Ethanol and cremophor

One of the major problems with water-insoluble compounds such as taxol which must be administered intravenously is obtaining a stable, homogeneous, nontoxic solution of the product. Currently, taxol is dissolved in ethanol, and Cremophor, a polyoxyethylated castor oil, is added (i). This is somewhat less than ideal as the adjuvant is toxic and can provoke serious allergies 154). As an alternative, use of a triacetin-based emulsion has been suggested (755). 

Paclitaxel is formulated in a mixture of ethanol and Cremophor EL (polyethoxylated castor oU). Cremophor reduced the electrophoretic mobility of serum lipoproteins along with the appearance of a hpoprotein dissociation product. After serum was exposed to Cremophor in vitro or in vivo there was substantial binding of pachtaxel to the lipoprotein dissociation product(s), and this could represent an important factor in the distribution of paclitaxel (11). 

The bis(jS-diketonato) Ti(IV) complex [Ti(bzac)2(OEt)2] 35 (budoti-tane, shown as the predominant cis,cis,cis isomer) entered phase I clinical trials in Germany in 1986 for the treatment of colon cancer (186). The complex is very susceptible to aquation, and to minimize this, the coprecipitate (Cremophor EL, 1,2-propylene glycol in ethanol and 35) is dissolved in water prior to administration. As for titano-cene dichloride, liver damage is the dose-limiting side-effect (187). The activity of this class of complexes shows little dependence on the nature of the leaving group (e.g., OEt, Cl), but aromatic substituents... 

Heat the mixture of benzyl benzoate and Cremophor RH 40 to about 60 °C, stir strongly and add slowly the water. Finally add the ethanol. 

Mix the active ingredients with Cremophor RH 40 and heat to 50-60 °C. Add the ethanol and slowly the warm water to the well stirred solution. 

Mix the peppermint oil with Cremophor RH 40, stir well and add slowly ethanol and water. 

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. 

Tacrolimus, an immunosuppressant used to prevent rejection of liver and kidney transplants, is insoluble in water and is solubilized in Prograf to 5mg/ml with 20% Cremophor RH 60 and 80% ethanol and is administered by IV infusion after a 250-fold or a 1,000-fold dilution with saline or dextrose 5%. The dose of tacrolimus is up to 35 mg, which is 7 ml of Prograf, of which 1.4 ml is Cremophor RH60 per dose, representing the estimated maximum amount administered intravenously. 

The next level of complexity of lipid-based formulations currently marketed contain mixtures of four excipients, which can be SEDDS formulations or mixtures such as beeswax, soybean oil, hydrogenated vegetable oils and hydrogenated soybean oil. There are at least two commercially available four-excipient lipid-based oral formulations and both are delivered in soft gelatin capsules. Aptivus soft gelatin capsule (tipranavir) is a SEDDS formulation with ethanol and PG as the polar solvents, cremophor EL as the surfactant, and medium-chain mono-and-diglycerides as the oily phase. 

Paclitaxel has very limited solubility and must be administered in a vehicle of 50% ethanol and 50% polyethoxylated castor oil (CREMOPHOR EL), a formation likely responsible for a high rate of hypersensitivity reactions. Patients receiving this formulation are protected by pretreatment with a histamine Hj receptor antagonist such as diphenhydramine, an receptor antagonist such as cimetidine fsee Chapter 24), and a glucocorticoid such as dexamethasone (see Chapter 59). Docetaxel, which is somewhat more soluble, is administered in polysorbate 80 and causes a lower incidence of hypersensitivity reactions. Pretreatment with dexamethasone is required to prevent progressive, and often disabling, fluid retention. 

PEG 400, propylene glycol, glycerine, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, hexanol, heptanol, octanol sorbitol, and Cremophor RH40 (polyoxyl 40 hydrogenated castrol oil). 

Well, the testing took some time, and also there were problems. Taxol is insoluble in many solvents, though in the end, a mixture of ethanol and a surfactant (Cremophor EL) was found to work. There were also environmental problems, and yet more controversies. 

Medicinal chemists should be aware that inexperienced biologists can erroneously conclude that poorly aqueous soluble compounds are orally absorbed when compounds are dosed in pharmaceutically unacceptable solvents. Always ask what is the dosing vehicle Heroic combinations of DMSO, Cremophor, poly(ethylene glycol), Tween-80 and ethanol are unacceptable and misleading. In case of doubt consult with a pharmaceutical scientist colleague. The reliable standards are an aqueous solution (with perhaps a trace of DMSO) or a suspension (perhaps stabilized with an acceptable quantity of adjuvant, e.g. Tween-80). 

The photodynamic effect of chloroaluminum(III) phthalocyanine ((47), with C1A1 in place of Zn), a commercial product, was reported by Ben-Hur and Rosenthal.302 The photosensitizer was delivered in ethanol to cultures of Chinese hamster fibroblasts. After equilibration (16 h), exposure to visible light (fluence rate 64 Wm-2) of a suspension in PBS for 2 min gave a 3 log kill. Lack of water solubility is a problem, and for in vivo PDT of EMT-6 mammary tumors in mice a Cremophor emulsion was employed.303 The compound was a more effective PDT sensitizer than... 

Subsequently, we expanded on these efforts by studying the effects of various formulations, routes, and schedules of i.v. administration. We discovered that slow infusion (6 h, Q2D, 30 mg/kg x 5 doses) of dEpoB in nude mice bearing human xenograft tumors with a Cremophor-ethanol vehicle was the most beneficial in terms of efficacy and decreased toxicity. 

Cremophor EL, polysorbate 80, propylene glycol sorbitan monooleate and ethanol... 

SGC, Liquid Corn oil mono- and diglycerides, Cremophor RH40, ethanol, propylene glycol-tocopherol PDR... 

Liquid cosolvents glycerin, polyethylene glycol (300, 400, 3350), propylene alcohol, and ethanol, Cremophor EL, sorbitol. 

Ritonavir is solubilized in a cosolvent mixture of propylene glycol, ethanol, water, the surfactant Cremophor EL, and peppermint oil to 80 mg/ml in the Norvir oral solution. A similar cosolvent mixture of propylene glycol, 42% ethanol, water, glycerin, the surfactant Cremophor RH 40, and peppermint oil is used to cosolubilize ritonavir to 20 mg/ml and lopinavir, a non-ionizable water-insoluble HIV protease inhibitor, to 80 mg/ml in the Kaletra oral solution. The dose of Kaletra Oral Solution is up to 5 ml twice daily, which is 2.1 ml of ethanol per dose representing the estimated maximum amount of ethanol administered orally per dose. 

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