Dual Functionality of Poloxamer 188 in Freeze-Dried Protein Formulations: A Stabilizer in Frozen Solutions and a Bulking Agent in Lyophiles.

Poloxamer 188 (P188) was hypothesized to be a dual functional excipient, (i) a stabilizer in frozen solution to prevent ice-surface-induced protein destabilization and (ii) a bulking agent to provide elegant lyophiles. Based on X-ray diffractometry and differential scanning calorimetry, sucrose, in a concentration-dependent manner, inhibited P188 crystallization during freeze-drying, while trehalose had no such effect. The recovery of lactate dehydrogenase (LDH), the model protein, was evaluated after reconstitution. While low LDH recovery (∼60%) was observed in the lyophiles prepared with P188, the addition of sugar improved the activity recovery to >85%. The secondary structure of LDH in the freeze-dried samples was assessed using infrared spectroscopy, and only moderate structural changes were observed in the lyophiles formulated with P188 and sugar. Thus, P188 can be a promising dual functional excipient in freeze-dried protein formulations. However, P188 alone does not function as a lyoprotectant and needs to be used in combination with a sugar.

Role of Poloxamer 188 in Preventing Ice-Surface-Induced Protein Destabilization during Freeze-Thawing.

The phase behavior of poloxamer 188 (P188) in aqueous solutions, characterized by differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry, revealed solute crystallization during both freezing and thawing. Sucrose and trehalose inhibited P188 crystallization during freeze-thawing (FT). While trehalose inhibited P188 crystallization only during cooling, sucrose completely suppressed P188 crystallization during both cooling and heating. Lactate dehydrogenase (LDH) served as a model protein to evaluate the stabilizing effect of P188. The ability of P188, over a concentration range of 0.003-0.800% w/v, to prevent LDH (10 µg/mL) destabilization was evaluated. After five FT cycles, the aggregation behavior (by dynamic light scattering) and activity recovery were evaluated. While LDH alone was sensitive to interfacial stress, P188 at concentrations of ≥0.100% w/v stabilized the protein. However, as the surfactant concentration decreased, protein aggregation after FT increased. The addition of sugar (1.0% w/v; sucrose or trehalose) improved the stabilizing function of P188 at lower concentrations (≤0.010% w/v), possibly due to the inhibition of surfactant crystallization. Based on a comparison with the stabilization effect of polysorbate (both 20 and 80), it was evident that P188 could be a promising alternative surfactant in frozen protein formulations. However, when the surfactant concentration is low, the potential for P188 crystallization and the consequent compromise in its functionality warrant careful consideration.

Effects of Additives on the Physical Stability and Dissolution of Polymeric Amorphous Solid Dispersions: a Review.

Polymeric amorphous solid dispersion (ASD) is a popular approach for enhancing the solubility of poorly water-soluble drugs. However, achieving both physical stability and dissolution performance in an ASD prepared with a single polymer can be challenging. Therefore, a secondary excipient can be added. In this paper, we review three classes of additives that can be added internally to ASDs: (i) a second polymer, to form a ternary drug-polymer-polymer ASD, (ii) counterions, to facilitate in situ salt formation, and (iii) surfactants. In an ASD prepared with a combination of polymers, each polymer exerts a unique function, such as a stabilizer in the solid state and a crystallization inhibitor during dissolution. In situ salt formation in ASD usually leads to substantial increases in the glass transition temperature, contributing to improved physical stability. Surfactants can enhance the wettability of ASD particles, thereby promoting rapid drug release. However, their potential adverse effects on physical stability and dissolution, resulting from enhanced molecular mobility and competitive molecular interaction with the polymer, respectively, warrant careful consideration. Finally, we discuss the impact of magnesium stearate and inorganic salts, excipients added externally upon downstream processing, on the solid-state stability as well as the dissolution of ASD tablets.

Polydopamine-Induced Multilevel Engineering of Regenerated Silk Fibroin Fiber for Photothermal Conversion.

