Preparation, Optimization and In Vitro Characterization of Fluticasoneloaded Mixed Micelles Based on Stearic Acid-g-chitosan as a Pulmonary Delivery System.

PURPOSE: The primary objective of this study was to optimize formulation variables and investigate the in vitro characteristics of fluticasone propionate (FP)-loaded mixed polymeric micelles, which were composed of depolymerized chitosan-stearic acid copolymer (DC-SA) in combination with either tocopheryl polyethylene glycol succinate or dipalmitoylphosphatidylcholine for pulmonary drug delivery. METHODS: A D-optimal design was employed for the optimization procedure, considering lipid/ polymer ratio, polymer concentration, drug/ polymer ratio, and lipid type as independent variables. Dependent variables included particle size, polydispersion index, zeta potential, drug encapsulation efficiency, and loading efficiency of the polymeric micelles. Additionally, the nebulization efficacy and cell viability of the optimal FP-loaded DC-SA micellar formulations were evaluated. RESULTS: The mixed polymeric micelles were successfully prepared with properties falling within the desired ranges, resulting in four optimized formulations. The release of FP from the optimal systems exhibited a sustained release profile over 72 hours, with 70% of the drug still retained within the core of the micelles. The nebulization efficiency of these optimal formulations reached up to 63%, and the fine particle fraction (FPF) ranged from 41% to 48%. Cellular viability assays demonstrated that FP-loaded DC-SA polymeric micelles exhibited lower cytotoxicity than the free drug but were slightly more cytotoxic than empty mixed micelles. CONCLUSION: In conclusion, this study suggests that DC-SA/ lipid mixed micelles have the potential to serve as effective carriers for nebulizing poorly soluble FP.

Effect of talc and vitamin E TPGS on manufacturability, stability and release properties of trilaurin-based formulations for hot-melt coating.

This study was focused on one particular case of hot-melt coating with trilaurin - a solid medium-chain monoacid triglyceride. The challenge of using trilaurin as coating agent in melting-based processes is linked to its relatively low melting profile: 15.6 °C (Tm,α), 35.1 °C ( [Formula: see text] ) and 45.7 °C (Tm,ß). From a process perspective, the only possibility to generate products coated with formulations composed of trilaurin is by setting thermal operational conditions above Tm,α. From a material perspective, this processing possibility depends principally on trilaurin crystallisation which was investigated via a set of analytical techniques including turbidimetry, calorimetry, hot-melt goniometry, and polarised light microscopy. A highly soluble drug model substrate (sodium chloride crystals) was coated with three selected trilaurin-based formulations: (i) trilaurin, (ii) trilaurin plus talc, and (iii) trilaurin plus vitamin E TPGS and talc. Coated salt crystals were then analysed to investigate processing performance, coating quality, stability and release properties under digestion effect. The results show that firstly, talc addition promotes nucleation and crystal growth and, as a consequence, it facilitates the manufacture of trilaurin-based formulations. Secondly, the formulation of a solid triglyceride and a hydrophilic surfactant could potentially cause release instability, but formula (iii) was found to be stabilised by a mechanism whereby trilaurin crystallization enhanced in the presence of talc immobilised vitamin E TPGS in its crystal lattice. Thirdly, talc addition did not significantly influence trilaurin digestion which endows products with an immediate release in lipolytic conditions instead of an extended liberation in pure water. Nor did the addition of one or two additives alter the extent of trilaurin digestion under the conditions studied. These important findings relate to product manufacturability, stability, and release properties. A good understanding of material properties (e.g. crystallisation, polymorphism, digestibility) is essential for melt-processing, lipid coating stabilising and modulation of release profile of solid lipid-coated product, as demonstrated in this case study with trilaurin.

Redefine the role of d-α-Tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein, multidrug resistance protein 1, and breast cancer resistance protein mediated cancer multidrug resistance.

