Co-solvent Evaporation Research Articles

Polycaprolactone-Vitamin E TPGS Micellar Formulation for Oral Delivery of Paclitaxel.

This study aimed to investigate the potential of polycaprolactone-vitamin E TPGS (PCL-TPGS) micelles as a delivery system for oral administration of paclitaxel (PTX). The PCL-TPGS copolymer was synthesized using ring opening polymerization, and PTX-loaded PCL-TPGS micelles (PTX micelles) were prepared via a co-solvent evaporation method. Characterization of these micelles included measurements of size, polydispersity, and encapsulation efficiency. The cellular uptake of PTX micelles was evaluated in Caco-2 cells using rhodamine 123 (Rh123) as a fluorescent probe. Moreover, an everted rat sac study was conducted to evaluate the ex vivo permeability of PTX micelles. Additionally, a comparative pharmacokinetic study of PTX micelles versus the marketed formulation, Ebetaxel® (a Taxol generic), was performed after a single oral administration to rats. The results demonstrated that the micellar formulation significantly improved PTX solubility (nearly 1 mg/mL). The in vitro stability and release of PTX micelles in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) demonstrated that PTX micelles remained stable for up to 24 h and significantly slowed the release of PTX in both media compared to Ebetaxel®. The in vitro cellular uptake, ex vivo intestinal permeability, and in vivo pharmacokinetic profile demonstrated that PTX micelles enhanced the permeability and facilitated a rapid absorption of the drug. Conclusively, the PCL7000-TPGS3500 micelles exhibit potential as an effective oral delivery system for PTX.

Polycaprolactone – Vitamin E TPGS micelles for delivery of paclitaxel: In vitro and in vivo evaluation

This study aimed to present findings on a paclitaxel (PTX)-loaded polymeric micellar formulation based on polycaprolactone-vitamin E TPGS (PCL-TPGS) and evaluate its in vitro anticancer activity as well as its in vivo pharmacokinetic profile in healthy mice in comparison to a marketed formulation. Micelles were prepared by a co-solvent evaporation method. The micelle's average diameter and polydispersity were determined using dynamic light scattering (DLS) technique. Drug encapsulation efficiency was assessed using an HPLC assay. The in vitro cytotoxicity was performed on human breast cancer cells (MCF-7 and MDA-MB-231) using MTT assay. The in vivo pharmacokinetic profile was characterized following a single intravenous dose of 4 mg/kg to healthy mice. The mean diameters of the prepared micelles were ≤ 100 nm. Moreover, these micelles increased the aqueous solubility of PTX from ∼0.3 μg/mL to reach nearly 1 mg/mL. While the PTX-loaded micelles showed an in vitro cytotoxicity comparable to the marketed formulation (Ebetaxel), drug-free PCL-TPGS micelles did not show any cytotoxic effects on both types of breast cancer cells (∼100% viability). Pharmacokinetics of PTX as part of PCL-TPGS showed a significant increase in its volume of distribution compared to PTX conventional formulation, Ebetaxel, which is in line with what was reported for clinical nano formulations of PTX, i.e., Abraxane, Genexol-PM, or Apealea. The findings of our studies indicate a significant potential for PCL-TPGS micelles to act as an effective system for solubilization and delivery of PTX.

Self-assembled micelles loaded with itraconazole as anti-Acanthamoeba nano-formulation.

