Paclitaxel, solubilization

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). 

Fig. 3 Hydrotropic agents identified for paclitaxel solubilization A,A-diethylnicotinamide (A) A-picolylnicotinamide (PNA) (B) ACallylnicotinamide (C) and sodium salicylate (D).

Paclitaxel Tarretal. (1987) Triacetin emulsion to solubilize drug, alternative to surfactants, and cosolvents... 

Ooya, T. Lee, J. Park, K. Effects of ethylene glycol-based 69. graft, star-shaped, and dendritic polymers on solubilization and controlled release of paclitaxel. Journal of Controlled Release 2003, 93, 121-127. 

The solid dispersion method (Fig. 2B) was used for solubilization of paclitaxel into PEG-poly(D,L-lactide) diblock copolymer micelles. Paclitaxel and the polymer were dissolved in acetonitrile followed by evaporation of the solvent under a stream of nitrogen at 60°C to obtain a gel-like polymer-drug matrix. Dissolution of the solid matrix in water at about 60° C with stirring led to formation of drug-loaded micelles. Because a heating is needed to completely dissolve the polymer-drug matrix, this method may not be not desirable for thermally unstable drugs. 

Phospholipid polymers having a 2-methacryloylox-yethyl phosphorylcholine (MPC) were investigated as a solubilizer for paclitaxel. The paclitaxel solubility was observed to increase up to 5.0mg/ml in the presence of a copolymer of MPC and Ai-butyl methacrylate (BMA), poly(MPC-co-BMA), with 70mol% of the BMA unit. The MPC polymer forms a polymer aggregate with the diameter of 23 nm, called a polymeric lipid nanosphere, in aqueous media by hydrophobic interaction, which may solubilize hydrophobic drugs. 

The solubilization techniques for injectable formulations are similar to those in oral formulations and include pH adjustment, mixed aqueous/organic cosolvents, organic solvent mixtures, cyclodextrin com-plexation, emulsions, liposomes, polymeric gels, and combinations of techniques. " Molecules that are non-ionizable, lipophilic, and non-polar are challenging to formulate owing to their low water solubility and no effect of pH on solubility. Examples include paclitaxel, docetaxel, cyclosporin A, etoposide, loraze-pam, tacrolimus, testosterone enanthate, and halo-peridol decanoate, and they are all solubilized in non-aqueous solutions composed entirely of organic solvent(s), which are usually but not always diluted prior to administration. 

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... 

Yao Z, Zhang C et al (2007) A series of novel chitosan derivatives synthesis, characterization and micellar solubilization of paclitaxel. Carbohydr Polym 68 781-792... 

Li H, Liu J et al (2009) Synthesis of novel pH-sensitive chitosan graft copolymers and micellar solubilization of paclitaxel. Int J Biol Macromol 44 249-256... 

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