Poloxamer-188 Research Articles

Spectroscopic characterization and pharmacokinetic evaluation of amorphous solid dispersions of glibenclamide for bioavailability enhancement in Wistar rats.

Oral bioavailability of glibenclamide (Glb) was appreciably improved by the formation of an amorphous solid dispersion with Poloxamer-188 (P-188). Poloxamer-188 substantially enhanced the solubility and thereby the dissolution rate of the biopharmaceutics classification system (BCS) class II drug Glb and simultaneously exhibited a better stabilizing effect of the amorphous solid dispersion prepared by the solvent evaporation method. The physical state of the dispersed Glb in the polymeric matrix was characterized by differential scanning calorimetry, X-ray diffraction, scanning electron microscope and Fourier transform infrared studies. In vitro drug release in buffer (pH 7.2) revealed that the amorphous solid dispersion at a Glb-P-188 ratio of 1:6 (SDE4) improved the dissolution of Glb by 90% within 3h. A pharmacokinetic study of the solid dispersion formulation SDE4 in Wistar rats showed that the oral bioavailability of the drug was greatly increased as compared with the market tablet formulation, Daonil®. The formulation SDE4 resulted in an AUC0-24h ~2-fold higher. The SDE4 formulation was found to be stable during the study period of 6 months.

Dissolution enhancement of Gefitinib by solid dispersion and complexation with β-cyclodextrins: In vitro testing, cytotoxic activity, and tablet formulation

Cancer is the leading cause of mortality worldwide. In patients with metastatic non-small cell lung cancer, epidermal growth factor receptor (EGFR) is often overexpressed. Gefitinib (GEF), an inhibitor of EGFR, is approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC). However, the low solubility and dissolution of GEF limits its bioavailability. Numerous methods, including solid dispersion (SD) and complexation, have been reported to enhance the dissolution of poorly soluble drugs. In this study, GEF complexes were prepared using methyl-β-cyclodextrin (MβCD) and hydroxypropyl-β-cyclodextrin (HPβCD) in two molar ratios (1:1 and 1:2), furthermore, GEF SDs were prepared using polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and poloxamer-188(PXM) in three different ratios (1:2, 1:4 and 1:6 w/w). Dissolution studies were conducted on the prepared formulations. Dissolution results showed a 1.22–2.17-fold enhancement in drug dissolution after one hour compared to untreated GEF. Two formulations that showed higher dissolution enhancement were subsequently evaluated for in-vitro cytotoxicity and were formulated into tablets. The selected PVP–GEF (1:4 w/w) and MβCD–GEF (1:1M) formulas displayed improved cytotoxicity compared to untreated GEF. The IC50 values of the PVP–GEF and MβCD–GEF were 4.33 ± 0.66 and 4.84 ± 0.38 µM, respectively which are significantly lower (p < 0.05) than free GEF. In addition, the formulated tablets exhibited enhanced dissolution compared to pure GEF tablets. PVP–GEF SD tablets released (35.1 %±0.4) of GEF after one hour, while GEF-MβCD tablets released (42.2 % ± 0.7) after one hour. In the meantime, tablets containing pure GEF showed only 15 % ± 0.5 release at the same time. The findings of this study offer valuable insights for optimizing the dissolution and hence therapeutic capabilities of GEF while mitigating its limitations.

Effect of hydrophilic polymers on the solubility and dissolution enhancement of rivaroxaban/beta-cyclodextrin inclusion complexes

