Studying the factors that impact the dissolution characteristic of complex drug product.

This article summarizes the critical factors involved in product development of a single dosage form formulated by compacting ethyl cellulose (EC) coated controlled release pellets into a tablet. The greatest challenge associated with this type of complex system is to minimize the effect of compression on the drug release. The effects of compression on the drug release were optimized with combination of the following factors (1) particle size of the core pellets, (2) the selection of the coating polymer's viscosity grade, and (3) emergence of cushioning agents. The optimization of these factors provided superior protection for the controlled release coated pellets; therefore, the desired drug release from the tablet was successfully achieved as designed. However, the drug release rates from the coated pellets before and after the compression were minimized and exhibited only a slight difference.

Physicochemical characterization and membrane binding properties of camptothecin.

The intrinsic solubility of the CPT-lactone free base in acidic pH was determined to be 3.44 and 5.11 microM at 22 and 37 degrees C, respectively. The equilibrium solubility of the drug was found to increase with increasing temperature and decreasing pH. The enhanced solubility of the drug at very low pH is attributed to the protonation of the nitrogen atom in the ring B and the increased solvency of the highly concentrated acidic media. The logarithmic value of the intrinsic partition coefficient P of the free base CPT-lactone form was estimated to be 1.65, characteristic of a molecule suitable for absorption. Association constants K(f) of the drug for bilayers composed of the zwitterionic (DOPC) and the negatively charged (DOPG) were determined at acidic pH by fluorescence anisotropy to be 35.4 +/- 4.5 M(-1) and 93.1 +/- 11.0 M(-1), respectively, indicative of the CPT tendency to preferentially bind to negatively charged membranes. The results indicate that at highly acidic media, CPT is positively charged and exists at its stable lactone form of increased solubility and capacity to bind to negatively charged membranes. These features could be used to invent novel formulation strategies to optimize the antitumor activity of CPT.

The Conventional Langmuir Trough Technique as a Convenient Means to Determine the Solubility of Sparingly Soluble Surface Active Molecules: Case Study Cholesterol.

The feasibility of a method based on mass preservation [G. Schwarz, J. Zhang, Chem. Phys. Lipids, 110 (2001) 35-45] to determine the solubility of Cholesterol in water from monomolecular films on air/water interface was investigated. Using a mass balance equation, it was found that Cholesterol undergoes an exponential desorption at very low surface pressures followed by an almost linear desorption into the subphase at higher surface pressures until monolayer collapse. Processing of the surface pressure measurements as a function of trough area in accord with the theory, enabled the accurate determination of the molecular dimensions of Cholesterol as a function of surface pressure. Slight modification of the theory enabled accurate quantification of the surface pressure-independent apparent solubility of Cholesterol and the amount of Cholesterol desorbed into the subphase as a function of surface pressure, in the nanomolar range.

Physicochemical properties affecting lipofection potency of a new series of 1,2-dialkoylamidopropane-based cationic lipids.

The in vitro transfection activity of a novel series of N,N'-diacyl-1,2-diaminopropyl-3-carbamoyl-(aminoethane) derivatives was evaluated against a mouse melanoma cell line at different +/- charge ratios, in the presence and absence of helper lipids. Only the unsaturated derivative N,N'-dioleoyl-1,2-diaminopropyl-3-carbamoyl-(aminoethane), (1,2lmp[5]) mediated significant increase in the reporter gene level which was significantly boosted in the presence of DOPE peaking at +/- charge ratio of 2. The electrostatic interactions between the cationic liposomes and plasmid DNA were investigated by gel electrophoresis, fluorescence spectroscopy, dynamic light scattering and electrophoretic mobility techniques. In agreement with the transfection results, 1,2lmp[5]/DOPE formulation was most efficient in associating with and retarding DNA migration. The improved association between the dioleoyl derivative and DNA was further confirmed by ethidium bromide displacement assay and particle size distribution analysis of the lipoplexes. Differential scanning calorimetry studies showed that 1,2lmp[5] was the only lipid that exhibited a main phase transition below 37 degrees C. Likewise, 1,2lmp[5] was the only lipid found to form all liquid expanded monolayers at 23 degrees C. In conclusion, the current findings suggest that high in vitro transfection activity is mediated by cationic lipids characterized by increased acyl chain fluidity and high interfacial elasticity.

In vitro lipofection with novel asymmetric series of 1,2-dialkoylamidopropane-based cytofectins containing single symmetric bis-(2-dimethylaminoethane) polar headgroups.

Novel N,N'-diacyl-1,2-diaminopropyl-3-carbamoyl[bis-(2-dimethylaminoethane)] bivalent cationic lipids were synthesized and evaluated for in vitro transfection activity against a murine melanoma cell line. In the absence of the helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), only the dioleoyl derivative 22 (1,2lb5) elicited transfection activity. The transfection activity of this lipid was reduced when formulated with DOPE. Contrary to that, the dimyristoyl derivative 19 (1,2lb2) mediated no activity when used alone but induced the highest levels of marker gene expression in the presence of DOPE. In an effort to correlate the transfection activity with cationic lipid structures, the physicochemical properties of cationic lipids in isolation and of lipoplexes were studied with surface tensiometry, photon correlation spectroscopy, gel electrophoresis mobility shift assay, and fluorescence techniques. In regard to the lipoplex properties, gel electrophoresis mobility shift assay and EtBr exclusion fluorescence assay revealed that the 1,2lb5 was the only lipid to associate and condense plasmid DNA, respectively. Photon correlation spectroscopy analysis found that 1,2lb5/DNA complexes were of relatively small size compared to all other lipoplexes. With respect to the properties of isolated lipids, Langmuir monolayer studies and fluorescence anisotropy on cationic lipid dispersions verified high two-plane elasticity and increased fluidity of the transfection competent dioleoyl derivative 1,2lb5, respectively. The results indicate that high transfection activity is mediated by cationic lipids characterized by an expanded mean molecular area, high molecular elasticity, and increased fluidity.