Cancer drug resistance is an ever-changing problem that most patients need to face in their later stages of treatment, especially the multidrug resistant (MDR) type. The drug efflux transporters, including P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP), play the crucial roles in this sophisticated battle. In recent decades, researchers try to find potential inhibitors to impede the drug efflux function of above transporters. d-α-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) is a prevalently used excipient in the formulation design. In the present study, the modulatory effects and mechanisms of vitamin E TPGS on the efflux transporters were investigated. And the cancer MDR reversing ability of vitamin E TPGS was evaluated as well. Stable-cloned transporter over-expressed cell lines were used for mechanisms study, while several types of MDR cancer cell lines were adopted as reversing evaluation models. The results exhibited that vitamin E TPGS significantly inhibited the efflux function of P-gp, MRP1, and BCRP under non-cytotoxic concentrations, but not influencing the protein expression levels. Through efflux assay and molecular docking, vitamin E TPGS was found to be an uncompetitive, non-competitive, and competitive inhibitor on chemotherapeutic drug doxorubicin efflux in P-gp, MRP1, and BCRP over-expressing cell lines, respectively. Furthermore, the basal ATPase activity of three transporters were significantly inhibited by vitamin E TPGS at 10 µM. And the cell membrane fluidity of P-gp over-expressing cell line was enhanced by 22.58% with 5 µM vitamin E TPGS treatment, compared to the parental Flp-In™-293 cell line (without P-gp). The resistance reversing ability of vitamin E TPGS was prominent in MCF-7/DOX MDR breast cancer cell line, which over-expressed P-gp, MRP1, and BCRP. These significant results suggested that vitamin E TPGS is a promising modulator on transporters mediated cancer MDR. Vitamin E TPGS is not an inert excipient, but possesses MDR-reversing pharmacological effects, and deserves a re-purposing application on the future combinatorial regimen design for MDR cancer treatment.

Comparison of topographic outcomes between HPMC based and vitamin E TPGS based riboflavin solutions after corneal cross-linking.

PURPOSE: To compare the visual and topographic results between patients who underwent epithelium-off cross-linking using riboflavin solutions compounds hydroxypropyl methylcellulose (HPMC) 1.1% and D-alpha-tocopheryl polyethylene-glycol 1000 succinate (VE-TPGS). METHODS: In this study, 37 eyes treated with HPMC and 29 eyes treated with VE-TPGS were evaluated retrospectively. Spherical equivalent (SE), refractive cylinder, corrected distance visual acuity tests (CDVA), corneal topography indices (flat and steep meridians' keratometry (K1 and K2)), maximum keratometry (K max), central, thinnest, and apical corneal thicknesses, the front and back keratoconus vertex index (KVf, KVb), and the surface asymmetry index of the front and back surface (SIf, SIb), and endothelial cell density were compared at baseline and postoperative follow-up visits (1, 3, 6, and 12months). RESULTS: At the end of the 12th-month, K1, K2, and Kmax were decreased in both groups. In comparison to baseline, there was a decline in the HPMC group in the 3rd- month Kmax change, an increase was observed in the VE-TPGS group. In the 12th-month KVb change, an increase was observed in the HPMC group compared to the baseline, while a decrease was observed in the VE-TPGS group. The other parameters did not show a statistically significant difference between the groups (p > 0.05). CONCLUSION: At the end of 12 months, both riboflavins were effective in stopping the progression of keratoconus and were safe for endothelium. Although both riboflavins provide a decrease in keratometry values, it can be said that VE-TPGS is superior to HPMC in correcting the ectasia on the posterior corneal surface.

In vitro profiling of fenofibrate solid dispersion mediated tablet formulation to treat high blood cholesterol.

OBJECTIVE: Fenofibrate (FNF), an anti-hyperlipidemic agent, suffers from poor water solubility (0.000707mg/ml) and belongs to class II drug as per BCS, shows a slow dissolution rate. The current investigation aimed to fabricate a fast-dissolving tablet of FNF (not available in the commercial market) using solid dispersion technique employing Vitamin E-D-α-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) as molecular biomaterial to enhance dissolution rate and reduce the time required to reach the systemic circulation. MATERIALS AND METHODS: Firstly, carrier material was selected based on the release study via preparing solid dispersion using the melting method, and prepared solid dispersion was characterized. Secondly, fast-dissolving tablets from solid dispersion were fabricated using the direct compression tool and characterized for X-ray diffraction (XRD) pattern, friability, hardness, content uniformity, weight variation and in vitro disintegration test. RESULTS: The X-ray diffraction study confirmed the successful formation of solid dispersion using vitamin E TPGS by analyzing the change in physical state. The fabricated solid dispersion exhibited higher drug content than a physical mixture of FNF. An excipient interference study was also performed in methanol and 0.75% w/v sodium lauryl sulphate. It revealed no significant alterations in the absorption peak of FNF as analyzed using UV spectroscopy at 287nm. In addition, water absorption ratio phase solubility and wetting time were also assessed. In -vitro release of FNF from developed tablets was found significantly higher (93.23%±3.11; p<0.001) as compared to prepared compressed tablet of pure FNF (12.21±2.34%). The dissolution rate was also determined, and data were then kept to various kinetic models such as zero-order chemical kinetic, first-order chemical kinetic, Hixon-Crowell and Higuchi chemical kinetic. CONCLUSION: A complete and sequential in vitro and physicochemical characterization of developed formulation was carried out to set-up improved and effective treatment for high blood cholesterol.

