Formulation Strategies To Enhance Solubility And Permeability Of Small Molecules For Drug Delivery Applications

Pradeep Kumar Bolla, University of Texas at El Paso


All the new chemical entities/drug molecules intended for therapeutic use must be administered using an appropriate delivery system/dosage form to achieve maximum bioavailability. However, designing a drug delivery system is complex as several factors such as lipophilicity, molecular mass, crystallinity, ionic charge, polymorphic forms and hydrogen bonding) affect the solubility and permeability of these molecules. Biopharmaceutics drug classification system (BCS) categorizes the existing drugs into four classes based on the aqueous solubility and membrane permeability and it is reported that >70% of the drugs are poorly soluble and belong to BCS class II and BCS class IV. Several physical, chemical and formulation techniques have been employed to improve the bioavailability. This dissertation delineates several formulation strategies to improve the solubility and permeability of small molecules for drug delivery applications. Global incidence of superficial fungal infections caused by dermatophytes is high and affects around 40 million people. It is the fourth most common cause of infection. Clotrimazole, a broad-spectrum imidazole antifungal agent is widely used to treat fungal infections. Conventional topical formulations of clotrimazole are intended to treat infections by effective penetration of drugs into the stratum corneum. However, drawbacks such as poor dermal bioavailability, poor penetration, variable drug levels limit the efficiency. The first study was aimed to load clotrimazole into ufosomes and evaluate its topical bioavailability. Clotrimazole loaded ufosomes were prepared using cholesterol and sodium oleate by thin film hydration technique and evaluated for size, poly dispersity index (PDI), and entrapment efficiency to obtain optimized formulation. Optimized formulation was characterized using scanning electron microscopy (SEM), x-ray diffraction (XRD) and differential scanning calorimetry (DSC). Skin diffusion studies and tape-stripping were performed using human skin to determine the amount of clotrimazole accumulated in different layers of the skin. Results showed that the optimized formulation had vesicle size <250 nm with>~84% entrapment efficiency. XRD and DSC confirmed the entrapment of clotrimazole into ufosomes. No permeation was observed through the skin up to 24 h following the permeation studies. Tape-stripping revealed that ufosomes led to accumulation of more clotrimazole in the skin compared to marketed formulation (Perrigo). Overall, results revealed the capability of ufosomes in improving the skin bioavailability of clotrimazole. Perinatal asphyxia caused due to hypoxia complicates and causes hypoxic-ischemic encephalopathy (HIE). Therapeutic hypothermia widely used to treat HIE and is successful in 50%-60% patient population. It was reported that lutein supplementation showed neuroprotective properties in rat model of neonatal HIE. Lutein has poor bioavailability owing to poor aqueous solubility. In the second study, lutein was encapsulated into polymeric nanoparticles (PLGA and PLGA-PEG-FOLATE) and evaluated enhanced uptake in human neuroblastoma cells. Lutein loaded polymeric nanoparticles were prepared using O/W emulsion solvent-evaporation technique. Particle diameter and zeta potential (ZP) were measured using dynamic light scattering (DLS). Other characterizations included DSC, FTIR, SEM, and in vitro release studies. In vitro uptake studies were conducted in neuroblastoma cells using flow cytometry, confocal microscopy and high-performance liquid chromatography analysis. Lutein was successfully encapsulated into PLGA and PLGA-PEG-FOLATE nanoparticles with uniform size distribution of around 200 nm and high ZP. Entrapment efficiency of lutein was ~61% and ~73% for lutein PLGA and PLGA-PEG-FOLATE nanoparticles, respectively. DSC and FTIR confirmed encapsulation of lutein into nanoparticles. Cumulative release of lutein was higher in PLGA nanoparticles with 100% release within 24 hours. In PLGA-PEG-FOLATE nanoparticles, cumulative release was ~80% at 48 hours. Cellular uptake studies in neuroblastoma cells confirmed a significant increase in lutein uptake with PLGA-PEG-FOLATE nanoparticles compared to PLGA nanoparticles and lutein alone. Findings from this study suggest that lutein loaded PLGA-PEG-FOLATE nanoparticles can be potentially used for treatment of HIE. Overuse and misuse of antibiotics in clinics and poor new antibiotic pipeline in pharmaceutical industries have contributed to antibiotic crisis. Silver complexes are effective as broad-spectrum antibiotics due to chemical nature. Furosemide-silver complex (Ag-FSE) has been recently reported to have antibacterial activity that is, however, limited by its poor solubility in water and majority of organic solvents. Solid lipid nanoparticles (SLNs) offer advantages such as controlled and sustained release, enhanced solubility, scale-up and, biocompatibility. Present study aims to encapsulate Ag-FSE into SLNs and evaluate its sustained and improved antibacterial activity. Ag-FSE SLNs were prepared using hot homogenization and ultrasonication method. Size, PDI and ZP of Ag–FSE SLNs, evaluated using DLS, were 129.8±38.5 nm, 0.114 ± 0.033 and -23.9 ± 3.62 mV, respectively. Ag-FSE SLNs exhibited high encapsulation efficiency (~93%) and drug loading (~9.3%). Shape of Ag-FSE SLNs was roughly spherical with smooth surfaces. In vitro release studies confirmed that encapsulation of Ag-FSE into SLNs resulted in sustained release of Ag-FSE over 96 h. Results also confirmed 2-fold and 4-fold enhancement of activity against Pseudomonas aeruginosa and Staphylococcus aureus, respectively. In conclusion, Ag-FSE SLNs can be considered as promising topical antibacterial agent against bacterial infections.

Subject Area

Biomedical engineering|Pharmaceutical sciences|Chemical engineering

Recommended Citation

Bolla, Pradeep Kumar, "Formulation Strategies To Enhance Solubility And Permeability Of Small Molecules For Drug Delivery Applications" (2020). ETD Collection for University of Texas, El Paso. AAI27998678.