Solid dispersion of ketoprofen in pellets.

The formulation of ternary solid dispersions of ketoprofen with Macrogol and kollagen hydrolizate derivative as carriers was elaborated on the basis of the results of the experiments in which different methods of solid dispersion preparation (melting, solvent method, different cooling), different concentrations of drug/carriers and molecular weight of Macrogol were tested. The best solid dispersion consisted of: ketoprofen-Macrogol 6000-KLH(T) (1+8. 9+0.1) was chosen to formulate the pellets on the basis of the pharmaceutical availability of ketoprofen from solid dispersion and the physical chemical studies: thermomicroscopic, DSC and X-ray diffraction. The pellets were prepared by the extrusion and spheronization method. The mechanical properties of the pellets as well as ketoprofen released from pellets containing solid dispersion, in comparison with physical mixtures and the drug alone, were evaluated. The increase in the amount of released ketoprofen from solid dispersion pellets was 3.8-times greater than from the pellets containing the drug alone. The stability of solid dispersion pellets was satisfactory.

[Evaluation of topical drugs with reference to indications. A selection]. / Bewertung von Wirkstoffen für Externa unter Berücksichtigung ihrer Anwendungsgebiete. Eine Auswahl.

Between 1988 and 1994 more than 40 monographs dealing with dermatologically relevant drugs have been published in an official German government publication, the "Bundesanzeiger". These monographs represent reviews compiled by independent dermatological and pharmaceutical authorities working together in an expert commission and most of their information has proved valid. Thus, knowledge of these official reviews could help physicians to decide about the use of many drugs. However, they are not well-known to doctors. With this brief summary we hope to make more physicians familiar with these important monographs published in the "Bundesanzeiger".

Long-term amelioration of rat adjuvant arthritis following systemic elimination of macrophages by clodronate-containing liposomes.

OBJECTIVE: To determine whether systemic elimination of macrophages by means of clodronate-containing liposomes counteracts inflammation and joint destruction in rats with established adjuvant arthritis (AA). METHODS: Rats with AA received a total of 2.7 mg of clodronate encapsulated in liposomes in 3 intravenous doses on days 10, 11, and 12 of arthritis. Phosphate buffered saline (PBS), PBS-laden liposomes, or free clodronate were used as negative controls. Clinical, hematologic, and histopathologic signs of AA were monitored, and depletion of macrophages by clodronate-liposomes was evaluated both in the synovial membrane (SM) and in organs of the mononuclear phagocyte system (MPS). RESULTS: Clodronate-laden liposomes led to significant, long-term amelioration of the clinical signs of AA, a reduction in the erythrocyte sedimentation rate (ESR), and counteraction of joint destruction, not only immediately after treatment, but also for 2 weeks thereafter. Free clodronate induced moderate clinical improvement and a significant decrease in the ESR, but only during the late phase of AA. Drug-free vesicles even aggravated the joint destruction. Clodronate-laden liposomes did not induce significant depletion of resident macrophages in the SM, but rather, in the paracortical region of popliteal lymph nodes, in the liver, and in the marginal zone and periarteriolar lymphatic sheaths of the spleen. CONCLUSION: Clodronate-laden liposomes induce long-term amelioration of AA, even if administered for a brief period during the florid phase of the disease. The amelioration is paralleled by the elimination of macrophages in immunocompetent areas of the spleen and draining lymph nodes, but not locally in the SM. This suggests an influence of the treatment on the immunoregulatory rather than effector, functions of macrophages.

A non-ionic vesicle lipid enhances mastoparan-stimulated GTPase activity of heterotrimeric G-proteins.

Isolated heterotrimeric G-proteins exhibit full biological activity when reconstituted into liposomes. Here, we investigated the non-ionic surfactant macrogol-260-cetylstearylether (TA 6) as an efficient vehicle for the reconstitution of G-proteins. Reconstitution efficiency of G-proteins was recorded by GTP gamma S-binding. Their biological potency was measured as basal and mastoparan-stimulated GTPase-activity. G-proteins were fully active when associated with liposomes. On the other hand, G-proteins solubilized by TA 6 micelles or reconstituted into pure TA 6 vesicles exhibited impaired biological activity. However, vesicles containing different ratios of azolectin and non-ionic TA 6 showed about 50% higher reconstitution efficiency as compared to pure liposomes. In addition, basal and mastoparan-stimulated GTPase-activity in vesicles containing an axolectin/TA 6 ratio of 3:1 were 2.7 and 9.1 fold higher than in pure liposomes, respectively. These data emphasize that the composition of the lipid membranous environment significantly influences G-protein activity.

Treatment of rat arthritides with clodronate-containing liposomes.

Large multilamellar liposomes containing dichloro-methylene-bisphosphonate (clodronate; Clo), a bisphosphonate that becomes toxic when intracellularly concentrated, were used to therapeutically target macrophages (M phi) in rats with established adjuvant arthritis (AA; i.v. on days 10,11,12) or antigen-induced arthritis (AIA; i.v. or i.a. on 3 h, days 1,2). In established AA, i.v. injection of Clo-liposomes led to significant, long-lasting amelioration of clinical parameters, and to reduced destruction of the ankle joint even several weeks after termination of treatment. In the acute phase of established AIA, intravenous treatment induced transient clinical amelioration, but did not counteract joint destruction. I.a. treatment in AIA was ineffective. Systemic treatment with anti-M phi principles induces amelioration of both AA and AIA; the improvement appears more profound in AA, i.e., the model with a more systemic character. Preliminary data indicate that depletion of M phi occurs in the liver rather than in spleen, draining lymph nodes or synovial membrane. In addition, local treatment with the same principle is ineffective in AIA. Therefore, systemic elimination of M phi in different sites may be crucial for effective therapy of arthritis with anti-M phi agents.