Small Angle X-Ray Scattering Data Analysis and Theoretical Modelling for the Size and Shape Characterization of Drug Delivery Systems Based on Vitamin E TPGS Micelles.

We developed a simple two-dimensional/two-components theoretical model that describes the structure and functionality of a VitE-TPGS system of micelles assuming a hydrophobic inner core and an outer hydrated hydrophilic shell. We then conceptually applied the developed methodology to a simple system of VitE-TPGS micelles unloaded and loaded with an active pharmaceutical ingredient, eltrombopag, to verify if the model could reliably monitor the size change of the micelle upon loading. The fit of laboratory Small Angle X-Ray Scattering data against such model allows us to extract absolute values of the micelles size under a spherical shape hypothesis as well as the distribution within the system between components and level of hydration. The intensity scale of the SAXS experimental data needs to be normalized to a reference standard (pure water) to get absolute scattered intensities. The mathematical model which has been developed under a general hypothesis of ellipsoidal micelles, is applied to our experimental data under the simplified spherical assumption, which suitably fits our experimental data.

Increasing Cellular Uptake and Permeation of Curcumin Using a Novel Polymer-Surfactant Formulation.

Several therapeutically active molecules are poorly water-soluble, thereby creating a challenge for pharmaceutical scientists to develop an active solution for their oral drug delivery. This study aimed to investigate the potential for novel polymer-surfactant-based formulations (designated A and B) to improve the solubility and permeability of curcumin. A solubility study and characterization studies (FTIR, DSC and XRD) were conducted for the various formulations. The cytotoxicity of formulations and commercial comparators was tested via MTT and LDH assays, and their permeability by in vitro drug transport and cellular drug uptake was established using the Caco-2 cell model. The apparent permeability coefficients (Papp) are considered a good indicator of drug permeation. However, it can be argued that the magnitude of Papp, when used to reflect the permeability of the cells to the drug, can be influenced by the initial drug concentration (C0) in the donor chamber. Therefore, Papp (suspension) and Papp (solution) were calculated based on the different values of C0. It was clear that Papp (solution) can more accurately reflect drug permeation than Papp (suspension). Formulation A, containing Soluplus® and vitamin E TPGs, significantly increased the permeation and cellular uptake of curcumin compared to other samples, which is believed to be related to the increased aqueous solubility of the drug in this formulation.

Unfolding the Potency of Adenosine in Targeting Triple Negative Breast Cancer via Paclitaxel-Incorporated pH-Responsive Stealth Liposomes.

Triple-negative breast cancer (TNBC) belongs to the category of the most destructive forms of breast cancer. Being a highly potent chemotherapeutic agent, paclitaxel (PTX) is extensively utilized in the management of various cancers. Commercially available PTX formulations contain non-targeted drug carriers that result in low antitumor activity because of non-specific tissue distribution. Thus, to resolve this issue, we designed PTX-loaded pH-sensitive liposomes (pH Lipos) in the present investigation and used adenosine (ADN) as a targeting ligand. Further, d-α-tocopheryl polyethylene glycol succinate (TPGS) was incorporated into the liposomes to impart a stealth effect to the system. For the development of these pH Lipos, different conjugates were synthesized (ADN-CHEMS and TPGS-ADN) and further utilized for the preparation of ADN-PEG-pH Lipo and ADN-pH Lipo by a thin-film hydration method. DOPE:HSPC:CHEMS:cholesterol at a molar ratio of 3:3:2:2 was selected for the preparation of pH-Lipo possessing 7.5% w/w drug loading. They showed a particle size below 140 nm, a PDI below 0.205, and a % EE greater than 60%. All of the pH Lipos displayed a biphasic pattern of PTX release at pH 7.4 and 5.5. However, the percent drug release at pH 5.5 was substantially greater because of the pH-sensitive nature of the liposomes. The MDA MB 231 and 4T1 cell lines depicted improvement in the qualitative as well as quantitative cellular uptake of PTX ADN-PEG-pH Lipo with a substantial decrease in the IC50 value. Moreover, a higher apoptotic index was observed with pH Lipo compared to free PTX. PTX ADN-PEG-pH Lipo revealed a 3.98- and 3.41-fold rise in the AUC and t1/2 values of PTX compared to Intaxel, respectively. Overall, characteristic decreases in tumor volume and serum toxicity marker levels were observed, which confirmed the development of an efficient and safe formulation.