BCS class II drugs exhibit low aqueous solubility and high permeability. Such drugs often have an incomplete or erratic absorption profile. This study aimed to predict the effects of β-cyclodextrin (βCD) and different hydrophilic polymers (poloxamer 188 (PXM-188), polyvinyl pyrrolidone (PVP) and soluplus (SOLO)) on the saturated solubility and dissolution profile of hydrophobic model drug rivaroxaban (RIV). Binary inclusion complex with βCD were prepared by kneading and solvent evaporation method, at drug to cyclodextrin weight molar ratios of 1:1, 1:2, and 1:4. Saturated solubility of the hydrophobic model moiety was evaluated with βCD to explore the increment in saturated solubility. Dissolution test was carried out to assess the drug release from the produced binary inclusion complex in the aqueous medium. Solid state analysis was performed using Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Scanning electron microscopy (SEM) techniques. When compared to pure drug, the binary complex (Drug: βCD at molar ratio of 1:2 w/w) demonstrated the best performance in terms of enhanced solubility and drug release. Furthermore, ternary inclusion complex was prepared with hydrophilic polymers SOLO, PVP K-30 and PXM-188 at 0.5%,1%,2.5%,5% and 10% w/w to optimized binary formulation RIV:βCD (1:2) prepared by kneading (KN) and solvent evaporation (S.E) method. The findings demonstrated that among ternary formulations (1:2 Drug: βCD: SOLO 10% S.E) manifested greatest improvement in saturated solubility and dissolution rate. Results of solubility enhancement and improvement in dissolution profile of model drug by ternary inclusion complexation were also supported by FTIR, DSC, XRD, and SEM analysis. So, it can be concluded that the ternary inclusion systems were more effective compared to the binary combinations in improving solubility as well as dissolution of hydrophobic model drug rivaroxaban.

Design, Characterization and Pharmacokinetic-Pharmacodynamic Evaluation of Poloxamer and Kappa-Carrageenan-Based Dual-Responsive In Situ Gel of Nebivolol for Treatment of Open-Angle Glaucoma.

This study developed a dual-responsive in situ gel of nebivolol (NEB), a selective β-adrenergic antagonist. The gel could achieve sustained concentrations in the aqueous humor to effectively treat glaucoma. The gel was prepared using a combination of poloxamers (Poloxamer-407 (P407) and Poloxamer-188 (P188)) and kappa-carrageenan (κCRG) as thermo-responsive and ion-sensitive polymers, respectively. Box-Behnken design (BBD) was used to optimize the effect of three critical formulation factors (concentration of P407, P188 and κCRG) on two critical response variables (sol-to-gel transition temperature of 33-35 °C and minimum solution state viscosity) of the in situ gel. A desirability function was employed to find the optimal concentrations of P407, P188 and κCRG that yielded a gel with the desired sol-to-gel transition temperature and solution state viscosity. An NEB-loaded gel was prepared using the optimized conditions and evaluated for in vitro drug release properties and ex vivo ocular irritation studies. Furthermore, ocular pharmacokinetic and pharmacodynamics studies were conducted in rabbits for the optimized formulation. The optimized NEB-loaded gel containing P407, P188 and κCRG had a sol-to-gel transition temperature of 34 °C and exhibited minimum viscosity (212 ± 2 cP at 25 °C). The optimized NEB-loaded gel sustained drug release with 86% drug release at the end of 24 h. The optimized formulation was well tolerated in the eye. Ocular pharmacokinetic studies revealed that the optimized in situ gel resulted in higher concentrations of NEB in aqueous humor compared to the NEB suspension. The aqueous humor Cmax of the optimized in situ gel (35.14 ± 2.25 ng/mL) was 1.2 fold higher than that of the NEB suspension (28.2 ± 3.1 ng/mL), while the AUC0-∞ of the optimized in situ gel (381.8 ± 18.32 ng/mL*h) was 2 fold higher than that of the NEB suspension (194.9 ± 12.17 ng/mL*h). The systemic exposure of NEB was significantly reduced for the optimized in situ gel, with a 2.7-fold reduction in the plasma Cmax and a 4.1-fold reduction in the plasma AUC0-∞ compared with the NEB suspension. The optimized gel produced a higher and sustained reduction in the intra-ocular pressure compared with the NEB suspension. The optimized gel was more effective in treating glaucoma than the NEB suspension due to its mucoadhesive properties, sustained drug release and reduced drug loss. Lower systemic exposure of the optimized gel indicates that the systemic side effects can be significantly reduced compared to the NEB suspension, particularly in the long-term management of glaucoma.