[Hemolytic activity of tensides--determination of the interaction between O/W- and W/O-surfactants]. / Hämolytische Aktivität von Tensiden--Beitrag zur Bestimmung der Wechselwirkung zwischen O/W- und W/O-Emulgatoren.

Using an newly-developed haemolysis method it is possible to determine quantitatively a KLH-surfactant 3000 that exists unbound in the aqueous phase of a tertiary system containing W/O-surfactants. The method depends on membrane damage of erythrocytes and is therefore a measure of the skin acceptability of a sample. The selective analysis technique works without previous preparation of complex mixtures that could lead to errors. It gives decisive evidence that KLH-surfactant 3000 that is fixed to either the W/O-surfactants or the lipid/water interface causes no membrane damage compared with free coconut/fatty acid. Haemolysis studies show that the fraction of KLH-surfactant 3000 dissolved in the aqueous phase decreases strongly with increasing amount of cetylstearyl-alcohol (CSA) up to a ratio of fatty alcohol/KLH-surfactant of approx. 0.3:5. In this range the fatty alcohol binds ten times as much O/W-surfactant in the mixed surfactant system. Further addition of CSA above the ratio 0.3:5 cause relatively little additional fixation of coconut/fatty acid, and the co-surfactant crystallises out. The rate of binding of a 1:1 mixture of CSA and glycerolmonostearate (GMS) is comparable with that of pure fatty alcohol. This mixtures also shows reduced tendency to crystallisation.

Participation of Macrogolstearate 400 lamellar phases in hydrophilic creams and vesicles.

In binary Macrogolstearate 400 (MS 400)/water systems, lamellar surfactant arrangements can be detected by polarized light and transmission electron microscopy. As demonstrated by X-ray diffraction and differential scanning calorimetry, the alkyl chains of the emulsifier are in the crystalline state. Ternary systems with liquid paraffin represent optically isotropic, homogeneous o/w creams for a wide composition range. Incorporation of up to 50 mol% cholesterol into the MS 400 lamellar structures leads to a gel-liquid crystalline phase separation within the bilayer, thus enabling the formation of spherical nonionic vesicles. The transition enthalpy of the samples decreases linearly with increasing cholesterol concentrations. The Macrogolstearate 400/cholesterol vesicles proved to be stable in hydrophilic cream systems. Cationic vesicles can be prepared using cetyltrimethylammonium bromide (CTAB) as a charge inducer. Low-CTAB portions are inhomogeneously distributed within the bilayer, as detected by DSC. The results also indicate a perturbation of the alkyl chains packing for the positively charged vesicles.

Use of liposomes, viral capsids, and nanoparticles as DNA carriers.

We tested a variety of liposomes for parameters such as DNA binding capacity and DNase I protection of incorporated and attached DNA to elucidate their use as vehicles for DNA transfer into cells and animals. The results were compared to other potential DNA vehicles, empty viral capsids, and nanoparticles. Maximal binding capacity was achieved for positively charged nanoparticles, DNase I protection was observed for most preparations with neosome preparations being least efficient. The uptake of radiolabeled DNA by cells in culture was determined for cationic and nonionic surfactant vesicles, viral capsids, and nanoparticles. Cellular DNA uptake was best for dioleoyl-derived positively charged liposomes (N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride; DOTMA) and the DNA could be shown to be physiologically active. The recombination rate for DNA fragments transfected in polyoma capsids in live mice was higher than for liposome mediated transfection. Homologous recombination could be observed for both DOTMA and polyoma-mediated DNA transfer.

[The suitability of propylene glycol (1,2-propanediol) as an active antimicrobial adjuvant in ointments]. / Uber die Eignung von Propylenglykol (1,2-Propandiol) als antimikrobiell wirksamer Hilfsstoff für Cremesysteme.

Propylene glycol was tested for its antimicrobial activity as well as its possible irritant effect in ointments. With regard to the antimicrobial effect, vehicles containing more than 5% propylene glycol proved to be superior to those containing glycerol. 269 volunteers with or without eczema who had been treated with 10% propylene glycol under occlusion and by means of the Duhring chamber method, showed very few irritations; there was almost none observed in patients tested with an ointment containing glycerol instead. We did not find any allergic sensitization against propylene glycol.

[Which galenic bases are in use nowadays for skin treatment?]. / Welche galenischen Grundlagen werden heute für die Hautbehandlung eingesetzt?

Different base types are necessary for dermatological preparations. The dominating part is played today and probably will also be played in the future by the hydrocarbon gels and the derivated cream systems. Possible interferences of the ingredients with the base components have to be watched by the dispensing of medical preparations for dermatological therapy. In regard to an optimal distribution of the ingredients solubility of the ingredients in the bases are important. Specific preservatives can be omitted if ethanol is added in concentrations of at least 15 per cent. There is a tendency to use mainly indifferent components.