Self-Assembled Nanomicellar Formulation of Docetaxel as a Potential Breast Cancer Chemotherapeutic System.

Docetaxel (DTX) is classified as a class IV drug that exhibits poor aqueous solubility (6-7 µg/mL in water) and permeability (P-glycoprotein substrate). The main objective of this study was to construct, characterize, and evaluate docetaxel loaded nanomicellar formulation in vitro for oral delivery to enhance the absorption and bioavailability of DTX, as well as to circumvent P-gp efflux inhibition. Formulations were prepared with two polymeric surfactants, hydrogenated castor oil-40 (HCO-40) and D-α-Tocopherol polyethylene glycol 1000 succinate (VIT E TPGS) with solvent evaporation technique, and the resulting DTX nanomicellar formulations were characterized by proton nuclear magnetic resonance spectroscopy (1H NMR), Fourier Transform Infrared Spectroscopy (FT-IR), X-ray powder diffraction (XRD), and transmission electron microscopy (TEM). Proton NMR, FT-IR, and XRD data indicated that DTX was completely encapsulated within the hydrophobic core of the nanomicelles in its amorphous state. TEM data revealed a smooth spherical shape of the nanomicellar formulation. The optimized formulation (F-2) possessed a mean diameter of 13.42 nm, a zeta potential of -0.19 mV, with a 99.3% entrapment efficiency. Dilution stability study indicated that nanomicelles were stable up to 100-fold dilution with minimal change in size, poly dispersity index (PDI), and zeta potential. In vitro cytotoxicity study revealed higher anticancer activity of DTX nanomicelles at 5 µM compared to the native drug against breast cancer cell line (MCF-7) cells. The LC-MS data confirmed the chemical stability of DTX within the nanomicelles. In vitro drug release study demonstrated faster dissolution of DTX from the nanomicelles compared to the naked drug. Our experimental results exhibit that nanomicelles could be a drug delivery system of choice to encapsulate drugs with low aqueous solubility and permeability that can preserve the stability of the active constituents to provide anticancer activity.

Dual Targeting with Cell Surface Electrical Charge and Folic Acid via Superparamagnetic Fe3O4@Cu2-xS for Photothermal Cancer Cell Killing.

A major challenge in cancer therapy is to achieve high cell targeting specificity for the highest therapeutic efficacy. Two major approaches have been shown to be quite effective, namely, (1) bio-marker mediated cell targeting, and (2) electrical charge driven cell binding. The former utilizes the tumor-specific moieties on nano carrier surfaces for active targeting, while the latter relies on nanoparticles binding onto the cancer cell surfaces due to differences in electrical charge. Cancer cells are known for their hallmark metabolic pattern: high rates of glycolysis that lead to negatively charged cell surfaces. In this study, the nanoparticles of Fe3O4@Cu2-xS were rendered positively charged by conjugating their surfaces with different functional groups for strong electrostatic binding onto the negatively-charged cancer cells. In addition to the positively charged surfaces, the Fe3O4@Cu2-xS nanoparticles were also modified with folic acid (FA) for biomarker-based cell targeting. The dual-targeting approach synergistically utilizes the effectiveness of both charge- and biomarker-based cell binding for enhanced cell targeting. Further, these superparamagnetic Fe3O4@Cu2-xS nanoparticles exhibit much stronger IR absorptions compared to Fe3O4, therefore much more effective in photothermal therapy.

Topo-Pachimetric Accelerated Epi-On Cross-Linking Compared to the Dresden Protocol Using Riboflavin with Vitamin E TPGS: Results of a 2-Year Randomized Study.