Solid photothermal materials with favorable biocompatibility and modifiable mechanical properties demonstrate obvious superiority and growing demand. In this work, polydopamine (PDA) induced functionalization of regenerated silk fibroin (RSF) fibers has satisfactory photothermal conversion ability and flexibility. Based on multilevel engineering, RSF solution containing PDA nanoparticles is wet spun to PDA-incorporating RSF (PDA@RSF) fibers, and then the fibers are coated with PDA via oxidative self-polymerization of dopamine to form PDA@RSF-PDA (PRP) fibers. During the wet spinning process, PDA is to adjust the mechanical properties of RSF by affecting its hierarchical structure. Meanwhile, coated PDA gives the PRP fibers extensive absorption of near-infrared light and sunlight, which is further fabricated into PRP fibrous membranes. The temperature of PRP fibrous membranes can be adjusted and increases to about 50 °C within 360 s under 808 nm laser irradiation with a power density of 0.6 W cm-2 , and PRP fibrous membranes exhibit effective photothermal cytotoxicity both in vitro and in vivo. Under the simulated sunlight, the temperature of PRP fiber increases to more than 200 °C from room temperature and the material can generate 4.5 V voltage when assembled with a differential thermal battery, which means that the material also has the potential for flexible wearable electronic devices.

Design of Ternary Amorphous Solid Dispersions for Enhanced Dissolution of Drug Combinations.

Using sulfamethoxazole (SMZ) and trimethoprim (TMP) as model drugs, we designed amorphous solid dispersions (ASDs) for the simultaneous solubility enhancement of two active pharmaceutical ingredients (APIs) by exploiting the drug-drug and drug-polymer interactions. In order to make this approach broadly applicable and over a wide dose range, a mixture of SMZ and TMP at weight ratios of 5:1 and 1:5 (w/w) were formulated into ternary ASDs. Depending on the dose ratio of the two drugs, the polymer used was either an aminoalkyl methacrylate copolymer (Eudragit, EDE) or polyacrylic acid. The drug-drug and drug-polymer interactions were characterized to be ionic by infrared and solid-state nuclear magnetic resonance spectroscopy. The interactions resulted in a substantial reduction in molecular mobility, evident from the increase in the structural relaxation time determined by dielectric spectroscopy. The drug-drug interaction resulted in ∼3 orders of magnitude reduction in molecular mobility. The addition of a polymer led to a further decrease in molecular mobility of up to 4 orders of magnitude. The strength of intermolecular interactions was also estimated from the glass transition temperatures of the ASDs obtained by differential scanning calorimetry. The strong intermolecular interactions yielded highly stable ASDs with no evidence of crystallization, both at elevated temperatures and under accelerated storage conditions (40 °C/75% relative humidity; 6 weeks). The dissolution performances of the ASDs were evaluated using the area under the curve (AUC) obtained from the concentration-time profiles under the non-sink condition. SMZ and TMP in their ternary ASDs, when compared with their crystalline counterparts, exhibited up to 6.4- and 4.6-fold increases in AUC, respectively. Importantly, the synchronized release of the two drugs was observed, a desirable attribute in synergistic formulations. A single-phase ternary ASD, stabilized by drug-drug and drug-polymer interactions, is likely responsible for the unique release profile.

Role of polymers in the physical and chemical stability of amorphous solid dispersion: A case study of carbamazepine.

Incorporating the amorphous drug in polymeric components has been demonstrated as a feasible approach to enhance the bioavailability of poorly water-soluble drugs. The objective of this study was to investigate the role of polymers in the stability of amorphous solid dispersion (ASD) by evaluating the drug-polymer interaction, microenvironmental pH, and stability of ASD. Carbamazepine (CBZ), a Biopharmaceutics Classification System Class II compound, was utilized as a model drug. Polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), polyacrylic acid (PAA), and hydroxypropyl methylcellulose (HPMCAS) were selected as model polymers. CBZ ASDs were characterized by X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared (FTIR) spectroscopy, and dissolution studies. Molecular modeling was conducted to understand the strength of interaction between CBZ and each polymer. FTIR spectroscopy and molecular modeling results show that the interaction between CBZ and PAA is the strongest among all the ASDs, as PAA is an acidic polymer with the potential to form strong hydrogen bonding with CBZ. Besides, hydrophobic interaction is detected between CBZ and HPMCAS. CBZ-PAA and CBZ-HPMCAS ASDs reveal better physical stability than CBZ-PVP and CBZ-PVPVA ASDs under 40 °C/75% RH for 8 weeks. However, CBZ-PAA ASD shows chemical degradation after stability testing due to its acidic microenvironmental pH. This paper shows that strong intermolecular interactions between CBZ and polymers contribute to the physical stability of the ASDs. Additionally, acidic polymers yield an acidic microenvironment pH of the ASDs that causes chemical degradation during storage. Hence, a balance between the ability of a given polymer to promote physical stability and chemical stability may need to be considered.