Mechanism of Protein–PDMS Visible Particles Formation in Liquid Vial Monoclonal Antibody Formulation

Visible particles (VPs) formation in liquid monoclonal antibody formulations is a critical quality issue. Formulations that include poloxamer 188 (PX188) as a surfactant are prone to the formation of VPs comprising aggregated complexes of protein and polydimethylsiloxane (PDMS; silicone oil) derived from primary containers. However, the mechanisms through which these VPs form are complicated and remain to be fully elucidated. This study demonstrates for the first time the dominant spot and pathway of protein–PDMS VP formation in a particular liquid vial formulation. Specifically, when a vial sealed with a PDMS-coated stopper is stored in an upright position under conditions whereby the antibody solution has become well-adhered to the stopper and an air phase exists in the vicinity, protein–PDMS aggregates form on the stopper and are then desorbed into the drug solution to be detected as VPs. Here, we evaluated the effects of several factors on VP formation: adhesion of the drug solution to the stopper, storage orientation, silicone coating on the stopper, vial material, and hydrophobicity of PX188. Remarkably, we found that changing any one of the factors could significantly affect VP formation. Our findings are instructive for better understanding the mechanisms of VP formation in vial products and can provide strategies for VP mitigation in biotherapeutics.

Poloxamer-188 Adjuvant Efficiently Maintains Adaptive Immunity of SARS-CoV-2 RBD Subunit Vaccination through Repressing p38MAPK Signaling

Poloxamer-188 (P188) is a nonionic triblock linear copolymer that can be used as a pharmaceutical excipient because of its amphiphilic nature. This study investigated whether P188 can act as an adjuvant to improve the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) subunit vaccine. BALB/c mice were vaccinated twice with the RBD antigen alone or in combination with P188 or MF59 (a commercial adjuvant for comparison purposes). The resulting humoral and cellular immunity were assessed. Results showed that P188 helped elicit higher neutralizing activity than MF59 after vaccination. P188 induced significant humoral immune response, along with type 1 T helper (Th1) and type 2 T helper (Th2) cellular immune response when compared with MF59 due to repressing p38MAPK phosphorylation. Furthermore, P188 did not result in adverse effects such as fibrosis of liver or kidney after vaccination. In conclusion, P188 is a novel adjuvant that may be used for safe and effective immune enhancement of the SARS-CoV-2 RBD antigen.

Impact of Poloxamer 188 Material Attributes on Proteinaceous Visible Particle Formation in Liquid Monoclonal Antibody Formulations

Surfactants such as Poloxamer 188 (PX188) play an important role in controlling particle formation in biotherapeutic formulations due to interfacial stresses. This study demonstrates for the first time that hydrophobicity of PX188 is a potential critical material attribute (CMA) as far as control of visible particle (VP) formation is concerned. We have found that within PX188 lots satisfying pharmacopeial specifications, there is variability in material attributes such as hydrophobicity, as determined from their reversed-phase high-performance liquid chromatography profiles. However, it currently remains unknown how such variability in hydrophobicity of PX188 affects surfactant function and VP formation. Here, we compared the effect of seven PX188 lots in two monoclonal antibody drug product formulations under various stress conditions. Notably, proteinaceous VP formation was reduced while using a PX188 lot with higher hydrophobicity. Our findings emphasize the importance of monitoring lot-to-lot variability of PX188 and provide insight into potential CMA for improving and controlling material attributes of PX188 for use in liquid biotherapeutic formulations.

Poloxamer-188 Exacerbates Brain Amyloidosis, Presynaptic Dystrophies, and Pathogenic Microglial Activation in 5XFAD Mice.