In the present study (clinical trial registration number: NCT05019768), we compared the clinical outcome of corneal cross-linking with either the standard Dresden (sCXL) or the accelerated custom-fast (aCFXL) ultraviolet A irradiation protocol using riboflavin-D-α-tocopheryl poly(ethylene glycol)-1000 succinate for progressive keratoconus. Fifty-four eyes of forty-one patients were randomized to either of the two CXL protocols and checked before treatment and at the 2-year follow-up. The sCXL group was subjected to CXL with 30 min of pre-soaking and 3 mW/cm2 UVA irradiation for 30 min. The aCFXL group was subjected to CXL with 10 min of pre-soaking and UVA irradiation of 1.8 ± 0.9 mW/cm2 for 10 min ± 1.5 min. In both groups, a solution of riboflavin-vitamin E TPGS was used. Uncorrected distance visual acuity, corrected distance visual acuity, pachymetry, Scheimpflug tomography, and corneal hysteresis were performed at baseline and after 24 months. Both groups showed a statistically significant improvement in corrected distance visual acuity, and keratometric and corneal hysteresis compared to baseline conditions; no statistically significant differences in outcomes between the two groups were observed. Improvement in refractive, topographic, and biomechanical parameters were observed after sCXL and aCFXL, making the riboflavin-VE-TPGS solution an effective option as a permeation enhancer in CXL procedures. Deeper stromal penetration of riboflavin could be complemented by photo-protection against UVA and free radicals formed during photoinduced processes.

Octreotide-Targeted Lcn2 siRNA PEGylated Liposomes as a Treatment for Metastatic Breast Cancer.

Lcn2 overexpression in metastatic breast cancer (MBC) can lead to cancer progression by inducing the epithelial-to-mesenchymal transition and enhancing tumor angiogenesis. In this study, we engineered a PEGylated liposomal system encapsulating lipocalin 2 (Lcn2) small interfering RNA (Lcn2 siRNA) for selective targeting MBC cell line MCF-7 and triple-negative breast cancer cell line MDA-MB-231. The PEGylated liposomes were decorated with octreotide (OCT) peptide. OCT is an octapeptide analog of somatostatin growth hormone, having affinity for somatostatin receptors, overexpressed on breast cancer cells. Optimized OCT-targeted Lcn2 siRNA encapsulated PEGylated liposomes (OCT-Lcn2-Lipo) had a mean size of 152.00 nm, PDI, 0.13, zeta potential 4.10 mV and entrapment and loading efficiencies of 69.5% and 7.8%, respectively. In vitro uptake and intracellular distribution of OCT-Lcn2-Lipo in MCF-7 and MDA-MB-231 and MCF-12A cells demonstrated higher uptake for the OCT-targeted liposomes at 6 h by flow cytometry and confocal microscopy. OCT-Lcn2-lipo could achieve approximately 55-60% silencing of Lcn2 mRNA in MCF-7 and MDA-MB-231 cells. OCT-Lcn2-Lipo also demonstrated in vitro anti-angiogenic effects in MCF-7 and MDA-MB-231 cells by reducing VEGF-A and reducing the endothelial cells (HUVEC) migration levels. This approach may be useful in inhibiting angiogenesis in MBC.

Novel Vitamin E TPGS based docetaxel nanovesicle formulation for its safe and effective parenteral delivery: Toxicological, pharmacokinetic and pharmacodynamic evaluation.

Docetaxel (DTX) is a highly lipophilic, BCS class IV drug with poor aqueous solubility (12.7 µg/mL). Presently, only injectable formulation is available in the market which uses a large amount of surfactant (Tween 80) and dehydrated alcohol as a solubilizer. High concentrations of Tween 80 in injectable formulations are associated with severe consequences i.e. nephrotoxicity, fluid retention, and hypersensitivity reactions. The present study aims to eliminate Tween 80, thus novel biocompatible surfactant Vitamin E TPGS based nanovesicle formulation of DTX (20 mg/mL) was developed and evaluated for different quality control parameters. Optimized nanovesicular formulation (NV-TPGS-3) showed nanometric size (102.9 ± 2.9 nm), spherical vesicular shape, high drug encapsulation efficiency (95.2 ± 0.5%), sustained-release profile and high dilution integrity with normal saline. In vitro cytotoxicity assay, showed threefold elevation in the IC50 value of the optimized formulation in comparison to the commercial formulation. Further, no mortality and toxicity were observed during 28 days repeated dose sub-acute toxicity studies in Swiss albino mice up to the dose of 138 mg/kg, whereas, commercial formulation showed toxicity at 40 mg/kg. In addition, in vivo anticancer activity on Ehrlich Ascites Carcinoma induced mice showed a significant tumour growth inhibition of 76.3 ± 5.3% with the NV-TPGS-3 treatment when compared to Ehrlich Ascites Carcinoma control. Results demonstrated that the developed Vitamin E TPGS based nanovesicular formulation of DTX could be a better alternative to increase its clinical uses with improved therapeutic efficacy, reduced toxicity and dosing frequency, and sustained drug release behaviour.

