This study aimed to investigate the role of micellization of sodium lauryl sulfate (SLS) in poloxamer 407 (POX)-based solid dispersions (POX-based SDs) using the anti-solvent method in enhancing the dissolution rate of practically water-insoluble cilostazol (CLT). Herein, SLS was incorporated into CLT-loaded SDs, at a weight ratio of 50:50:10 of CLT, POX, and SLS by three different methods: anti-solvent, fusion (60 °C), and solvent (ethanol) evaporation. The SDs containing micellar SLS in the anti-solvent method were superior in the transformation of the crystalline form of the drug into a partial amorphous state. It was notable that there was an existence of a hydrophobic interaction between the surfactant and the hydrophobic regions of polymer chain via non-covalent bonding and the adsorption of micellar SLS to the POX-based SDs matrix. Moreover, SLS micellization via the anti-solvent method was effectively interleaved in SDs and adhered by the dissolved CLT, which precluded drug particles from aggregation and recrystallization, resulting in improved SD wettability (lower contact angle) and reduced particle size and dissolution rate. In contrast, SDs without micellar SLS prepared by the solvent method exerted drug recrystallization and an increase of particle size, resulting in decreased dissolution. Incorporation of surfactant below or above critical micellar concentration (CMC) in SDs using the anti-solvent method should be considered in advance. Dissolution results showed that the pre-added incorporation of micellar SLS into POX-based SDs using the anti-solvent method could provide a way of a solubilization mechanism to enhance the dissolution rate of poorly water-soluble drugs.

Purpose: To conjugate different degree of saturation of C18 fatty acids (stearic acid, oleic acid, and linoleic acid) with the hydroxyl groups of leuprolide acetate (LEU acetate) and to investigate the controlled release and enhanced permeability through self-assembled nanoparticles (L18FNs). Methods: Yamaguchi esterification with benzoyl chloride and DMAP (4-Dimethylaminopyridine) allowed the conjugation of the fatty acid to the hydroxyl group of LEU. The three conjugates were then designated as stearic acid-conjugated LEU, LSC, oleic acid-conjugated LEU, LOC, and linoleic acid-conjugated LEU, LLC, respectively. The conjugates (L18FCs) were purified using preparative HPLC (Prep-HPLC) and identified through various instrumental analyses. Results: The zeta potential, particle size, and morphology of each L18FNs were evaluated. In the case of LSNs, the zeta potential value was relatively low and the particle size was larger than LONs and LLNs owing to the higher hydrophobicity of saturated fatty chain, while the LLNs showed a higher zeta potential and smaller particle size. In human plasma, LLC showed the fastest degradation rate with the highest accumulative drug release. The permeability of L18FNs was analyzed through the Franz diffusion cell experiment, confirming that the degree of saturation of fatty acids affects the permeability of LFNs. While the permeability of LSNs was not significantly enhanced due to higher particle size after nanonization, LONs and LLNs increased 1.56 and 1.85 times in permeation, respectively, compared to LEU. Conclusion: Utilization of different degree of saturation of fatty acids to conjugate a peptide drug could provide pharmaceutical versatility via self-assembly and modification of physicochemical properties.

Background: Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity. Purpose: To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs). Methods: LEU–fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3. Results: Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days. Conclusion: The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides. Graphical Abstract:

Purpose: To investigate the effects of solvents on the formation of self-assembled nanonization of albumin-oleic acid conjugates (AOCs) using a solvent exchange mechanism for the construction of in situ forming implants (ISFI). Methods: A poorly water-soluble drug, paliperidone palmitate (PPP), was chosen as the model drug. AOC was synthesized with the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) reaction. Dichloromethane, tetrahydrofuran, ethanol, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and deionized water were selected to investigate the formation of self-assembled AOC nanoparticles (AONs). The volume ratios of organic solvents against water could determine the miscibility, injectability, and in situ nanonizing capability without aggregation. Results: As the polarity of the organic solvents increased, the AONs exhibited a spherical shape, and the larger the volume of the solvent, the smaller the size of the AONs. To use AOC in ISFI for controlled release of PPP, poly(d,l-lactide-co-glycolide) (PLGA) was combined with the AOC in 2 mL of N-methyl-2-pyrrolidone and water solution (1.8/0.2 ratio). The release rates of all formulations exhibited similar curve patterns overall but were more controlled in decreasing order as follows: AOC, PLGA, and AOC/PLGA for 14 days. Conclusion: A combined formulation of AOC and PLGA was found to effectively control the initial burst release of the drug.