Acanthamoeba castellanii are opportunistic pathogens known to cause infection of the central nervous system termed: granulomatous amoebic encephalitis, that mostly effects immunocompromised individuals, and a sight threatening keratitis, known as Acanthamoeba keratitis, which mostly affects contact lens wearers. The current treatment available is problematic, and is toxic. Herein, an amphiphilic star polymer with AB2 miktoarms [A = hydrophobic poly(ℇ-Caprolacton) and B = hydrophilic poly (ethylene glycol)] was synthesized by ring opening polymerization and CuI catalyzed azide-alkyne cycloaddition. Characterization by 1H and 13C NMR spectroscopy, size-exclusion chromatography and fluorescence spectroscopy was accomplished. The hydrophobic drug itraconazole (ITZ) was incorporated in self-assembled micellar structure of AB2 miktoarms through co-solvent evaporation. The properties of ITZ loaded (ITZ-PCL-PEG2) and blank micelles (PCL-PEG2) were investigated through zeta sizer, scanning electron microscopy and Fourier-transform infrared spectroscopy. Itraconazole alone (ITZ), polymer (DPB-PCL), empty polymeric micelles (PCL-PEG2) alone, and itraconazole loaded in polymeric micelles (ITZ-PCL-PEG2) were tested for anti-amoebic potential against Acanthamoeba, and the cytotoxicity on human cells were determined. The polymer was able to self-assemble in aqueous conditions and exhibited low value for critical micelle concentration (CMC) 0.05-0.06µg/mL. The maximum entrapment efficiency of ITZ was 68%. Of note, ITZ, DPB, PCL-PEG2 and ITZ-PCL-PEG2 inhibited amoebae trophozoites by 37.34%, 36.30%, 35.77%, and 68.24%, respectively, as compared to controls. Moreover, ITZ-PCL-PEG2 revealed limited cytotoxicity against human keratinocyte cells. These results are indicative that ITZ-PCL-PEG2 micelle show significantly better anti-amoebic effects as compared to ITZ alone and thus shouldbe investigated further in vivo to determine its clinical potential.

Supersaturable diacyl phospholipid dispersion for improving oral bioavailability of brick dust molecule: A case study of Aprepitant

This study aims to investigate the potential use of polymer inclusion in the phospholipid-based solid dispersion approach for augmenting the biopharmaceutical performance of Aprepitant (APT). Initially, different polymers were screened using the microarray plate method to assess their ability to inhibit drug precipitation in the supersaturated solution and HPMCAS outperformed the others. Later, the binary (BD) and ternary (TD) phospholipid dispersions were prepared using the co-solvent evaporation method. Solid-state characterization was performed using SEM and PXRD to examine the physical properties, while molecular interactions were probed through FTIR and NMR analysis. In vitro dissolution studies were performed in both fasted and fed state biorelevant media. The results demonstrated a substantial increase in drug release from BD and TD, approximately 4.8 and 9.9 times higher compared to crystalline APT in FaSSIF. Notably, TD also showed a lowered dissolution difference between fed and fasted states in comparison to crystalline APT, indicating a reduction in the positive food effect of APT. Moreover, we assessed the impact of polymer inclusion on permeation under in vitro biomimetic conditions. In comparison with the crystalline APT suspension, both BD and TD demonstrated approximately 3.3 times and 14 times higher steady-state flux (Jss values), respectively. This can be ascribed to the supersaturation and presence of drug-rich submicron particles (nanodroplets) along with the multiple aggregates of drug with phospholipids and polymer in the donor compartment, consequently resulting in a more substantial driving force for passive diffusion. Lastly, in vivo pharmacokinetic evaluation demonstrated the enhanced absorption of both TD and BD over the free drug suspension in the fasted state. This enhancement was evident through a 2.1-fold and 1.3-fold increase in Cmax and a 2.3-fold and 1.4-fold increase in AUC0-t, respectively. Overall, these findings emphasize the potential of polymer-based phospholipid dispersion in enhancing the overall biopharmaceutical performance of APT.

Investigating the potential of degradable poly(vinyl acetate) copolymer microparticles for encapsulation and in vitro release studies

