Cremophor solubilization

Ethoxylated castor ods or ethoxylated castorwaxes are used as solubilizers of hydrophobic substances in cosmetics. Examples are Cremophor EL (ethyoxylated castor od) and Cremophor RH (40/60 ethoxylated hydrogenated castor od). Other ethoxylated triglycerides are not as effective as castor od. Ethoxylated castor od is also a good solubilizer for vitamin A palmitate (121). 

Excipients offer several possibilities and mechanisms. For microemulsions, Cremophor RH 40, Cremophor EL, and Solutol HS 15 act as surface active solubilizers in water and form the structures of micelles. The micelle that envelops the active substance is so small that it is invisible, or perhaps visible in the form of opalescence. Typical fields of application are oil-soluble vitamins, antimycotics of the miconazole type, mouth disinfectants (e.g., hexiditin), and etherian oils or fragrances. Solutol HS 15 is recommended for parenteral use of this solubilizing system and has been specially developed for this purpose. 

Active substances can also be solubilized by Lutrol F 68 in addition to the Cremophor and Kollidon products. The... 

Cremophor RH 40, Cremophor EL, and Solutol HS 15 act as surface-active solubilizers in water and form the structures of micelles. The micelle that envelops the active substance is so small that it is invisible or perhaps visible in the form of an opalescence. 

Active substances can also be solubilized by Lutrol F 68 in addition to the Cremophor and Kollidon products. The mechanism is probably based, for the most part, on the principle of hydrophilization. Micelle formation is certainly of minor significance, if it exists at all. 

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). 

FIGURE 4.25 Three-component phase diagram for the solubilization. Cre, Cremophor RH 40 Gly, glyceride Pol, poloxamer 124 L, isotropic microemulsion G, gel E, crude OAV emulsion E2, W/O emulsion. [Graph reconstructed from data by Kim et al. Pharm. Res., 18, 454 (2002).]... 

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). 

Lorenz W, Schmal A, Schult H et al. Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids Analysis of various components in Cremophor EL and development of a compound with reduced toxicity. Agents Actions 1982 12 64-80. 

To act as solubilizing, wetting, or emulsifying agents such as Cremophor EL, sodium desoxy-cholate, Polysorbate 20 or 80, PEG 40 castor oil, PEG 60 castor oil, sodium dodecyl sulfate, lecithin, or egg yolk phospholipid. 

Cremophors are pegylated castor oil or hydrogenated castor oil, and are complex mixtures of relatively hydrophobic and hydrophilic molecules, and are synthesized by causing reaction of either castor oil or hydrogenated castor oil with varying amounts of ethylene oxide. Cremophors are quite effective at solubilizing very hydrophobic drugs and are normally not used alone. 

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. 

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. 

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. 

Polyoxyl 35 castor oil is mainly used as an emulsifing and solubilizing agent, and is particularly suitable for the production of aqueous liquid preparations containing volatile oils, fat-soluble vitamins, and other hydrophobic substances. Cremophor EL emulsifies or solubilizes the fat-soluble vitamins A, D, E, and K in aqueous solutions for oral and topical administration. In 1 mL of a 25% v/v aqueous polyoxyl 35 castor oil (Cremophor EL) solution it is possible to incorporate approximately 10 mg of vitamin A palmitate approximately 10 mg of vitamin D approximately 120 mg of vitamin E acetate or approximately 120 mg of vitamin Kj. 

In aqueous alcoholic solutions, it very readily solubilizes essential oils. Aqueous solutions of hydrophobic drugs (e.g. miconazole, hexetidine, clotrimazole, benzocaine) can also be prepared with Cremophor EL. Cremophor EL has also been used as a solubilizing agent for drugs like cyclosporin A, paclitaxel, and cisplatin. Cremophor LLP is manufactured by purifying Cremophor EL and is therefore suitable for parenteral applications, e.g. Taxol preparations. In oral formulations, the taste of polyoxyl 35 castor oil (Cremophor EL) can be masked by a banana flavor. 

After cyclodextrins and co-solvents, other approaches can be applied including the use of surfactants and micelle forming agents. Surfactants can be classified as amphoteric (lecithin), non-ionic (Tween 80 or Cremophor EF) or ionic (sodium lauryl sulfate or sodium palmitate). Cremophor is a polyoxyethylenated castor oil derivative which is a common solubilizing excipient in a number of formulations including those for paclitaxel, propofol, teniposide and clanfenur... 

Water-miscible surfactant molecules contain both a hydrophobic and hydrophilic portion, and can solubilize many poorly water-soluble drugs. Surfactants can also self-assemble to form micelles once the surfactant monomer concentration reaches the critical micelle concentration. Thus surfactants can solubilize drug molecules by either a direct cosolvent elfect or by uptake into micelles. The non-ionic surfactants in commercially available solubilized oral formulations include polyoxyl 35 castor oil (cremophor EL), polyoxyl 40 hydrogenated... 

A mixture of oleic add, cremophor EL and propylene glycol solubilizes 133.3 mg of lopinavir and 33.3 mg of ritonavir, which are water-insoluble HIV protease inhibitors used in the treatment of HIV infection, in the hxed-dose combination Kaletra soft gelatin capsules. The dose of Kaletra is three capsules twice daily and the product must be stored refrigerated at 2—8°C or at controlled room temperature for no more than two months. Kaletra has been available in the UK since 2001, and is also available in the USA. 

A mixture of oleic acid, cremophor EL, and ethanol solubilizes 100 mg of ritonavir in Norvir soft gelatin capsules. Ritonavir is an HIV protease inhibitor with a peptide-like structure that has an intrinsic water solubility of 1.0 pg/mL and two weakly basic thiazole groups with pKa s of 1.8 and 2.6, which preclude... 

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