Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.

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Epithelial flux and permeability across bovine olfactory tissue were compared when levodopa (L-DOPA) was loaded in different physical states. Aqueous solution of L-DOPA was prepared in Krebs-Ringer buffer (KRB), at a concentration (0.75 mg/mL) verified to be less than the saturation solubility at both 25 and 37°C. Sodium metabisulfite was added to solution to minimize L-DOPA oxidation; chemical stability of aqueous L-DOPA was evaluated using HPLC-UV. Solid-state characterization of unprocessed, dry, crystalline L-DOPA powder was performed using TGA, DSC, PXRD, and optical microscopy to ensure that preparation of L-DOPA microparticles used for diffusion experiments did not elicit a phase change. Measurements of in vitro flux were made for all preparations, using freshly excised bovine olfactory mucosal membrane. Samples obtained from transport studies were analyzed by HPLC-UV. Tissue viability was measured before and after experiments using transdermal epithelial electrical resistance (TEER). The average steady-state flux (J ) of L-DOPA from solid microparticles directly deposited on nasal epithelial tissue was 6.08 ± 0.69 μg/cm/min, approximately three times greater than the J measured for L-DOPA from solution (2.13 ± 0.97 μg/cm/min). The average apparent permeability coefficient (P ) of L-DOPA was calculated to be 4.73 × 10 cm/s. These findings suggest that nasal delivery of L-DOPA by administration of solid microparticles not only benefits from improved chemical and microbiological stability by avoiding the use of aqueous formulation vehicle but also does not compromise cumulative mass transport across the olfactory membrane.

Nose-to-central nervous system (CNS) drug delivery has shown promising results in preclinical efficacy models and exploratory human clinical trials. There are two primary limitations to direct CNS uptake of drugs following intranasal administration. Firstly, non-specific deposition in the nasal cavity leads to systemic absorption instead of CNS absorption, altering CNS bioavailability. Secondly, mucociliary clearance affects the residence time of the formulation at the site of deposition. In vivo results have demonstrated that therapeutic agents targeted to the olfactory region can translocate directly into the CNS via neuronal uptake. In this review, liquid and solid formulations are investigated for their effect on olfactory deposition and clearance based on their physical properties. The influence of delivery device and mode of administration is also reviewed. Case examples are provided to illustrate the importance of optimal deposition in olfactory region.

Fifteen model drugs were quenched from 3:1 (w/w) mixtures with polyethylene glycol 4000 (PEG4000). The resulting solids were characterized using powder X-ray diffraction (PXRD), analysis of pair distribution function-transformed PXRD data (where appropriate), hot-stage polarized light microscopy, and differential scanning calorimetry (DSC). Drug/polymer dispersion behavior was classified using the data from each technique, independent of the others, and limitations to single-method characterization of PEG-based systems are highlighted. The data from all characterization techniques were collectively used to classify dispersion behavior, which was compared with single-technique characterization. Of the 15 combinations, only six resulted in solids whose dispersion behavior was consistently described using each standalone technique. The other nine were misclassified using at least one standalone technique, mainly because the phase behavior was ambiguously interpreted when only the data from one technique were considered. The data indicated that a suite of complementary techniques provided better classifications of the phase behavior. Of all the quenched solids, only cimetidine was fully dispersed in PEG4000, suggesting that it solidified from a completely miscible mixture of molten drug and polymer that did not phase separate upon cooling. In contrast, ibuprofen and PEG4000 completely recrystallized during preparation, whereas the remaining 13 drugs were partially dispersed in PEG4000 at this composition.