Poly(vinyl acetate) is a well-known polymer synthesized through the free radical polymerization of vinyl acetate (VAc) monomer. However, enhancing the degradability of this polymer is best achieved by copolymerizing cyclic ketene acetal (CKA) with VAc. Despite their potential, the practical use of these degradable polymers remains limited. Therefore, our study aimed to develop a sustainable technology encompassing the synthesis and application of poly(VAc-co-MDO), and environmental biodegradability of poly(vinyl alcohol (VA)). To achieve this, we synthesized a series of degradable copolymers, namely poly(VAc-co-MDO), via free radical ring-opening polymerization (rROP) of 2-methylene-1,3-dioxepane (MDO) with VAc. The number of degradable ester units in the polymer backbone was systematically controlled by varying the initial monomer feed compositions, resulting in a range of 8–85 mol%. To compare their properties, we also synthesized homopolymers, namely poly(VAc) and poly(MDO). Subsequently, we formulated the homo and copolymers into microparticles using the co-solvent evaporation method, which yielded spherical particles with a particle size distribution ranging from 5 to 10 µm. Furthermore, we demonstrated the applicability of these degradable copolymers, exemplified by a poly[VAc(0.92)-co-MDO(0.08)] with 8 mol% MDO in the polymer backbone, in an encapsulation modeling study using curcumin as the active molecule. Successful encapsulation of curcumin into degradable polymer particles was confirmed and quantified via HPLC analysis. The degradability of the copolymers was evaluated through accelerated alkali hydrolysis, resulting in the formation of oligomeric degradation products. Additionally, we investigated the environmental biodegradability of poly(VA-co-MDO) as a proof of concept, revealing a biodegradability of 89% within 28 days for this polymer consisting of 88 mol% poly(VA) and 12 mol% poly(MDO) in the backbone. Preparing stable formulation for applications and performing biodegradability tests for the copolymers or microparticles derived from random poly(VAc-co-MDO) was challenging due to the insolubility of the polymer or instability in the form of sedimentation of the microparticles in the inoculum. Hence, in order to achieve stable formulation, we synthesized random poly(VA-co-MDO) through the selective cleavage of chloroacetyl group (ClAc) from its precursor, poly(VClAc-co-MDO). This method was preferred because obtaining poly(VA-co-MDO) directly from poly(VAc-co-MDO) was hindered by significant ester backbone cleavage, even under mild conditions. Our research assumes significance in light of recent restrictions imposed by various chemical agencies on the use of non-degradable polymers and microparticles in formulations.

Chrysin and chrysin-loaded nanocarriers induced immunogenic cell death on B16 melanoma cells.

Induction of immunogenic cell death (ICD) is a promising strategy for cancer immunotherapy. Chrysin, which has potential anticancer effects, faces limitations in clinical applications due to its poor water solubility. This study aimed to formulate chrysin with PEG-poly(α-benzylcarboxylate-ε-caprolactone) (PBCL) nanoparticles (NPs) and assess their anticancer and ICD-inducing potency in melanoma cells, comparing with free chrysin. The co-solvent evaporation method was employed to develop chrysin-loaded NPs. UV spectroscopy, dynamic light scattering, and the dialysis bag method were used to evaluate the encapsulation efficiency (EE), particle size, polydispersity index (PDI), and drug release profile, respectively. The anticancer effects of the drugs were assessed using the MTT and trypan blue exclusion assays. Flow cytometry was employed to evaluate apoptosis and calreticulin (CRT) expression. ELISA and western blotting were used to detect heat shock protein 90 (HSP90), Annexin A1, GRP78 (Glucose-related protein78), and activated protein kinase R-like endoplasmic reticulum kinase (p-PERK). Chrysin-loaded PEG-PBCL NPs (chrysin-PEG-PBCL) showed an EE of 97 ± 1%. Chrysin-PEG-PBCL was 38.18 ± 3.96nm in size, with a PDI being 0.62 ± 0.23. Chrysin-PEG-PBCL showed an initial burst release, followed by sustained release over 24h. Chrysin-PEG-PBCL exhibited a significantly stronger anticancer effect in B16 cells. Chrysin-PEG-PBCL was found to be more potent in inducing apoptosis. Both free chrysin and chrysin NPs induced ICD as indicated by an increase in the levels of ICD biomarkers. Interestingly, chrysin NPs were found to be more potent inducers of ICD than the free drug. These findings demonstrate that chrysin and chrysin-PEG-PBCL NPs can induce ICD in B16 cells. PEG-PBCL NPs significantly enhanced the potency of chrysin in inducing ICD compared to its free form.

Enhancement of the Bioavailability and Anti-Inflammatory Activity of Glycyrrhetinic Acid via Novel Soluplus®-A Glycyrrhetinic Acid Solid Dispersion.

