Antibiotics solubilization

Depicted in Fig. 2, microemulsion-based liquid liquid extraction (LLE) of biomolecules consists of the contacting of a biomolecule-containing aqueous solution with a surfactant-containing lipophilic phase. Upon contact, some of the water and biomolecules will transfer to the organic phase, depending on the phase equilibrium position, resulting in a biphasic Winsor II system (w/o-ME phase in equilibrium with an excess aqueous phase). Besides serving as a means to solubilize biomolecules in w/o-MEs, LLE has been frequently used to isolate and separate amino acids, peptides and proteins [4, and references therein]. In addition, LLE has recently been employed to isolate vitamins, antibiotics, and nucleotides [6,19,40,77-79]. Industrially relevant applications of LLE are listed in Table 2 [14,15,20,80-90]. 

Certain compounds are known to achieve higher absorption rates from the GI tract if they are taken with food, and this observation has been linked to their solubilization by bile salts [74], Bile salts, especially those of cholic and deoxycholic acids, have been used to solubilize steroid hormones [75], antibiotics [76], and nonsteroidal antiinflammatory drugs [77]. For example, amphotericin B (an antifungal agent) has been solubilized for parenteral use in micelles composed of sodium desoxycholate [78], As illustrated in Fig. 11, the degree of solubilization of carbamazepine by sodium desoxycholate is minimal below the critical micelle concentration but increases rapidly above this value [79]. At sufficiently high concentrations, when the micelles become saturated in carb-amezepine, the apparent solubility reaches a limiting value approximately seven times the true aqueous solubility in the absence of desoxycholate. 

Buckwalter has indicated that gramicidin solutions in propylene glycol and carbowaxes are stable to autoclaving123. He also showed that the antibiotic can be solubilized in water with the aid of non-ionic wetting agents. 

The soluble Kollidon products form reversible complexes with many hydrophobic active substances, and clear solutions in water are thus obtained. This may be affected by the molecular weight. The longer the chains or the higher the -value of the Kollidon type are, the stronger the solubility effect is, and thus the greater the solubility that can be obtained by the active substance. In practice, this effect was mostly exploited for the solubilization of antibiotics in human and veterinary medicine. There are also restrictions on the use of this substance in human parenter-als. In many countries the -value must not exceed 18, and there is also a restriction on the amount to be used for each dose administered in intramuscular application. 

Human skin fibroblasts are cultured from skin biopsy samples. The dermis is cut into small pieces (0.5 mm on each side) and placed into a dish in DMEM containing 10% (v/v) FCS and 1% (v/v) antibiotic-antimycotic solution. When these primary cultures are confluent they are split and cells between passage three and six are used for experiments. For the cholesterol efflux assay, cells are grown in 24-well plates to 60-80% confluence and are labeled with [1,2-3H]-cholesterol (1 pCi/well) for 24 h. Cells are then washed with DMEM and incubated for 4 h at 37°C with DMEM containing BSA (0.2%, v/v) and either 0 (negative control) or 5-30 pg/ml apoA-I. The efflux medium is collected and centrifuged to remove cell debris. Cells are solubilized in 0.1 mol/1 NaOH and the radioactivity in the efflux media and in the cell lysates is determined by scintillation counting [11, 30, 75]. 

H] thymidine, 2-deoxy [1-3H] glucose antibiotics, and 1% fetal calf serum or 5% lipoprotein deficient serum was added to each dish and the cells incubated for 48 hrs. Subsequently, the medium was removed and the monolayers washed as described above, but at 4° C. The entire monolayer was solubilized in 1 N NaOH. Radioactivity and protein were subsequently measured in the alkali solubilized cell extracts. The data are expressed as c.p.m. per mg protein. 

The ability of crown ethers to bind selectively to particular Group IA and Group IIA metal ions, because of the relationship between hole size and metal ion radius, has led to considerable interest in them in relation to membranes (models for selective ion transport), antibiotics (similar polyether structure), organic synthesis [solubilization of inorganic reagents leading to milder routes for oxidation (122), nucleophilic substitution (123), fluoridation (90)] and extraction of alkali... 

Various drugs, for example, diazepam and indomethacin, doxorubicin, anthracy-cline antibiotics, and polynucleotides, were effectively solubilized in polymeric micelles. Also polymeric micelles can carry various reporter (contrast) groups and... 

Menaquinones are synthesized by intestinal bacteria, but it is unclear how much they contribute to vitamin K nutrition, because they are extremely hydrophobic, and win only be absorbed from regions of the gastrointestinal tract where bUe salts are present - mainly the terminal Ueum. However, prolonged use of antibiotics can lead to vitamin K deficiency and the development of vitamin K-responsive hypoprothrombinemia (Section 5.4), as can dietary deprivation of phylloquinone. In vitro, menaquinones 2 to 6 have the same activity as phylloquinone as coenzyme for the solubilized liver microsomal vitamin K-dependent carboxylase (Section 5.3.1), whereas menaquinones with a side chain longer than seven have lower activity (Suttie, 1995). In extrahepatic tissues, the principal active vitamer is menaquinone-4 (Thijssen and Drittij-Reijnders, 1996 Thijssen et al., 1996). 

Cipro rV (Ciprofloxacin, Bayer) contains lactic acid as a solubilizing agent for the antibiotic. 

If it is not possible to improve the bioavailability of a substance as desired by the addition of a solubilizing agent, this is frequently because the surface area of the crystals of active ingredient exposed to the solvent is too small. It is therefore necessary to increase the surface area, to accelerate dissolution. The first solid dispersions with antibiotics in povidone were described in the literature in about i960 [49,60]. In solid solutions and dispersions the active substance is embedded in a hydrophilic carrier to improve its bioavailability. The difference between a solid solution and a solid dispersion can be defined in terms of the state of the active substance. In a solid solution, it is present in an amorphous molecular form, while in a solid dispersion it is in the form of crystals that must be as fine as possible. 

Low-molecular povidones are nowadays widely used in different injectables e.g. in antibiotic and sulfonamide formulations. Fig. 54 shows, as an example, how the solubilization of rifampicin depends directly on the povidone concentration. 

KoIUdon . [BASF AG] PVP solubilizer, crystallization retarder, stabilizer fcM- antibiotic suspensknis bindns f[Pg.197]

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