Alzheimer's disease (AD) is initiated by aberrant accumulation of amyloid beta (Aβ) protein in the brain parenchyma. The microenvironment surrounding amyloid plaques is characterized by the swelling of presynaptic terminals (dystrophic neurites) associated with lysosomal dysfunction, microtubule disruption, and impaired axonal transport. Aβ-induced plasma membrane damage and calcium influx could be potential mechanisms underlying dystrophic neurite formation. We tested whether promoting membrane integrity by brain administration of a safe FDA approved surfactant molecule poloxamer-188 (P188) could attenuate AD pathology in vivo. Three-month-old 5XFAD male mice were administered several concentrations of P188 in the brain for 42 days with mini-osmotic pumps. After 42 days, mice were euthanized and assessed for amyloid pathology, dystrophic neurites, pathogenic microglia activation, tau phosphorylation, and lysosomal / vesicular trafficking markers in the brain. P188 was lethal at the highest concentration of 10mM. Lower concentrations of P188 (1.2, 12, and 120μM) were well tolerated. P188 increased brain Aβ burden, potentially through activation of the γ-secretase pathway. Dystrophic neurite pathology was exacerbated in P188 treated mice as indicated by increased LAMP1 accumulation around Aβ deposits. Pathogenic microglial activation was increased by P188. Total tau levels were decreased by P188. Lysosomal enzyme cathepsin D and calciumdependent vesicular trafficking regulator synaptotagmin-7 (SYT7) were dysregulated upon P188 administration. P188 brain delivery exacerbated amyloid pathology, dystrophic neurites, and pathogenic microglial activation in 5XFAD mice. These effects correlated with lysosomal dysfunction and dysregulation of plasma membrane vesicular trafficking. P188 is not a promising therapeutic strategy against AD pathogenesis.

The Promising Role of Chitosan-Poloxamer 188 Nanocrystals in Improving Diosmin Dissolution and Therapeutic Efficacy against Ferrous Sulfate-Induced Hepatic Injury in Rats.

Diosmin (DSN) exhibits poor water solubility and low bioavailability. Although nanocrystals (NCs) are successful for improving drug solubility, they may undergo crystal growth. Therefore, DSN NCs were prepared, employing sonoprecipitation utilizing different stabilizers. The optimum stabilizer was combined with chitosan (CS) as an electrostatic stabilizer. NCs based on 0.15% w/v poloxamer 188 (PLX188) as a steric stabilizer and 0.04% w/v CS were selected because they showed the smallest diameter (368.93 ± 0.47 nm) and the highest ζ-potential (+40.43 ± 0.15 mV). Mannitol (1% w/v) hindered NC enlargement on lyophilization. FT-IR negated the chemical interaction of NC components. DSC and XRD were performed to verify the crystalline state. DSN dissolution enhancement was attributed to the nanometric rod-shaped NCs, the high surface area, and the improved wettability. CS insolubility and its diffusion layer may explain controlled DSN release from CS-PLX188 NCs. CS-PLX188 NCs were more stable than PLX188 NCs, suggesting the significance of the combined electrostatic and steric stabilization strategies. The superiority of CS-PLX188 NCs was indicated by the significantly regulated biomarkers, pathological alterations, and inducible nitric oxide synthase (iNOS) expression of the hepatic tissue compared to DSN suspension and PLX188 NCs. Permeation, mucoadhesion, and cellular uptake enhancement by CS may explain this superiority.

Tissue Distribution Study of Poloxamer188 in Rats by Ultra-High-Performance Liquid Chromatography Quadrupole Time of Flight/Mass Spectrometry with MSALL-Based Approach.

Poloxamer188 (PL188), as one of the most commonly used pharmaceutical excipients, has unique physicochemical properties and good biocompatibility, and so is playing an increasingly extensive role in the field of medicine. Currently, there are few studies on the tissue distribution of PL188 in vivo. In this study, the LC-MS method based on MSALL technique of quadrupole time of flight mass spectrometry for absolute quantitative analysis of poloxamer 188 in biological substrates was established for the first time. The tissue distribution of poloxamer188 in SD rats were studied using the established quantitative analysis method. To explore the distribution of PL188 in organs and tissues, PL188 was administered via rat tail vein at a dose of 5 mg/kg. Eight kinds of tissues including heart, liver, spleen, lung, kidney, stomach, muscle and brain of rats were collected at 0.25 h, 1 h and 4 h after administration. Tissue distributions showed the highest level was observed in kidney, then in stomach, which indicated PL188 mainly bioaccumulated in the kidney. This study can provide references for the further study of PL188.