Glycyrrhetinic acid (GA) is an anti-inflammatory drug with potential for development. However, the poor solubility of GA in water leads to extremely low bioavailability, which limits its clinical applications. Solid dispersions have become some of the most effective strategies for improving the solubility of poorly soluble drugs. Soluplus®, a non-cytotoxic amphiphilic solubilizer, significantly improves the solubility of BCS II drugs and improves the bioavailability of insoluble drugs. l-arginine (L-Arg) can be used as a small molecular weight excipient to assist in improving the solubility of insoluble drugs. In this study, we developed a new formulation for oral administration by reacting GA and L-Arg to form salts by co-solvent evaporation and then adding the polymer-solvent Soluplus® with an amphiphilic chemical structure to prepare a solid dispersion GA-SD. The chemical and physical properties of GA-SD were characterized by DLS, TEM, XRD, FT-IR and TG. The anti-inflammatory activity of GA-SD was verified by LPS stimulation of RAW 267.5 cells simulating a cellular inflammation model, TPA-induced ear edema model in mice, and ethanol-induced gastric ulcer model. The results showed that the amide bond and salt formation of GA-SD greatly improved GA solubility. GA-SD effectively improved the anti-inflammatory effect of free GA in vivo and in vitro, and GA-SD had no significant effect on liver and kidney function, no significant tissue toxicity, and good biosafety. In conclusion, GA-SD with L-Arg and Soluplus® is an effective method to improve the solubility and bioavailability of GA. As a safe and effective solid dispersion, it is a promising anti-inflammatory oral formulation and provides some references for other oral drug candidates with low bioavailability.

Lithocholic acid conjugated mPEG-b-PCL micelles for pH responsive delivery to breast cancer cells

In this study, micelles composed of methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) copolymer (mPEG-b-PCL), which has ionically conjugated lithocholic acid (LCA) and providing pH sensitive release of LCA in acidic media, were prepared as drug carrier devices for cancer therapy. Micelles were produced by co-solvent evaporation method at two different temperatures (60 °C and 25 °C) and coded as LCA60**M and LCA25**M, respectively). Hydrodynamic diameters were 86.9 nm and 228.2 nm, and zeta potentials were −7.54 mV and −18.83 mV for LCA60**M and LCA25**M, respectively. For all micelles, release of LCA was higher in acidic media (pH 5.0) compared to physiological media (pH 7.4). Micelles loaded with a fluorescent dye, coumarin 6, demonstrated effective internalization into triple negative MDA-MB-231 breast cancer cells in 4 h. LCA60**M (41.7 ± 1.5%) and LCA25**M (44.5 ± 2.2%) had higher inhibitory effect on the cell migration compared to free LCA (64.7 ± 1.3%). Both LCA conjugated micelles decreased lipogenic activity and increased expressions of Bax (1.3 fold) and p53 (1.2 fold) apoptotic genes. Annexin V-FITC results exhibited high apoptotic cell number after the treatment of MDA-MB-231 cells with micelles. Free LCA and LCA conjugated LCA60**M and LCA25**M micelles decreased mitochondrial transmembrane potential of the cells by 41.8 ± 3.0%, 30.4 ± 0.9%, and 57.1 ± 0.5, respectively. Micelles also caused an effective decrease in angiogenesis ability of HUVECs. The novelty of this study is the prepared micelles, which have ionic conjugation of LCA to mPEG-b-PCL, and pH responsive release of LCA demonstrating effective apoptosis on breast cancer cells. These micelles may have great potential for cancer treatment. However, further in vivo studies are needed before clinical translation.

Development and Characterization of PEGylated Fatty Acid-Block-Poly(ε-caprolactone) Novel Block Copolymers and Their Self-Assembled Nanostructures for Ocular Delivery of Cyclosporine A.

Low aqueous solubility and membrane permeability of some drugs are considered major limitations for their use in clinical practice. Polymeric micelles are one of the potential nano-drug delivery systems that were found to ameliorate the low aqueous solubility of hydrophobic drugs. The main objective of this study was to develop and characterize a novel copolymer based on poly (ethylene glycol) stearate (Myrj™)-block-poly(ε-caprolactone) (Myrj-b-PCL) and evaluate its potential as a nanosystem for ocular delivery of cyclosporine A (CyA). Myrj-b-PCL copolymer with various PCL/Myrj ratios were synthesized via ring-opening bulk polymerization of ε-caprolactone using Myrj (Myrj S40 or Myrj S100), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. The co-solvent evaporation method was used to prepare CyA-loaded Myrj-b-PCL micelles. The prepared micelles were characterized for their size, polydispersity, and CMC using the dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Transmission electron microscopy (TEM) images of the prepared micelles showed spherical shapes with diameters in the nano range (<200 nm). Ex vivo corneal permeation study showed sustained release of CyA from the developed Myrj S100-b-PCL micelles. In vivo ocular irritation study (Draize test) showed that CyA-loaded Myrj S100-b-PCL88 was well tolerated in the rabbit eye. Our results point to a great potential of Myrj S100-b-PCL as an ocular drug delivery system.

