Utility of Films to Anticipate Effect of Drug Load and Polymer on Dissolution Performance from Tablets of Amorphous Itraconazole Spray-Dried Dispersions.

Because spray-dried dispersion (SDD) performance depends on polymer selection and drug load, time- and resource-sparing methods to screen drug/polymer combinations before spray drying are desirable. The primary objective was to assess the utility of films to anticipate the effects of drug load and polymer grade on dissolution performance of tablets containing SDDs of itraconazole (ITZ). A secondary objective was to characterize the solid-state attributes of films and SDDs to explain drug load and polymer effects on dissolution performance. SDDs employed three different grades of hypromellose acetate succinate (i.e., either HPMCAS-L, HPMCAS-M, or HPMCAS-H). Solid-state characterization employed differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Results indicate that films correctly anticipated the effects of drug load and polymer on dissolution performance. The best dissolution profiles were observed under the following conditions: 20% drug loading performed better than 30% for both films and SDDs, and the polymer grade rank order was HPMCAS-L > HPMCAS-M > HPMCAS-H for both films and SDDs. No dissolution was detected from films or SDDs containing HPMCAS-H. Solid-state characterization revealed percent crystallinity and phase miscibility as contributing factors to dissolution, but were not the sole factors. Amorphous content in films varied with drug load (10% > 20% > 30%) and polymer grades (HPMCAS-L > HPMCAS-M > HPMCAS-H), in agreement with dissolution. In conclusion, films anticipated the rank-order effects of drug load and polymer grade on dissolution performance from SDDs of ITZ, in part through percent crystallinity and phase miscibility influences.

The effects of spray drying, HPMCAS grade, and compression speed on the compaction properties of itraconazole-HPMCAS spray dried dispersions.

Spray dried dispersions (SDDs) have the potential to dramatically improve the oral bioavailability of drugs with poor water solubility. However, SDDs tend to have material attributes, such as small particle size, low bulk density, and poor flowability, which are undesirable for downstream processing such as tableting. The objective was to perform a comprehensive compaction characterization of both physical mixtures and SDDs consisting of itraconazole (ITZ) and hypromellose acetate succinate (HPMCAS) to elucidate process and material influences on compressibility and compactibility. We fabricated SDDs with 20% ITZ as a model BCS Class 2 drug and 80% HPMCAS as a polymer carrier. Results indicate that SDDs, as well physical mixtures of ITZ and HPMCAS, were easily deformable with similar compressibility profiles across all compression speeds. Analysis of Heckel plots revealed that yield pressures were fairly low for both physical mixtures and SDDs (43.97-59.75 MPa), indicative of ductile materials. SDDs had a much greater propensity to laminate, especially at higher compression speeds, compared to physical mixtures. This difference is likely due to the higher elastic recovery of SDDs. However, for intact tablets, the mechanical strength of compacts from SDDs tended to be higher than those produced from physical mixtures, likely due to the much smaller particle size of the SDDs. Importantly, examination of the compacts with differential scanning calorimetry did not detect any drug crystallization as a result of compaction. In conclusion, while spray drying did not significantly alter the compressibility of binary mixtures ITZ and HPMCAS, it dramatically impacted compactibility and tabletability, increasing elastic recovery, and making the mixtures more prone to lamination. However, at low compression speeds, SDDs produced tablets with higher tensile strength than physical mixtures.

Pharmacokinetics and Safety Assessment of l-Tetrahydropalmatine in Cocaine Users: A Randomized, Double-Blind, Placebo-Controlled Study.

Cocaine use disorder (CUD) remains a significant public health challenge. l-Tetrahydropalmatine (l-THP), a well-tolerated and nonaddictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self-administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of l-THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty-four cocaine-using adult men were randomized to receive l-THP (30 mg twice a day orally) or placebo double-blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, ECG, clinical laboratory tests, and standardized self-report instruments. Peripheral venous blood was collected periodically and later assayed for l-THP and cocaine using highly sensitive and specific ultraperformance liquid chromatography-fluorescence detection (UPLC-FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5-day course of l-THP was safe and well tolerated and did not affect cocaine's PK or its acute cardiovascular effects. The cocaine AUC0→∞ was 211.5 and 261.4 h·ng/mL, and the Cmax was 83.3 and 104.5 ng/mL for the l-THP and placebo groups, respectively. In addition there were no significant differences in the number of side effects reported in each group (l-THP group 22 [48%], placebo group 24 [52%]) or vital signs including, heart rate, blood pressure, complete blood count, or ECG. These findings suggest that oral THP has promise for further development as a treatment for CUD.