Fabrication of oral nanovesicle in-situ gel based on Epigallocatechin gallate phospholipid complex: Application in dental anti-caries

The conventional anti-caries agents exhibit many shortcomings such as poor stability, low efficacy or short residence time in the oral environment, it is urgent to develop efficacy treatments to prevent dental caries. As the most active polyphenols from tea, Epigallocatechin gallate (EGCG) shows remarkable anti-cariogenic bioactivity. However, the poor stability and low bioavailability of EGCG limit its potential application. This study aimed to fabricate nanovesicles in-situ gel based on EGCG phospholipid complex in order to increase its stability and efficacy. The formation of EGCG phospholipid complex was characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The ethanol injection method was used to prepare the EGCG-loaded nanovesicles, an optimal ratio of Poloxamer407 (P407) and Poloxamer188 (P188) as in-situ gel matrix was selected to fabricate oral nanovesicles in-situ gel. EGCG-loaded nanovesicle in-situ gel based on the phospholipid complex had uniform spherical shape without any agglomeration. The discrete nanoparticle with a size (131.44 ± 4.24 nm) and a negative zeta potential value at −30.7 ± 0.5 mV possessed good physical stability and high entrapment efficiency (83.66 ± 3.2%). The formulation exhibited a strong antibacterial activity on S. mutans, which could reduce acid production and tooth surface adhesion. In addition, EGCG formulation could inhibit the formation of glucan and biofilm from S. mutans by suppressing the activity of glycosyltransferase enzymes (GTF). In conclusion, the EGCG-loaded nanovesicle in-situ gel holds great promise as an efficient anti-cariogenic formulation for topical oral delivery.

Preparation, optimization, and transcorneal permeability study of lutein-loaded solid lipid nanoparticles

To improve the stability and corneal permeability of unstable poorly biocompatible lutein, lutein solid lipid nanoparticles (Lutein-SLNs) were prepared using ultrasonic assisted emulsion evaporation-low temperature curing method and optimized by response surface methodology (RSM). The properties of Lutein-SLNs were evaluated in terms of these encapsulation efficiency, particle size, zeta potential, transmission electron morphology (TEM), and corneal permeability in vitro. The stability and in vitro release behavior of the nanoparticles were also investigated. The optimal formulation was drug: glyceryl monostearate (GM): lecithin high potency (LHP): poloxamer-188 (P-188) = 1: 3.75: 1.78: 2.58 (w/w/w/w), which resulted in particle size, polydispersity index (PDI), encapsulation efficiency and zeta potential of 118.50 ± 1.02 nm, 0.136 ± 0.017, 94.43 ± 1.08% and −25.84 ± 2.45 mV, respectively. Specifically, compared with free lutein, the stability of the Lutein-SLNs against heat, light and oxygen were improved by 4.42-fold, 3.41-fold and 3.21-fold, respectively. Finally, the in vitro release studies revealed that Lutein-SLNs had a good sustained release effect, and in permeation study the apparent permeability coefficient (Papp) of Lutein-SLNs was 1.52-fold greater than free lutein. Therefore, the method used in this study for preparing Lutein-SLNs was an efficient approach, and Lutein-SLNs could increase the transcorneal flux, improve the stability of lutein, and serve as an effective ophthalmic drug delivery system for lutein.

Effect of Hydrophilic Polymers on Complexation Efficiency of Cyclodextrins in Enhancing Solubility and Release of Diflunisal.

The effects of three hydrophilic polymers, namely, carboxymethyl cellulose sodium (CMC-Na), polyvinyl alcohol (PVA) and poloxamer-188 (PXM-188) on the solubility and dissolution of diflunisal (DIF) in complexation with β-cyclodextrin (βCD) or hydroxypropyl β-cyclodextrin (HPβCD), were investigated. The kneading method was used at different drug to cyclodextrin weight ratios. Increases in solubility and drug release were observed with the DIF/βCD and DIF/HPβCD complexes. The addition of hydrophilic polymers at 2.5, 5.0 and 10.0% w/w markedly improved the complexation and solubilizing efficiency of βCD and HPβCD. Fourier-transform infrared (FTIR) showed that DIF was successfully included into the cyclodextrin cavity. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) confirmed stronger drug amorphization and entrapment in the molecular cage of cyclodextrins. The addition of PVA, CMC-Na or PXM-188 reduced further the intensity of the DIF endothermic peak. Most of the sharp and intense peaks of DIF disappeared with the addition of hydrophilic polymers. In conclusion, PXM-188 at a weight ratio of 10.0% w/w was the best candidate in enhancing the solubility, stability and release of DIF.