A Universal Cosolvent Evaporation Strategy Enables Direct Printing of Perovskite Single Crystals for Optoelectronic Device Applications.

Solution-processed metal halide perovskite (MHP) single crystals (SCs) are in high demand for a growing number of printed electronic applications due to their superior optoelectronic properties compared to polycrystalline thin films. There is an urgent need to make SC fabrication facile, scalable, and compatible with the printed electronic manufacturing infrastructure. Here, a universal cosolvent evaporation (CSE) strategy is presented by which perovskite SCs and arrays are produced directly on substrates via printing and coating methods within minutes at room temperature from drying droplets. The CSE strategy successfully guides the supersaturation via controlled drying of droplets to suppress all crystallization pathways but one, and is shown to produce SCs of a wide variety of 3D, 2D, and mixed-cation/halide perovskites with consistency. This approach works with commonly used precursors and solvents, making it universal. Importantly, the SC consumes the precursor in the droplet, which enables the large-scale fabrication of SC arrays with minimal residue. Direct on-chip fabrication of 3D and 2D perovskite photodetector devices with outstanding performance is demonstrated. The approach shows that any MHP SC can now be manufactured on substrates using precision printing and scalable, high-throughput coating methods.

Enhanced bioavailability and biosafety of cannabidiol nanomicelles for effective anti-inflammatory therapy

Cannabidiol (CBD) shows great anti-inflammatory potential; however, the hydrophobicity and strong first-pass effect of CBD leads to its extremely low oral bioavailability. Poloxamer 407 (P407) is a triblock copolymer composed of (poly)ethylene oxide (PEO) and (poly)propylene oxide (PPO) sections. It has a PEO-PPO-PEO structure, which is widely used in the preparation of drug delivery systems that are highly biocompatible. When it reaches a certain concentration in water, P407 can self-assemble into a micelle structure containing a hydrophobic core and a hydrophilic shell. A potential approach to enhancing the oral bioavailability of hydrophobic drugs incorporating them into the hydrophilic carrier. We prepared CBD nanomicelles with a drug loading of 14.29% by a cosolvent evaporation method using P407 with appropriate antioxidants. Cell experiments indicated that anti-inflammatory markers (IL-4 and IL-10) increased, while inflammatory markers (TNF-α and IL-6) decreased. Moreover, animal experiments showed that inflammatory cells were inhibited by CBD nanomicelles, and the anti-inflammatory effect of micelles was better than that of CBD, while no obvious evidence indicated toxicity to the liver and kidney.

Abstract 10708: Cannabidiol Loaded Nanoparticles Exhibit an Anti-Fibrotic Effect in a Mouse Model of Non-Ischemic Heart Failure

Introduction: Cannabidiol (CBD) is being studied in a spectrum of ailments including cardiovascular disorders. It is also clinically prescribed for certain diseases. However, the hydrophobicity of CBD has been reported to contribute to low oral bioavailability. Here we use a polymeric nanoparticle formulation of CBD (nCBD) to overcome this limitation and evaluate its potential in heart failure (HF). Methods: HF was induced in 3-month old C57BL/6J mice with drinking water containing 1% NaCl and 0.3 mg/mL of L-NAME. After 1-week, subcutaneous osmotic pumps were implanted to deliver angiotensin-II at a rate of 0.7mg/kg/day for 4 weeks. nCBD was prepared using co-solvent evaporation of poly(ethylene oxide)-poly(α-benzyl carboxylate-ε-caprolactone) (PEO-b-PBCL) and pharmaceutical-grade CBD. nCBD (1 mg/kg) was injected 2 times per week subcutaneously in HF mice and Control mice. At week 5, Masson’s trichrome and H &amp; E staining was performed to evaluate severity of fibrosis and cardiomyocyte (CM) size respectively using Cell Sense Dimension Software from Olympus. Results: PEO-b-PBCL nanoparticles localized in both interstitial and replacement fibrotic regions in the heart of our HF mice. HF mice with nCBD treatment displayed less fibrosis when compared to HF mice without treatment as shown in a representative image of fibrosis staining (Figure A). Histological quantification depicted that fibrosis area was higher in HF mice and was significantly (p&lt;0.0001) reduced in HF mice exposed to nCBD (Figure B). Treatment of HF mice with nCBD also influenced CM size. Normal mice had a mean CM size of 12.33±2.07 μm. This increased to 21.17±2.88 μm in HF mice without treatment. However, nCBD treatment significantly (p&lt;0.0001) decreased CM size to a mean value 14.76±2.71 μm (Figure C). Conclusion: Our results show that nCBD has an anti-fibrotic and anti-hypertrophic effect in a mouse model of non-ischemic heart failure.