Effectiveness and Safety of Topical Chlorhexidine and Vitamin E TPGS in the Treatment of Acanthamoeba Keratitis: A Survey on 29 Cases.

This study aimed to test the effectiveness of a solution of chlorhexidine (CHX) and D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) in the treatment of Acanthamoeba keratitis (AK) via a prospective, interventional case series study. Twenty-nine consecutive patients with AK were enrolled. At baseline, best-corrected visual acuity (BCVA), slit lamp examination, confocal microscopy, and polymerase chain reaction (PCR) were performed. Topical therapy with CHX 0.02% and VE-TPGS 0.2% was administered hourly/24 h for the first day, hourly in the daytime for the next three days, and finally, every two hours in the daytime up to one month. BCVA and ocular inflammation were recorded after two weeks, four weeks, and three months from baseline. Mean logMAR BCVA significantly improved at two weeks (0.78) compared to baseline (1.76), remaining stable over time (0.80 at four weeks, 0.77 at three months). Ocular inflammation improved in 14 eyes at 2 weeks, with further slow improvements in all cases. At three months, no patient had signs of corneal inflammation. The presence of corneal scars was first recorded at the two-week follow-up, with an enlargement at the four-week follow-up. At the three-month follow-up, 19 eyes still showed corneal opacities. In conclusion, the tested solution was shown to be effective for the treatment of AK. Furthermore, it might represent a good first-line treatment.

Development, Characterization and Evaluation of Parenteral Formulation of Diclofenac Sodium.

Diclofenac sodium is a potent NSAID, classified under BCS class II category having a poor aqueous solubility. Recently, its injectable formulation got banned and withdrawn from the market due to its severe nephrotoxicity caused by the use of synthetic surfactant, i.e. Transcutol-P as solubilizer. Therefore, the present study was aimed to prepare Transcutol-P free injectable using Vitamin E TPGS as a biosurfactant which is in list of inactive ingredients by US-FDA. Various cost effective aqueous injectable formulations were prepared by mixed solvency method that were characterized and optimized for different in vitro quality control parameters. Further, ex vivo hemolytic study showed the increased safety (23.4 ± 1.6%) of optimized formulation as compared with its commercial counterpart (100 ± 4.2%) at 75 mg/ml. Furthermore, in vivo acute and sub-acute toxicity study demonstrated an increase in LD50 to 123.75 ± 6.2 mg/kg to that of a commercial counterpart (109.96 ± 5.5 mg/kg). In addition, optimized formulation demonstrated better mean residence time and area under curve when compared with commercial test group, respectively. Moreover, optimized formulation was also evaluated for its therapeutic efficacy. The results obtained from acetic acid-induced writhing test in albino mice showed 78 ± 2.1% protection from writhes after 120 min, whereas the commercial formulation had only 48.3 ± 1.9% protection. Additionally, carrageenan-induced rat paw edema model also confirmed the better anti-inflammatory activity of optimized aqueous injectable formulation than its commercial counterpart. Thus, the developed aqueous injectable formulation of diclofenac is free from toxic Transcutol-P with enhanced safety and therapeutic efficacy.

A Novel Vitamin E TPGS-Based Formulation Enhances Chlorhexidine Bioavailability in Corneal Layers.