Paclitaxel/methotrexate co-loaded PLGA nanoparticles in glioblastoma treatment: Formulation development and in vitro antitumor activity evaluation

AimThe aim of this study was to improve the therapeutic index of chemotherapeutic drugs on glioblastoma cells through an improved co-drug delivery system. Materials and methodsMethotrexate (MTX) and paclitaxel (PTX) were co-loaded into poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) coated with polyvinyl alcohol (PVA) and Poloxamer188 (P188). Key findingsThe mean size of the NPs was about 212 nm, with a zeta potential of about −15.7 mV. Encapsulation efficiency (EE%) and drug loading (DL%) were determined to be 72% and 4% for MTX and 85% and 4.9% for PTX, respectively. The prepared NPs were characterized by differential thermal analysis (DTA) and thermogravimetric analysis (TGA). Moreover, an in vitro sustained release profile was observed for both drug loaded PLGA NPs. Glioblastoma cellular uptake of the NPs was confirmed by fluorescence microscopy and cell survival rate was investigated through the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method after 48 h of incubation showing IC50 values of 24.5 μg·mL−1 for PTX and 9.5 μg·mL−1 for MTX for the MTX/PTX co-loaded PLGA nanoparticles coated with PVA/P188 (Co-2 NPs). Apoptosis and necrosis were also studied via flow cytometry, the lactate dehydrogenase (LDH) assay and the amount of anti-apoptotic protein (Bcl-2) expression. Blood compatibility of the co-delivery of PTX and MTX loaded PLGA NPs was investigated using a hemolysis method as well. SignificanceThe co-delivery of PTX and MTX loaded PLGA NPs is promising for the treatment of glioblastoma compared to their respective free drug formulations and, thus, should be further investigated.

Preparation and in vitro antitumor effects on MDA-MB-231 cells of niclosamide nanocrystals stabilized by poloxamer188 and PBS.

Niclosamide (NLM) has prominent antitumor activities on various kinds of cancer. In this study, we developed a novel niclosamide nanocrystals (NLM-NCs) stabilized by phosphate buffered saline (PBS) and poloxamer188 (P188). The formed NLM-NCs displayed 12,039 times solubility improvement (2.769mg/mL) than that of free NLM and desired storage stability. Transmission electron microscope (TEM) observation illustrated NLM-NCs were needle-like shape. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) analysis indicated that NLM-NCs were not anhydrate or any monohydrate but probable a polymorphic mixture. In vitro release evaluation manifested more than 95% NLM released in 48h from NLM-NCs. In comparison to free NLM, NLM-NCs showed stronger cytotoxic effect on MDA-MB-231 cells and promoted cellular uptake. Wound healing assays indicated that NLM-NCs could inhibit cell migration and also decrease the expression of CD44 which is a marker of breast cancer stem cells. Overall, NLM-NCs were of raised solubility, feasible storage stability and desired killing effect for MDA-MB-231 cell, which revealed the impacts of NLM crystal form on its nanocrystals and provided a novel idea for the design of NLM antineoplastic formulation.

Preparation and evaluation of identifiable quick response (QR)-coded orodispersible films using 3D printer with directly feeding nozzle.