Development of polymeric nanoparticles loaded with STAT3 inhibitory, Stattic, for targeted cancer therapy

Background: STAT3 is an oncogenic signaling pathway found constitutively active in many types of human malignancies and plays a key role in cancer progression. Stattic is a small molecule, which selectively inhibits SH2 domain of STAT3. In most of the studies, stattic has been proposed as a promising strategy for inhibition of STAT3 in cancer cells harboring constitutively active STAT3. However, lack of proper formulation due to the poor water solubility and low bioavailability of stattic is a major limitation for its usage in clinic. The aim of this project was to develop poly(ethylene glycole)-block-poly(caprolactone) (PEG-b-PCL)-based polymeric micelles loaded with stattic and evaluate drug encapsulation efficiency and release in the developed formulations. Methods: In this experimental study, to prepare stattic loaded micellar formulations, co-solvent evaporation method was used. Mean diameter and polydispersity index (PDI) of micelles were defined by light scattering method. Encapsulated drug levels were measured using high performance liquid chromatography (HPLC). Data were analyzed using Graph pad prism software through one-way ANOVA analysis of variance. Results: Stattic was loaded in the polymeric micelles with encapsulation efficiency ranging from 40 to 73%. Drug loaded micelles were measured between 90 to 130 nm in size. PDI was obtained 0.3-1 and encapsulation of stattic in Polyethylene glycol-block-poly(α-benzyl carboxylate ε-caprolactone(PEG-b-PBCL) micellar formulation resulted in more than 6-fold increase in the water solubility of stattic (0.36 vs. 0.06 mg/mL). Respecting to high encapsulation efficiency, two micellar formulations were selected for further analysis that both of them released 70-80% of drug within the first hour, indicated burst release of drug. Conclusion: These findings show that PEG-b-PBCL copolymers can be a suitable vehicle for solubilization of stattic.

Design and Development of D‒α‒Tocopheryl Polyethylene Glycol Succinate‒block‒Poly(ε-Caprolactone) (TPGS-b-PCL) Nanocarriers for Solubilization and Controlled Release of Paclitaxel.

The objective of this study was to synthesize and characterize a set of biodegradable block copolymers based on TPGS-block-poly(ε-caprolactone) (TPGS-b-PCL) and to assess their self-assembled structures as a nanodelivery system for paclitaxel (PAX). The conjugation of PCL to TPGS was hypothesized to increase the stability and the drug solubilization characteristics of TPGS micelles. TPGS-b-PCL copolymer with various PCL/TPGS ratios were synthesized via ring opening bulk polymerization of ε-caprolactone using TPGS, with different molecular weights of PEG (1–5 kDa), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. Assembly of block copolymers was achieved via the cosolvent evaporation method. The self-assembled structures were characterized for their size, polydispersity, and CMC using dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Only copolymers that consisted of TPGS with PEG molecular weights ≥ 2000 Da were able to self-assemble and form nanocarriers of ≤200 nm in diameter. Moreover, TPGS2000-b-PCL4000, TPGS3500-b-PCL7000, and TPGS5000-b-PCL15000 micelles enhanced the aqueous solubility of PAX from 0.3 µg/mL up to 88.4 ug/mL in TPGS5000-b-PCL15000. Of the abovementioned micellar formulations, TPGS5000-b-PCL15000 showed the slowest in vitro release of PAX. Specifically, the PAX-loaded TPGS5000-b-PCL15000 micellar formulation showed less than 10% drug release within the first 12 h, and around 36% cumulative drug release within 72 h compared to 61% and 100% PAX release, respectively, from the commercially available formulation (Ebetaxel®) at the same time points. Our results point to a great potential for TPGS-b-PCL micelles to efficiently solubilize and control the release of PAX.

