Use of Flory-Huggins Interaction Parameter and Contact Angle Values to Predict the Suitability of the Drug-Polymer System for the Production and Stability of Nanosuspensions.

PURPOSE: Use of Flory-Huggins interaction parameter and contact angle values to predict the suitability of the drug-polymer system for the production and stability of nanosuspensions. MATERIAL AND METHODS: Melting point depression of the drug was measured using differential scanning calorimetry. Interaction parameter, χ, was calculated using the melting point depression data to elucidate the drug-polymer interaction strength to predict the suitability of the drug-polymer system for the production and stability of nanosuspensions. Contact angle of the drug films were measured with purified water and 0.1%w/w polymer solutions to predict polymer's suitability for the production and stability of nanosuspension. Nanosuspensions were manufactured to validate the application of the melting point depression approach along with surface property information. RESULTS: All three polymers, HPMC, Soluplus®, and poloxamer exhibited a negative interaction parameter with naproxen and budesonide. Higher negative interaction parameter values for the naproxen-polymer system indicated stronger drug-polymer interactions, while smaller negative interaction parameter values for the budesonide-polymer system indicated weaker drug-polymer interactions. Interaction parameter was not obtained for fenofibrate with HPMC and Soluplus®, and similarly, no interaction parameter was obtained for carvedilol with HPMC, most likely due to weaker drug-polymer interactions. All three polymers provided lower equilibrium contact angle values when compared to purified water, indicating an affinity for polymers. CONCLUSIONS: Successful production and stability of several nanosuspensions were correlated with Flory-Huggins's interaction parameter and contact angle values. In the absence of melting point depression, contact angle values can also be used predict the agglomeration tendencies as we have shown for this study.

Lipid Nanoparticles Improve the Uptake of α-Asarone Into the Brain Parenchyma: Formulation, Characterization, In Vivo Pharmacokinetics, and Brain Delivery.

Treatment of brain-related diseases is one of the most strenuous challenges in drug delivery research due to numerous hurdles, including poor blood-brain barrier penetration, lack of specificity, and severe systemic toxicities. Our research primarily focuses on the delivery of natural therapeutic compound, α-asarone, for the treatment of brain-related diseases. However, α-asarone has poor aqueous solubility, bioavailability, and stability, all of which are critical issues that need to be addressed. This study aims at formulating a lipid nanoparticulate system of α-asarone (A-LNPs) that could be used as a brain drug delivery system. The physicochemical, solid-state properties, stability, and in vitro and in vivo studies of the A-LNPs were characterized. The release of α-asarone from the A-LNPs was prolonged and sustained. After intravenous administration of A-LNPs or free α-asarone, significantly higher levels of α-asarone from the A-LNPs were detected in murine plasma and brain parenchyma fractions, confirming the ability of A-LNPs to not only maintain a therapeutic concentration of α-asarone in the plasma, but also transport α-asarone across the blood-brain barrier. These findings confirm that lipid nanoparticulate systems enable penetration of natural therapeutic compound α-asarone through the blood-brain barrier and may be a candidate for the treatment of brain-related diseases.

COVID-19 associated complications and potential therapeutic targets.

The global pandemic COVID-19, caused by novel coronavirus SARS-CoV-2, has emerged as severe public health issue crippling world health care systems. Substantial knowledge has been generated about the pathophysiology of the disease and possible treatment modalities in a relatively short span of time. As of August 19, 2020, there is no approved drug for the treatment of COVID-19. More than 600 clinical trials for potential therapeutics are underway and the results are expected soon. Based on early experience, different treatment such as anti-viral drugs (remdesivir, favipiravir, lopinavir/ritonavir), corticosteroids (methylprednisolone, dexamethasone) or convalescent plasma therapy are recommended in addition to supportive care and symptomatic therapy. There are several treatments currently being investigated to address the pathological conditions associated with COVID-19. This review provides currently available information and insight into pathophysiology of the disease, potential targets, and relevant clinical trials for COVID-19.

Structural Stability of Recombinant Human Growth Hormone (r-hGH) as a Function of Polymer Surface Properties.

PURPOSE: Despite the fact that r-hGH was first approved for use by FDA in 1995 and the conventional dosage form in the market has a limitation of daily subcutaneous injections, there remains a lack of sustained delivery system in the market. Nutropin depot, a long-acting dosage form of r-hGH was approved for marketing by FDA in 1999, however, it was discontinued in 2004. Since then, unabating efforts have been made to develop biodegradable polymer based formulations for r-hGH delivery. However, grey area is the comprehension of structural stability of r-hGH at an interface with the polymer and it is of utmost important to attain safe and efficacious sustained delivery system. The purpose of this study was to evaluate the changes in structure of r-hGH upon adsorption at biodegradable PLGA nanoparticles of different hydrophobicity as a function of pH. METHODS: DLS, fluorescence spectroscopy, and CD were collectively employed to evaluate structural changes in r-hGH. RESULTS: The studies revealed that r-hGH is most stable with low to high hydrophobicity PLGA grades under pH 7.2 followed by 5.3. CONCLUSION: Overall, the nature and magnitude of structural changes observed has a strong dependence on the pH and differences and degree of hydrophobicity of PLGA.

Using PG-Liposome-Based System to Enhance Puerarin Liver-Targeted Therapy for Alcohol-Induced Liver Disease.