3D-printing technology is growing in importance due to increased availability and a wider range of applications. Here, we prepared and evaluated a hot melt pneumatic (HMP) 3D-printed QR (Quick Response)-coded orodispersible film (QRODF) containing a poorly water-soluble aripiprazole (ARP). Moreover, QRODF was formulated to evaluate the extrusion process and characterize physicochemical properties of drug-loaded films. QRODF was designed with a 30-mm length/width and 0.3-mm thickness by varying QRODF formulations with different polyethylene oxide 100,000(PEO)/poloxamer 188(POX188) ratios and then optimized for extrusion accessibility and film-forming capability. The optimal QRODF formulation was further controlled by ARP and citric acid addition (pH control) for salivary applicability and dissolution rate. Physicochemical evaluation of QRODF was performed by scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. Dissolution studies were performed in buffer media (pH 1.2) following USP Apparatus type II method. Drug-loaded QRODF was scannable using a smartphone. Drug release from QRODF rapidly reached over 95% and was dependent on polymer/poloxamer ratios. By optimizing PEO/POX/drug ratio, the morphology and physical properties of the oral film were changed. Furthermore, disintegration and dissolution rates of ARP-loaded QRODF were successfully established in a controlled manner.

Highly Water-Soluble Solid Dispersions of Honokiol: Preparation, Solubility, and Bioavailability Studies and Anti-Tumor Activity Evaluation.

Honokiol (HK), a well-tolerated natural product, has many multiple pharmacological activities. However, its poor water solubility and low bioavailability limit its clinical application and development. The aim of this research was to prepare the solid dispersion (SD) formulation of honokiol (HK) with poloxamer-188 (PLX) as the carrier, thereby improving its solubility and oral bioavailability. Firstly, by investigating the relationship between the addition amount of the PLX and the solubility of HK, and the effects of solid dispersions with different ratios of HK–PLX on the solubility of HK, we determined that the optimum ratio of PLX to HK was (1:4). Then, the HK–PLX (1:4) SD of HK was prepared using the solvent evaporation method. The morphology of the obtained HK–PLX (1:4) SD was different from that of free HK. The HK in the HK–PLX (1:4) SD existed in amorphous form and formed intermolecular hydrogen bonds with PLX. Additionally, the solubility values of the HK–PLX (1:4) SD were about 32.43 ± 0.36 mg/mL and 34.41 ± 0.38 mg/mL in artificial gastric juice (AGJ) and in artificial intestinal juice (AIJ), respectively. Compared with free HK, the release rate and the bioavailability was also substantially improved for HK in its SD form. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that the HK–PLX (1:4) SD showed higher inhibition of HepG2 cells than free HK. Taken together, the present study suggests that the HK–PLX (1:4) SD could become a new oral drug formulation with high bioavailability and could produce a better response for clinical applications of HK.

Hepato-Protective Studies of Poloxamer-188 by Paracetomol induced liver toxicity in Rats

Poloxamer-188 (P-188) is a polymer well renowned for possessing medical properties. Present study was conducted with an aim to evaluate Hepato-protective potential of P-188 against paracetamol induced liver damage in wistar albino rats. Group-I served as Normal control which received normal saline 5ml/kg of Body weight (BW) for 7 days. Group-II served as Negative control in which animals received same dose as mentioned in Group-I. Group-III, IV and V animals received P-188(50mg/kg), P-188(100mg/kg) and silymarin (25mg/kg) respectively for 7 days. Except Group-I all other groups challenged with a very high dose of paracetamol (750 mg/kg) to induce hepatotoxicity. Biochemical estimation results showed that SGOT, SGPT and ALP levels were increased in negative control group animals which were decreased to normal levels when treated with P-188. There was highly significant (p<0.0001) decrease of these values in all three treatment groups. Moreover decrease in P-188 treated groups is dose dependent. Histopathological study supports the results of biochemical estimation. Negative control animal showed inflammation with mild cholestasis. P-188 (50mg/kg) showed mild inflammation, more number of normal hepatocytes, whereas P-188 (100 mg/kg) showed scattered lymphocytes among normal hepatocytes and kupffer cell hyperplasia, no incidence of inflammation and necrosis. Based on these results we can conclude that P-188 is a hepatoprotective polymer.