Dissolution behavior of Olmesartan Medoxomil drug in Polymeric Micelles of Soluplus and Pluronic F127

The aim of the present work was to study the dissolution behaviour of a poorly water-soluble Olmesartan Medoxomil (class II drug), by forming polymeric micelles (PMs) of SoluPlus and Pluronic F127. Polymeric Micelles of SoluPlus and Pluronic F127 were prepared by the co-solvent evaporation method. Drug and excipient compatibility study were carried out by Fourier Transform Infrared Spectroscopy (FTIR) and Differential Scanning Calorimetry. The formulations were evaluated for particle size, Zeta Potential, Solubility studies, drug loading and encapsulation efficiency. Scanning Electron Microscopy (SEM) analysis was performed to study the surface morphology of the PMs. The SEM images showed spherical surface of the micelles. The drug loading efficiency was more for SoluPlus micelles compared to Pluronic F127 micelles. The Polymeric micelles showed negative zeta potential value indicating that they are stable and resist aggregation. The particle size was around 100nm and polydispersity index was less than 1 indicating uniform size distribution. The drug release from the SoluPlus micelles was higher than the Pluronic micelles. These results suggest that the polymeric micelles can be used to increase the solubility of poorly water-soluble drugs.

Rosuvastatin Nanomicelles Target Neuroinflammation and Improve Neurological Deficit in a Mouse Model of Intracerebral Hemorrhage.

BackgroundIntracerebral hemorrhage (ICH), a devastating subtype of stroke, has a poor prognosis. However, there is no effective therapy currently available due to its complex pathological progression, in which neuroinflammation plays a pivotal role in secondary brain injury. In this work, the use of statin-loaded nanomicelles to target the neuroinflammation and improve the efficacy was studied in a mouse model of ICH.MethodsRosuvastatin-loaded nanomicelles were prepared by a co-solvent evaporation method using polyethylene glycol-poly(ε-caprolactone) (PEG-PCL) copolymer as a carrier. The prepared nanomicelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), and then in vitro and in vivo studies were performed.ResultsTEM shows that the nanomicelles are spherical with a diameter of about 19.41 nm, and DLS shows that the size, zeta potential, and polymer dispersity index of the nanomicelles were 23.37 nm, −19.2 mV, and 0.221, respectively. The drug loading content is 8.28%. The in vivo study showed that the nanomicelles significantly reduced neuron degeneration, inhibited the inflammatory cell infiltration, reduced the brain edema, and improved neurological deficit. Furthermore, it was observed that the nanomicelles promoted the polarization of microglia/macrophages to M2 phenotype, and also the expression of the proinflammatory cytokines, such as IL-1β and TNF-α, was significantly down-regulated, while the expression of the anti-inflammatory cytokine IL-10 was significantly up-regulated. The related mechanism was proposed and discussed.ConclusionThe nanomicelles treatment suppressed the neuroinflammation that might contribute to the promoted nerve functional recovery of the ICH mouse, making it potential to be applied in clinic.

Experimental determination of indoor air concentration of 5-chloro-2-methylisothiazol-3(2H)-one/ 2-methylisothiazol-3(2H)-one (CMIT/MIT) emitted by the use of humidifier disinfectant.

A mixture of 5-chloro-2-methylisothiazol-3(2H)-one/2-methylisothiazol-3(2H)-one (CMIT/MIT) had been used as an active ingredient in humidifier disinfectants (HDs). Owing to its high reactivity, the atmospheric concentration of CMIT/MIT, following its use in HD, would be lower than expected assuming that it is removed by ventilation only. In order to evaluate the exposure concentration of CMIT/MIT used as an HD, room-scale chamber studies were conducted under plausible use of three different HD doses at air change rates (ACR) of 0.3, 0.5, and 1.0 h−1. Atmospheric CMIT/MIT was sampled using two serial impingers containing deionized water after the attainment of steady state. Water samples in which CMIT/MIT was dissolved were concentrated using a cosolvent evaporation method with efficiencies of 35.5 and 77.9% for CMIT and MIT, respectively. The estimated air concentration, assuming that all the CMIT/MIT is absorbed in deionized water, increased linearly with increasing emission rate, but was independent of the ACR. This indicates that the removal rate of CMIT/MIT via chemical reactions is more than the removal rate by ventilation. Further investigations on homogeneous and heterogeneous chemical reactions of CMIT/MIT under ambient conditions are necessary to understand the actual exposure concentration of the mixture in HD.