A critical issue for alcohol-induced liver disease (ALD) therapeutics is the lack of a highly efficient delivery system. In this study, a Puerarin-propylene glycol-liposome system was prepared for the purpose of targeting puerarin, an isoflavon, to the liver. Transmission electron microscope (TEM) results showed the liposomes to be spherical in shape with an average diameter of 182 nm with a polydispersity index of 0.239. The zeta potential of the particles was about -30 mV. The entrapment efficiency of puerarin was above 90%. MTT-based assay in HpeG2 cells showed no significant cytotoxicity in the presence of up to 25% concentration of the system containing 3% puerarin. In vivo performance of this system was studied in mice. Pharmacokinetics and distribution of puerarin-PG-liposome system was studied relative to puerarin solution at the same dose levels. The results show that puerarin-PG-liposome prolonged drug retention time and decreased elimination of puerarin in mice (AUC of liposome system and solution was 9.5 and 4.0 mg h L-1, respectively). Furthermore, propylene glycol (PG)-liposome system enhanced puerarin distribution into liver and spleen, while decreasing puerarin distribution in other tissues. Overall, the puerarin-PG-liposome system showed enhanced therapeutic effect in mice with ALD.

Design of amphiphilic oligopeptides as models for fine tuning peptide assembly with plasmid DNA.

We discuss the design of novel amphiphilic oligopeptides with hydrophobic and cationic amino acids to serve as models to understand peptide-DNA assembly. Biophysical and thermodynamic characterization of interaction of these amphiphilic peptides with plasmid DNA is presented. Peptides with at least +4 charges favor stable complex formation. Surface potential is dependent on the type of hydrophobic amino acid for a certain charge. Thermodynamically it is a spontaneous interaction between most of the peptides and plasmid DNA. Lys(7) and Tyr peptides with +4/+5 charges indicate cooperative binding with pDNA without saturation of interaction while Val(2)-Gly-Lys(4), Val-Gly-Lys(5), and Phe-Gly-Lys(5) lead to saturation of interaction indicating condensed pDNA within the range of N/Ps studied. We show that the biophysical properties of DNA-peptide complexes could be modulated by design and the peptides presented here could be used as building blocks for creating DNA-peptide complexes for various biomedical applications, mainly nucleic acid delivery.

Influence of N-terminal hydrophobicity of cationic peptides on thermodynamics of their interaction with plasmid DNA.

There is a need to understand the thermodynamics of interaction of cationic peptides with DNA to design better peptide based non-viral gene delivery vectors. The main aim of this study was to understand the influence of N-terminal hydrophobicity of cationic amphiphilic peptides on thermodynamics of interaction with plasmid DNA. The model peptides used were TATPTD and TATPTDs modified at the N-terminal with hydrophobic amino acids. The thermodynamic binding data from isothermal titration calorimetry were compared with ethidium bromide analysis and ultrafiltration to correlate the binding parameters with the structural features of the various peptides used. It was observed that peptides having a smaller hydrophobic domain at the N-terminal have good DNA condensing ability compared with the ones with a longer hydrophobic domain. Calorimetry of peptides that reached saturation binding indicated that enthalpy and entropy are favorable for the interaction. Moreover, the interaction of these peptides with DNA appears to be predominantly electrostatic.

The effect of the structure of small cationic peptides on the characteristics of peptide-DNA complexes.

A series of transcriptional activator (TAT)-protein transduction domains (PTDs) modified with hydrophobic amino acids were used as model cationic amphiphilic peptides to study the effect of hydrophobicity on interaction of such peptides with plasmid DNA. The peptide-DNA complexes were analyzed by dynamic light scattering and gel electrophoresis to determine their size and electrokinetic properties at various +/- charge ratios. Peptides in solution were found to have a tendency to aggregate and the hydrodynamic size of the aggregates depends on the structure of peptide. Peptides with smaller hydrophobic residues at the N-terminal formed smaller complexes with DNA compared to the ones with larger hydrophobic tails. DNA complexes having peptides with more than one hydrophobic moiety at the N-terminal had a tendency to aggregate. Among the peptides having single hydrophobic amino acid at the N-terminal, DNA complexes of Tyr-TAT and Phe-TAT were found to be stable in solution. The size of the hydrophobic domain and the type of hydrophobic amino acid at the N-terminal of cationic amphiphilic peptides play an important role not only in the complex formation but also in stabilizing the system. The studies presented here indicate that there is a potential for strategic development of these peptides into potential non-viral gene delivery vectors.

Effect of arginine hydrochloride and hydroxypropyl cellulose as stabilizers on the physical stability of high drug loading nanosuspensions of a poorly soluble compound.

The objective of the present study is to formulate Naproxen nanosuspensions at high drug concentrations of up to 300 mg/ml using ball milling and is to investigate the additive effect between hydroxypropyl cellulose (HPC) and arginine hydrochloride as stabilizers. The nanosuspensions were obtained at different arginine hydrochloride/polymer weight ratios. Stability of Naproxen suspensions at 100 and 300 mg/ml was determined over a period of 14 days by measuring the particle size. The control, which contained only drug and buffers without the stabilizers agglomerated immediately after preparation. The study of the effect of arginine hydrochloride as a primary stabilizer indicated that arginine hydrochloride levels of up to 0.8% (w/v) were not able to help reduce particle size below one micron, and were also not able to provide stabilization to the suspensions on storage. Therefore, HPC was also added to the system to increase suspensions stability, presumably by a steric repulsion mechanism. When the Naproxen concentration was increased to 300 mg/ml, 1% (w/v) HPC was not able to provide good stabilization and it was found that arginine hydrochloride increased the stabilization efficiency of 1% (w/v) HPC by preventing flocculation. When HPC level was increased to 4% (w/v), HPC was high enough to sufficiently stabilize the nanosuspensions for 2 weeks and thereby could maintain the mean size diameter of the suspensions without the presence of arginine hydrochloride. Furthermore, stable nanosuspensions were successfully lyophilized without the use of additional cryoprotectants.