Environmental Engineering Reference
In-Depth Information
16.1
Introduction
By some estimation, as much as 40 % of potentially valuable drug candidates
identified by high throughput screening are rejected and never enter a formulation
development stage due to their poor water solubility [ 1 ]. In order to attain expected
therapeutic effect of such drug, it is usually required that a solubilized form of the
drug be administered to a patient. For this purpose, a number of approaches have
been adopted, which are based on the use of cosolvents, surfactants, soluble form of
the drugs (salts), prodrugs, soluble polymer (
-cyclodextrin)-drug complexes, spe-
cial drug carriers such as liposomes, micro- or nano-emulsions, and others. Each of
the above methods is hampered by one or more particular problems. The capacity of
the liposomal membrane and cyclodextrin inner cavity for carrying water insoluble
molecules is limited and thus their solubilization capacity varies from drug to drug
[ 2 ]. Unfortunately, most liposome formulations are readily disrupted by intestinal
detergents, such as bile salts, and are subject to degradation by intestinal phospho-
lipases. Both mechanisms trigger the premature release of the liposome-entrapped
drug in the gastrointestinal (GI) fluid [ 3 ]. In addition to liposomes, other colloidal
formulations, such as emulsions and microemulsions, are effective for oral admin-
istration of drugs with limited solubility in biological fluids [ 4 ]. Compared to
emulsions, microemulsions offer several advantages as drug delivery systems,
such as high solubilization capacity, thermodynamic stability, and ease of prepara-
tion. However, the administration of microemulsions, especially castor oil-based
formulations has triggered adverse events, most frequently renal dysfunction,
hypertension, and hepatotoxicity [ 5 ].
The methods based on the surfactant micelles to solubilize hydrophobic drugs
have problems in that most of the surfactants are relatively toxic and that precip-
itation of hydrophobic drug occurs when subjected to dilution with aqueous solu-
tions (such as physiological fluids upon a parenteral administration) [ 6 ]. Another
option is to use certain micelle-forming surfactants in formulations of insoluble
drugs. Surfactants cannot retain solubilized material at concentrations lower than
their critical micelle concentration (CMC) value, which is typically rather high in
the cases of conventional low molecular weight surfactants [ 7 ].
Currently in clinical practice, the excipients used in intravenous formulations for
anticancer drugs are toxic, producing adverse reactions that prove lethal to patients.
Cremophor EL (polyethoxylated castor oil) induces hypersensitivity reactions
along with nephrotoxicity and neurotoxicity. This particular formulation has other
problems, i.e., it tends to form minute precipitates which require the use of a filter in
the injection line and the required period of administration is long about 24 h
[ 8 ]. Dimethyl sulfoxide, ethanol, and Tween also produce toxic reactions on
prolonged use. The formation of salts or pH adjustment facilitates the dissolution
of poorly soluble drugs if they contain ionizable groups. However, in some cases,
the extremes in pH that required for solubilization of drugs are not physiologically
acceptable.
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