Poly(ethylene glycol)-poly(ε-caprolactone)-based micelles for solubilization and tumor-targeted delivery of silibinin.

Introduction: Silibinin is a naturally occurring compound with known positive impacts on prevention and treatment of many types of human illnesses in general and cancer in particular. Silibinin is poorly water soluble which results in its insufficient bioavailability and lack of therapeutic efficacy in cancer. Here, we proposed to examine the potential of micelles composed of poly(ethylene glycol) (PEG) as the hydrophilic block and poly(ε-caprolactone) (PCL), poly(α-benzylcarboxylate-ε-caprolactone) (PBCL), or poly(lactide)-(PBCL) (PLA-PBCL) as hydrophobic blocks for enhancing the water solubility of silibinin and its targeted delivery to tumor. Methods: Co-solvent evaporation method was used to incorporate silibinin into PEG-PCL based micelles. Drug release profiles were assessed using dialysis bag method. MTT assay also was used to analyze functional activity of drug delivery in B16 melanoma cells. Results: Silibinin encapsulated micelles were shown to be less than 60 nm in size. Among different structures under study, the one with PEG-PBCL could incorporate silibinin with the highest encapsulation efficiency being 95.5%, on average. PEG-PBCL micelles could solubilize 1 mg silibinin in 1 mL water while the soluble amount of silibinin was found to be 0.092 mg/mL in the absence of polymeric micelles. PEG-PBCL micelles provided the sustained release of silibinin indicated with less than 30% release of silibinin within 24 hours. Silibinin encapsulated in PEG-PBCL micelles resulted in growth inhibitory effect in B16 cancer cells which was significantly higher than what observed with free drug. Conclusion: Our findings showed that PEG-PBCL micellar nanocarriers can be a useful vehicle for solubilization and targeted delivery of silibinin.

Preparation of polyarylene ether nitriles/fullerene composites with low dielectric constant by cosolvent evaporation

Fullerenes are widely used to reduce the dielectric constant of composites due to their special hollow cage structure. However, the main challenge for the realization of its material potential application is to improve the interfacial compatibility between the polymer matrix and fullerenes. Here we report a pure physical method of cosolvent evaporation to prepare polyarylene ether nitriles (PEN) composite films with well-defined monodisperse clusters of fullerenes for manufacturing flexible printed circuit boards. The presence of fullerenes is proven to be crucial to decrease the dielectric constant of composite films. The film with 3 wt% fullerenes loading possesses the lowest dielectric constant of 2.65 at 1 MHz, and its service life is detected as 3.3 years by Flynn–Wall–Ozawa method. Additionally, when the composite films used in flexible copper clad laminate (FCCL), the 180° peeling strength between the resin and copper foil is 6.91 N cm−1. Therefore, this PEN/fullerene composite provides potential application for the preparation of FCCL.

Biocompatibility and paclitaxel/cisplatin dual-loading of nanotubes prepared from poly(ethylene glycol)-polylactide-poly(ethylene glycol) triblock copolymers for combination cancer therapy

Nanotubes were prepared by self-assembly of the copolymer using co-solvent evaporation method. The biocompatibility of the nanotubes was assessed in comparison with spherical micelles and filomicelles prepared from poly(ethylene glycol)-poly(L-lactide-co-glycolide) (PEG-PLGA) and poly(ethylene glycol)-poly(L-lactide) (PEG-PLA), respectively. Several aspects of biocompatibility of the aggregates were considered, including agar diffusion and MTT assay, release of cytokines, hemolysis, protein adsorption, dynamic clotting in vitro, and Zebrafish embryonic compatibility in vivo. The nanotubes present good cell compatibility and blood compatibility in vitro, and almost no toxicity towards Zebrafish embryos development in vivo. Furthermore, dual-loading of hydrophilic cisplatin and hydrophobic paclitaxel was achieved in the nanotubes with high loading content and loading efficiency. The release of both drugs was slower from dual-loaded nanotubes than from single-loaded ones, but the total amount of released drugs in higher for dual-loaded nanotubes than from single-loaded ones. Cellular uptake and inhibition tests showed that the nanotubes were successfully taken up by tumor cells and effectively inhibited cell growth. It is thus concluded that PEG-PLA-PEG nanotubes with outstanding biocompatibility could be promising for co-delivery of hydrophilic and hydrophobic agents in combination cancer therapy.