Cremophor EL formulation

Drugs formulated with Cremophor EL (Althesin, propanidid, propofol EL)... 

Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 2001 (Sep) 37(13) 1590-1598. 

The micelle formulation approach often possesses disadvantages such as its toxicity associated with surfactants even at relatively low concentrations. In general, nonionic surfactants have the least toxic effects. Cremophor EL produces hypersensitivity reactions in human and animals (Jonkman-de Vries et al., 1996). Tween-80 is also believed to cause acute hepatitis and renal failure (Uchegbu and Florence, 1996). On intravenous administration, owing to their surface activity, surfactant molecules have the potential to penetrate and disrupt biological membranes and can be hemolytic (Ten Tije et al., 2003). Often the absorption capacity of the micelle is too small and the extent of the... 

Cuine, J. F., W N. Charman, C. W Pouton, G. A. Edwards, andC. J. H. Porter(2007). Increasingthe proportional content of surfactant (Cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of Danazol reduces oral bioavailability in beagle ddgj3arm. Res., 24 748-757. 

In terms of biodistribution, Zhang et al. (1997) were not able to demonstrate any difference between the biodistribution of paclitaxel loaded into MePEGQLLA micelles versus paclitaxel solubilized in Cremophor EL (a conventional surfactant). These two formulations also showed similar in vitro distribution between the lipoprotein and lipoprotein-deLcient fraction of plasma (Ramaswamy et al., 1997). As for other drug carriers, plasma half-life and uptake of polymeric micelles by the MPS depend on the molecular weight (Kwon et al., 1994) and density of the hydrophilic shell (Hagan et al., 1996). 

The permeability of two peptides, P-gp substrate and non P-gp substrate, across caco-2 cells in the presence or absence of polysorbate 80 and cremophor EL, commonly used surfactants in pharmaceutical formulations, was investigated. The permeability of the P-gp substrate peptide across caco-2 cells was enhanced in the presence of polysorbate 80 and cremophor EL, whereas the non-P-gp substrate peptide was not affected by these surfactants [94]. Another commonly used lipidic excipient that has been shown to inhibit P-gp mediated efflux is D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) [95]. The insertion of a known CYP3A4 and P-gp inhibitor to the formulation is another approach to elevate bioavailability. 

In addition to the light-harvesting property, this host-guest complex also exhibits a high photocytotoxicity. Its IC50 value, defined as the dye concentration required to kill 50% of the cells, for HT29 human colon adenocarcinoma cells is only 0.09 p,M, which is comparable with that of 113 itself formulated with Cremophor EL (0.15 p,M). The complexation with 93 (M = 2H) enhances the water solubility of 113 and therefore can prevent the use of Cremophor EL, which may cause serious hypersensitivity reactions. 

C21-Amino-Epo B [BMS-310705 (23)] is undergoing clinical evaluation in humans, but only hmited biological data are currently available in the literature for this compound. Thus, an IC50 value of 0.8 nM for growth inhibition of the human epidermoid cancer cell line KB.31 has been reported in a patent application (vs 1.2nM for Epo B under comparable experimental conditions" ). More recently, Uyar et al." have demonstrated that 50 nM BMS-310705 induces substantial apoptosis in early passage ovarian cancer cells (OC-2), which were derived from a clinical tumor sample and were refractory to paclitaxel and platinum treatment. A concentration of 50 nM of BMS-310705 (23) is clinically achievable at a dose of 10 mg/m, which is below the phase 1 maximum tolerated dose (MTD) for the compound. " BMS-310705 (23) exhibits improved water-solubility over BMS-247550 (1), which enables the use of chnical formulations not containing Cremophor-EL. ... 

The most recent additions to the portfolio of epothilone-type clinical development compounds are the semisynthetic derivatives BMS-310705 (23), which differs from Epo B by the presence of a primary amino group at C21, and C20-desmethyl-C20-methylsulfanyl-Epo B (32, ABJ879). As indicated above, BMS-310705 (23) exhibits improved water-solubility over BMS-247550 (1), thus allowing the use of clinical formulations not containing Cremophor-EL. Accordingly, no hypersensitivity reactions were observed in phase I studies with BMS-310705 (23) in contrast to BMS-247550 (1) (in the absence of premedication). 

Formulation studies are performed to develop a suitable vehicle to solubilize the drug for administration to patients, generally by intravenous injection or infusion in the case of cancer. The low solubility of many natural products in water poses considerable problems, but these can be overcome by use of co-solvents or emulsifying agents (surfactants) such as Cremophore EL (polyoxyethylated castor oil). 

Ritonavir, an HIV protease inhibitor with peptidelike structure, has an intrinsic water solubility of l.Opg/ml. Norvir is a thermodynamically stable solution formulation containing 100 mg of ritonavir dissolved in a mixture of oleic acid, Cremophor EL, ethanol, and the antioxidant butylated hydroxytoluene (BHT), and filled into soft gelatin capsules. However, Norvir is being replaced by Kaletra oral solution and soft gelatin capsule, which is a combination of 133.3 mg of lopinavir and 33.3 mg ritonavir dissolved in a mixture of oleic acid, polyoxyl 35 castor oil (Cremophor EL), and propylene glycol. The water-insoluble HIV protease inhibitor, saquinavir, is solubilized by a mixture of Vitamin E and medium-chain mono- and diglycerides in 200 mg Fortovase soft gelatin capsules. 

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