Impact of Methods of Preparation on Mechanical Properties, Dissolution Behavior, and Tableting Characteristics of Ibuprofen-Loaded Amorphous Solid Dispersions.

This study aims to improve the biopharmaceutical, mechanical, and tableting properties of a poorly soluble drug, ibuprofen (IBP), by preparing amorphous solid dispersion (ASD) followed by a sustained-release tablet formulation. A suitable polymer to develop an ASD system was chosen by utilizing the apparent solubility of IBP in various polymer solutions. ASDs containing various ratios of IBP and selected polymer were prepared by the melt fusion (MF) method. ASD containing optimized drug-polymer ratio prepared by freeze-drying (FD) method was characterized and compared physicochemically. The solubility of IBP in water increased 28-fold and 35-fold when formulated as ASD by MF and FD, respectively. Precise formulations showed amorphization of IBP and increased surface area, improving solubility. The dissolution pattern of optimized ASD-IBP in pH 6.8 phosphate buffer after 60 min in MF and FD was enhanced 3-fold. In addition, direct compression tablets comprising optimized ASD granules from MF and FD were made and assessed using compendial and noncompendial methods. ASD-IBP/MF and ASD-IBP/FD formulations showed a similar drug release profile. In addition, 12 h of sustained IBP release from the ASD-IBP-containing tablets was obtained in a phosphate buffer with a pH of 6.8. From the dissolution kinetics analysis, the Weibull model fitted well. The drug release pattern indicated minimal variations between tablets formed using ASD-IBP prepared by both procedures; however, pre- and postcompression assessment parameters differed. From these findings, the application of ASD and sustained-release polymers in matrix formation might be beneficial in improving the solubility and absorption of poorly soluble drugs such as IBP.

Parkinson's Disease: Exploring Different Animal Model Systems.

Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson's disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson's disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient's motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson's diseases. These include animal systems with induction of Parkinson's, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson's disease animal model systems and their applications and limitations.

Biophysical Insights into Implications of PEG-400 on the α-Crystallin Structure: Multispectroscopic and Microscopic Approach.

Aggregation and precipitation of α-crystallin play a vital role in the cataract development. This study was targeted to delineate the effect of PEG-400 on the structural integrity of α-crystallin employing a multispectroscopic and microscopic approach. Intrinsic fluorescence and UV-vis spectroscopy suggested alterations in the tertiary structure of α-crystallin, namely global transition of native α-crystallin to a non-native form in the presence of PEG-400. Circular dichroism spectroscopy suggested secondary structural transition in a native conformation of α-crystallin in the presence of PEG-400. Loss in the native conformation of α-crystallin is implicated in cataract developments, thus highlighting the clinical significance of this work. Further, a significant increase in ANS fluorescence of PEG-400-incubated α-crystallin (7 days) suggested this non-native form to be molten globule (MG)-like state. Increased Thioflavin T fluorescence (ThT) and congo red (CR) absorbance along with transmission electron microscopy (TEM) confirmed the formation of the aggregates of α-crystallin after prolonged incubation with PEG-400. Insights into PEG-400-induced structural alterations can provide a platform to search for new therapeutic molecules that can combat α-crystallin-directed eye diseases.

Effects of Ethylene Glycol on the Structure and Stability of Myoglobin Using Spectroscopic, Interaction, and In Silico Approaches: Monomer Is Different from Those of Its Polymers.

Investigation of changes in thermal stabilities and structures of proteins in the presence of different co-solutes (ligands) is an integral part in the basic research, discovery, and development of drugs. Ethylene glycol (EG) is known to be toxic and causes teratogenic, inducing primarily skeletal and external malformations and other diseases. The effect of EG on the structure and thermal stability of myoglobin (Mb) was studied using various spectroscopic techniques at pH 7.0 and two different temperatures. As revealed by circular dichroism, Trp fluorescence, nano-DSF, and absorption (UV and visible) measurements, EG (i) has no significant effect on secondary and tertiary structures of Mb at 25 °C, and (ii) it decreases the thermal stability of the protein, which increases with increasing concentration of EG. As revealed by ANS (8-anilino-1-naphthalene sulfonic acid) fluorescence measurements, heat-induced denatured protein has newly exposed hydrophobic patches that bind to ANS. Isothermal titration calorimetry revealed that the interaction between EG and Mb is temperature dependent; the preferential interaction of EG is entropy driven at low temperature, 298 K (25 °C), and it is enthalpy driven at higher temperature, 343 K (70 °C). Molecular docking study showed that EG interacts with side chains of amino acid residues of Mb through van der Waals interactions and hydrogen bonding.

Carbohydrate-Based Macromolecular Crowding-Induced Stabilization of Proteins: Towards Understanding the Significance of the Size of the Crowder.

There are a large number of biomolecules that are accountable for the extremely crowded intracellular environment, which is totally different from the dilute solutions, i.e., the idealized conditions. Such crowded environment due to the presence of macromolecules of different sizes, shapes, and composition governs the level of crowding inside a cell. Thus, we investigated the effect of different sizes and shapes of crowders (ficoll 70, dextran 70, and dextran 40), which are polysaccharide in nature, on the thermodynamic stability, structure, and functional activity of two model proteins using UV-Vis spectroscopy and circular dichroism techniques. We observed that (a) the extent of stabilization of α-lactalbumin and lysozyme increases with the increasing concentration of the crowding agents due to the excluded volume effect and the small-sized and rod-shaped crowder, i.e., dextran 40 resulted in greater stabilization of both proteins than dextran 70 and ficoll 70; (b) structure of both the proteins remains unperturbed; and (c) enzymatic activity of lysozyme decreases with the increasing concentration of the crowder.

Design, characterization and in vitro evaluation of HPMC K100 M CR loaded Fexofenadine HCl microspheres.

The aim of the current study was to formulate Fexofenadine hydrochloride loaded sustained release microspheres using HPMC K100 M CR, a release retardant hydrophilic polymer by solvent evaporation method. The effect of different drug loading on drug content, drug encapsulation efficiency and release of drug was monitored. The studies on in vitro release mechanism were performed using USP paddle method with 900 ml of phosphate buffer (pH 6.8) for 10 h at 100 rpm. The mechanism of the drug release was determined by fitting in vitro release data to various release kinetic models such as the zero order, first order, Higuchi, Hixson Crowell and Korsemeyer-Peppas model and finding R(2) values for the release profile corresponding to each model. The results confirm that the release rate of the drug from the microspheres is highly affected by the drug to polymer ratio. The study finds that Higuchi release kinetics, Korsmeyer-Peppas release kinetics and Hixson-Crowell release kinetics were the major release mechanism. The release mechanism was found to be non-Fickian with increase of polymer content. Scanning electron microscopic technique was performed to obtain the morphological changes due to different drug loading. Differential scanning calorimetry and Fourier transform infra-red spectroscopy was performed to determine any interaction of drug with the polymer. A statistically significant variation in release rate was observed for variation in the amount of HPMC K100 M CR. In the present study, a series of sustained release formulations of Fexofenadine hydrochloride were developed with different drug loading so that these formulations could further be evaluated from the in vivo studies. The formulations were found to be stable and reproducible.