PREPARATION AND CHARACTERIZATION OF ORAL NANOSUSPENSION LOADED WITH CURCUMIN

Objective: The principle objective of the present research work was to improve the bioavailability of curcumin (CUR) by decreasing its particle size. Nanosuspension (NS) of CUR was prepared using poloxamer-188 (P188) as a surfactant. The prepared NSs were characterized for particle size, polydispersity index (PDI), zeta potential, drug loading, saturation solubility, and drug release kinetic studies.Methods: Components required for NS preparation, such as solvent, anti-solvent and surfactant were screened. Precipitation high-speed homogenization (HSH) method was used for the preparation of NS using selected components. Evaluation of NS for particle size, PDI, drug loading, saturation solubility and in vitro drug release was done. Pharmacokinetic studies of the NS in sprague dawley (SD) rats were performed.Results: The particle size, PDI and zeta potential of the optimized formulation was 596.5±5 nm, 0.233±0.010 and-23±2 mV respectively. The pH of all the formulations was in the range of 5-6 which is acceptable when related to drug stability. The optimized formulation showed an increase in saturation solubility in water and phosphate buffer pH 6.8 when compared to plain CUR suspension (S). Results of pharmacokinetic studies indicated that Cmax and AUC0-6 were increased 8 and 10 times respectively from plain CUR S to CUR NS.Conclusion: CUR NS was prepared using P188 as the stabilizer. Amongst various stabilizers screened P188 rendered a stable NS with the particle size in nano range. Pharmacokinetic studies revealed the better performance of CUR NS as compared to plain CUR S.

Effect Of Membrane Sealing Copolymer Poloxamer188 On Cardiac Mitochondrial Subpopulations In A Porcine Model Of Acute Myocardial Infarction

Acute myocardial infarction (AMI) is characterized by the sudden loss of blood supply to the coronary arteries, leading to permanent cell death if left untreated. Every year, around 800,000 Americans are affected by AMI. Currently, the only successful treatment for AMI is the restoration of blood flow using angioplasty and fibrinolytic drugs. In spite of a higher success rate post treatment, AMI greatly increases the risk of future arrhythmia, stroke and cardiac arrest. Additionally, the abrupt reintroduction of oxygen to the ischemic tissue causes reperfusion injury (RI). In the mitochondria, RI leads to calcium overload, increased ROS production, opening of mitochondrial permeability transition pore (MPTP) and release of caspases, all contributing to cell death. Hence, mitochondria offer a promising target in reducing reperfusion injury post AMI. Previously, we showed that the administration of the membrane sealing copolymer Poloxamer188 (P188) post ST‐elevation myocardial infarction (STEMI) reperfusion reduced infarct size and improved cardiac myocardial and mixed mitochondrial function in pigs. In this current study, our aim was to identify the specific effects of P188 in improving the mitochondrial function post STEMI of the two cardiac mitochondrial subpopulations‐subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. Female pigs that underwent 45 minutes of partial left anterior descending artery (LAD) occlusion were randomized to be reperfused with P188 (250 mg/kg, n=5) or saline(n=5). Each of these animals received an initial intracoronary bolus of either drug for 30 minutes, followed by an intravenous drip of the same dose for 3 hours. At 4 hours post reperfusion, the hearts were harvested and cardiac SSM and IFM were isolated from both the ischemic (LAD) and healthy circumflex (Circ) area through differential centrifugation. Their functions were assessed by measuring mitochondrial oxygen consumption and calcium buffering capacity. Initial results show that P188 likely improved complex 1 mediated mitochondrial oxygen consumption in the SSM (not significant) while there was no effect on IFM. P188 also improved the calcium buffering capacity of cardiac SSM and IFM (p=0.009 for SSM and p=0.03 for IFM) in the ischemic area. Together these results show a potential treatment benefit of P188 on cardiac SSM. Future studies include measurement of the levels of reactive oxygen species and total calcium content in the mitochondria, assessment of mitochondrial damage through electron microscopy as well as investigation of the mechanism of benefit conferred by P188 in the mitochondria. To our knowledge, this is the first study to investigate the effect of P188 in cardiac mitochondrial subpopulations. Results from this study will help in the development of better targeted compounds with greater accuracy for the treatment of heart disease.Support or Funding InformationSource of funding: National Institutes of Heath, RO1 HL122323‐01A1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.