Ag doped Sn3O4 nanostructure and immobilized on hyperbranched polypyrrole for visible light sensitized photocatalytic, antibacterial agent and microbial detection process.

Ag doped Sn3O4 Nanostructure and immobilized on hyperbranched polypyrrole is investigated in this project. The product was synthesized by the hydrothermal synthesis method. The surface and structural characteristics of the product was studied by different instrumental analysis. The fabricated nanocomposites was utilized as a nano photocatalyst in the removal of methylene blue dye. The crystallography results depicts the triclinic phase of Sn3O4 with the crystallite size 36.3 nm. The band gap of the Ag-Sn3O4/hyperbranched polypyrrole was found 1.50 eV from kubelka-munk measurements. The specific surface area was increased in the presence of the hyperbranched polypyrrole as compared to Ag-Sn3O4 samples. The photo-catalytic activity of composites was found 100.0% degradation of CR in 30 min under visible light irradiation. The catalytic kinetic was followed from the first kinetic model. Moreover, the Ag/Sn3O4/hyperbranched polypyrrole was applied as a bactericidal agent against Streptococcus pneumoniae, and Pseudomonas aeruginosa bacteria. Determination of Streptococcus pyogenes as a pathogenic bacteria was investigated by using aptamer/Ag/Sn3O4/hyperbranched polypyrrole in peroxidase activity. The detection limit of S. pyogenes was 71.0 CFU/mL by using the nano-aptamer.

Development and evaluation of orally disintegrating tablets containing the mosapride resin complex.

The purpose of this study was to prepare a mosapride citrate-resin (Amberlite® IRP 88) complex and orally fast-disintegrating tablets of the resin complex. The resinate complex of mosapride-Amberlite® IRP 88, mass ratio 2:1, was prepared in an ethanol-water solution. The effects of alcohol concentration, temperature, and pH of the solution on complex formation were evaluated. The complex physicochemical properties were characterized by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Orally disintegrating tablets were prepared by direct compression and were optimized using the response surface method. Optimized orally fast-disintegrating tablets disintegrated within 18 s. The pH dependence of mosapride release from the tablet decreased drug dissolution in simulated saliva, whereas it promptly released in the pH 1.0 solution. The data reported herein clearly demonstrate that tablets containing the mosapride-Amberlite® IRP 88 complex for oral disintegration could be particularly useful for patients with swallowing difficulties.

Preparation, characterization and pharmacokinetics evaluation of clarithromycin-loaded Eudragit(®) L-100 microspheres.

The aim of this work was to prepare pH-dependent clarithromycin microsphere formulation by emulsion solvent evaporation method, employing Eudragit(®) L-100. Prepared microspheres were evaluated by carrying out in vitro release and in vivo pharmacokinetics studies. Drug-polymer interactions were studied by differential scanning calorimetry, X-ray diffractometry analyses and results showed that clarithromycin was molecularly dispersed in the polymer. The particle size distribution of microspheres was found over the range of 10~50 µm. The drug is hardly released in the HCl solution pH 1.2 in the first 2 h, but is rapidly released in phosphate buffer pH 7.2, and the cumulated release reached 98.1 % at 8 h. The pharmacokinetic profiles were conducted open, randomized, two-period crossover design with a 7-day interval between doses in healthy beagle dogs. The results indicated that the extent of absorption of the clarithromycin-load microspheres was the same as pure drug, but different in the rate of drug absorption in vivo.