results in low flowability. Because of the bad compaction behavior ibuprofen has to be granulated usually before tableting. Another problem in manufacturing is the high tendency for sticking to the punches. A crystal form with optimized properties of ibuprofen was prepared and characterized in this study. Crystallization was carried out using the solvent change technique in the presence of different water-soluble additives. These additives were only present during the crystallization process and removed after precipitation by a washing process. A nearly pure ibuprofen powder was received, as GC-analysis showed. Plate-shaped crystals with increased powder dissolution, increased flowability and good tableting behavior were obtained. All crystals were determined as isomorphic by DSC and X-ray analysis. Thus the improvement of the substance characteristics of ibuprofen is reached by changes in the outer appearance of the crystals and in surface modifications. Due to the fact that ibuprofen molecules can form hydrogen bonds, additives that can interact with these hydrogen bonds during the crystallization process can modify the properties of the resulting crystals.

Analgesics, Non-Narcotic↗

PubMed2002

Crystal habit and tableting behavior.

The tableting behavior of drugs can be affected by changes in the crystal habit. Different crystal habits of the common analgesic drugs ibuprofen and acetaminophen were prepared. Their tableting behavior was characterized. In the case of ibuprofen, a plate-shaped crystal was compared with the common needle-shaped form. In the case of acetaminophen, plate-shaped and prismatic crystals of two different particle sizes were prepared. The aim was to find a crystal form that is suitable for direct compression with only a low amount of excipients. This requires a substance that forms stable compacts at low punch forces, having a good flowability and only a low tendency to stick to the punches. In order to compare the tableting behavior of different substances, a comparative factor (T-factor) was calculated, based on typical parts of the punch force/displacement-profile and properties of the resulting compact. This method works with low amounts of substance and allows a rapid reproducible determination of the tableting behavior. The method was evaluated by characterizing different typical excipients normally used for the production of tablets.

Acetaminophen↗

PubMed2002

A new lipid emulsion formulation with high antimicrobial efficacy using chitosan.

The antimicrobial activity of chitosan in lipid emulsions as well as in aqueous solutions was investigated. Two types of long-chained chitosan were used differing in the molecular weights, degree of the deacetylation and their viscosity: type I, mol. weight 8.7 x 10(4) g/mol, 92% degree of deacetylation and a viscosity of 14 mPa s, type II, mol. weight of 5.32 x 10(5) g/mol, 73% degree of deacetylation and a viscosity of 461 mPa s. In order to assess the pH optimum of the antimicrobial activity of the biopolymer, suspensions of the microorganisms Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus niger were incubated at different pH-values in lactic acid solution (1% w/v) containing different concentrations of chitosan up to 1.5% (w/v). Emulsion formulations containing either 0.25%, 0.5% or no chitosan, respectively, were inoculated with the same microorganisms and were incubated at 25 degrees C. The aqueous solutions as well as the emulsions were examined for microbial counts on agar plates after different periods of incubation. After 24 h of incubation in aqueous solutions only the cfu numbers of the bacteria were reduced. Both types of chitosan revealed a pH optimum of their antibacterial activity at pH 5.0-5.1 for P. aeruginosa, and at pH 5.3 for S. aureus. In addition, chitosan with a mol. weight of 8.7 x 10(4) g/mol, high degree of deacetylation and low viscosity showed a higher antimicrobial activity than the other chitosan type of this study. It was found that lipid emulsions containing 0.5% chitosan (type I) conformed to the requirements of the preservation efficacy test for topical formulations according to the European Pharmacopoeia while the emulsion without chitosan and a lactic acid solution with and without the biopolymer did not conform. In hemolysis studies on human erythrocytes, the hemolytic activity of the lipid emulsions with chitosan was assessed. These emulsions showed a negligible hemolytic behavior. The results indicate a use of chitosan as antimicrobial preservative in emulsion formulations for mucosal as well for parenteral applications.

Anti-Bacterial Agents↗

PubMed2002

Parenteral emulsions stabilized with a mixture of phospholipids and PEG-660-12-hydroxy-stearate: evaluation of accelerated and long-term stability.

Different emulsion formulations were prepared using phospholipids (Lipoid S57) and PEG-660-12-hydroxy-stearate (Solutol HS15) as single emulsifiers or in mixtures. The accelerated stability after autoclaving, freezing and centrifugation was investigated. The long-term stability was also studied at different temperatures (4, 20, and 37 degrees C) for 8 months. Emulsion stabilized with phospholipids displayed a stable behavior after the autoclaving and centrifugation, but it broke down after the freezing process. In mixture with Solutol HS15, however, the emulsion showed appropriate shelf stability at different temperatures for 8 months. A change in the particle size of the emulsion prepared only with Solutol HS15 was observed after centrifugation (slight) and after autoclaving (marked). In contrast to phospholipid emulsion, this emulsion (with only Solutol HS15) was less prone to breaking down after the freezing, as no complete phase separation was observed. The results obtained using an emulsifier mixture revealed that a combination of an anionic surfactant (phospholipids) and non-ionic surfactant (PEG-660-12-hydroxy-stearate) improves the emulsion's stability, compared to the emulsion's stability prepared using only a single emulsifier. However, no direct correlation could be found between the accelerated and the long-term stability data.

Centrifugation↗

PubMed2002

Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs.

PURPOSE: The purpose of this study was to evaluate a novel in situ micronization method avoiding any milling techniques to produce nano- or microsized drug particles by controlled crystallization to enhance the dissolution rate of poorly water-soluble drugs. METHODS: Ibuprofen, itraconazole, and ketoconazole microcrystals were prepared by the association of the previously molecularly dispersed drug using a rapid solvent change process. The drug was precipitated in the presence of stabilizing agents, such as hydrocolloids. The obtained dispersion was spray-dried. Particle size, morphology, dissolution rate, specific surface area, and wettability were analyzed. Physicochemical properties were characterized using differential scanning calorimetry and X-ray diffractometry. RESULTS: The obtained dispersions showed a homogeneous particle size distribution. Drugs are obtained in a mean particle size of approximately 2 microm and below. A high specific surface area was created and in situ stabilized. Different stabilizers showed differences in protecting the precipitated drug from crystal growth. The surface was hydrophilized because of the adsorbed stabilizer. Thus, a drug powder with markedly enhanced dissolution rate was obtained. CONCLUSIONS: In situ micronization is a suitable method for the production of micro-sized drugs. This technique can be performed continuously or discontinuously and uses only common technical equipment. Compared to milled products drug properties are optimized as all particle surfaces are naturally grown, the particle size is more uniformly distributed and the powder is less cohesive.

Chemical Precipitation↗