Polymeric Micelles Based on Amphiphilic Scorpion-like Macromolecules: Novel Carriers for Water-Insoluble Drugs

No HeadingPurpose. The objective was to evaluate amphiphilic scorpion-like macromolecules (AScMs) as drug carriers for hydrophobic drugs.Methods. Indomethacin (IMC) was incorporated into two AScM micelles (M₁₂P₅ and M₁₂P₂) by the O/W emulsion technique. The influences of IMC:polymer feed ratio and molecular weight of the hydrophilic block of AScMs on the micelle size, IMC entrapment efficiency and release behavior were investigated. Furthermore, cytotoxicity of the AScMs was evaluated with human umbilical vein endothelial cells (HUVEC).Results. The maximal IMC entrapment efficiency in M₁₂P₅ and M₁₂P₂ micelles (72.3 and 20.2%, respectively) was obtained at ratios of 0.1 to 1 for indomethacin:polymer. The sizes of IMC-loaded M₁₂P₅ and M₁₂P₂ polymeric micelles were <20 nm with a narrow size distribution. In vitro release studies revealed that IMC released from M₁₂P₅ and M₁₂P₂ polymeric micelles showed sustained release behavior during the 24 h of experiment. Additionally, M₁₂P₅ and M₁₂P₂ polymeric micelles did not induce remarkable cytotoxicity against HUVEC cells at concentrations up to 1 and 0.5 mM, respectively.Conclusions. The amphiphilic scorpion-like macromolecules may be useful as novel drug carriers because of their small size, ability to encapsulate hydrophobic drugs and release them in a sustained manner as well as low cytotoxicity.     

Mixed Micelles as a Proliposomal,Lymphotropic Drug Carrier

Four lipophilic, low molecular weight drugs solubilized in phosphatidylcholine–bile salt mixed micelles were injected s.c. into the hind legs of sheep and their cumulative recoveries in lymph draining from the site of application were determined. Surprisingly, the cumulative recoveries (percentage of dose) varied between less than 1 and 60%. We found that there is a correlation between the lipophilicity of the drug (log P octanol/water R _m° value) and the proportion of the dose absorbed by the lymphatic route. Drugs with R _m° values >10 are absorbed preferentially by the lymphatics (>50% of dose), whereas compounds with R_m° values <4 are hardly absorbed at all by the lymphatics (<10% of dose). By applying the prodrug principle we demonstrated that it is also possible to target drugs with R_m° values <4 to the lymphatics. Furthermore, the analysis of the collected lymph samples by gel filtration, quasi-elastic light scattering, and electron microscopy revealed that, following s.c. administration, mixed micelles are converted into homogeneous, unilamellar vesicles. In conclusion, these results suggest that mixed micelles may represent a suitable delivery system for low molecular weight drugs whose targets are lymphoid cells. In addition, for drugs where liposomal application leads to a therapeutic advantage, the thermo-dynamically stable mixed micelle could be a good alternative to the liposome. However, for both applications a high drug lipophilicity is a prerequisite.     

Evaluation of Granulated Lactose as a Carrier for Dry Powder Inhaler Formulations 2: Effect of Drugs and Drug Loading

Previously, granulated lactose carriers were shown to improve uniformity and aerosolization of a low-dose model drug. In the present study, the blending uniformity and aerosol dispersion performance were assessed for 2 model drugs salbutamol sulfate (SS) and rifampicin (RIF), blended at high loadings (10% or 30% drug) with granulated lactose carriers. The model drug powders differed in particle size distribution, morphology, density, and surface energies. Content uniformity of RIF blends was better than that of SS. Aerosolization studies showed that all blend formulations had acceptable emitted fractions (>70%). The SS blends showed low induction-port deposition (6%-10%) compared to RIF (5%-30%). This difference was greater at high flow rates. At 90 L/min, the low induction port deposition of SS blends allowed high fine particle fraction (FPF) of 73%-81%, whereas the FPF of the RIF blends was around 43%-45% with higher induction port deposition. However, SS blends exhibited strong flow rate–dependent performance. Increasing the flow rate from 30 L/min to 90 L/min increased SS FPF from approximately 20% to 80%. Conversely, RIF blends were flow rate and drug loading independent. It was concluded that the aerosolization of high drug–loaded dry powder inhaler formulations using granulated lactose, particularly flow rate dependency, varies with active pharmaceutical ingredient properties.