Keratitis is a severe condition characterized by inflammation of the cornea following a local trauma. The most common ocular disease is the bacterial one, which requires an antibiotic treatment. The major limitation of this therapy is the resistance of the antibiotic. For this reason, alternative procedures have been developed and consist of antimicrobial molecules. One of the most used is the chlorhexidine gluconate, which has shown activity versus Gram-positive and Gram-negative bacteria and fungi. In addition to its efficiency, chlorhexidine shows low toxicity levels for mammalian cells and is a low-cost molecule. Despite its multiple benefits, chlorhexidine, if used at concentrations higher than 0.02% (w/w), can cause local eye irritation. Additionally, its poor penetrability through the cornea makes necessary frequent instillation of eye drops for a prolonged time. Due to these limitations, alternative drug delivery strategies are required. Here, we report a novel formulation based on the combination of d-alpha-tocopherol polyethylene glycol 1000 succinate with chlorhexidine, which results in higher accumulation of the drug in human corneas measured by liquid chromatography and strong antimicrobial activity. Moreover, this formulation does not cause any toxic effect on human cells and is well tolerated by rabbit eyes. Therefore this novel formulation represents a good candidate for the treatment of keratitis that overcomes the risk of antibiotic resistance.

Central composite design-based optimization of lopinavir vitamin E-TPGS micelle: In vitro characterization and in vivo pharmacokinetic study.

This study was aimed at formulating Lopinavir loaded Vitamin E-TPGS micelles to enhance its oral bioavailability. Lopinavir is an HIV-1 protease inhibitor with low aqueous solubility leading to poor oral bioavailability and thus frequent dosing. Drug loaded micelles were fabricated using thin film hydration technique and optimized by two-factor five-level central composite design. For this purpose independent variables selected were TPGS to drug ratio and rotational speed of rotary evaporator, whereas dependent variables chosen were particle size and % entrapment efficiency. The effect of an independent variable on the dependent variable was studied by generating a quadratic polynomial model. Results of in vitro characterization showed that prepared lopinavir micelles exhibited particle size 91.71 nm, polydispersity index 0.129, zeta potential -24.8 mV, entrapment efficiency 99.36 ±â€¯1.06% and drug loading 20.83 ±â€¯1.23%. Results of DSC and P-XRD evaluation revealed that drugs were successfully encapsulated inside the Vitamin E-TPGS micelles. In vitro release studies displayed enhancement in drug dissolution as a result of its loading into micelles. TEM images showed that micelles were spherical. On oral administration of lopinavir micelles; the relative bioavailability was boosted by 3.17 folds compared to lopinavir suspensions. Thus, we can conclude that TPGS based micelles possess the prodigious potential to overcome the challenges of current HAART therapy.

Characterization and Cytotoxicity of Polyprenol Lipid and Vitamin E-TPGS Hybrid Nanoparticles for Betulinic Acid and Low-Substituted Hydroxyl Fullerenol in MHCC97H and L02 Cells.

BACKGROUND: This study demonstrated an innovative formulation including the polyprenol (GBP) lipid and vitamin E-TPGS hybrid nanoparticles (NPs) which was aimed to control the transfer of betulinic acid (BA) and low-substituted hydroxyl fullerenol (C60(OH)n). Additionally, it developed BA-C60(OH)n-GBP-TPGS-NPs delivery system and researched the anti-hepatocellular carcinoma (HCC) effects. MATERIALS AND METHODS: The NPs were prepared by nanoprecipitation with ultrasonic-assisted emulsification (UAE) method. It was characterized by scanning electronic microscopy (SEM), transmission electron microscopy (TEM), FTIR spectrum, size distribution and zeta potential. Physical and chemical properties were evaluated through measurement of drug release, stability studies, drug loading efficiency (DE) and encapsulation efficiency (EE). Biological activities were evaluated through measurement of MTT assay, lactate dehydrogenase leakage assay (LDH), cell proliferation assays, cell apoptosis analysis, comet assay, wound healing assay, cell invasion and Western blot analysis. RESULTS AND CONCLUSIONS: The NPs exhibited clear distribution characteristics, improved solubility and stability. BA and C60(OH)n for the NPs displayed a biphasic release pattern with sustained drug release properties. The mixture of C60(OH)n with different hydroxyl groups may have a certain effect on the stability of the NPs system itself. The NPs could effectively inhibit MHCC97H cell proliferation, migration and invasion in vitro. Combined use of C60(OH)n and BA in GBP lipids may improve the inhibit effect of C60(OH)n or BA against HCC cells and reduce cytotoxicity and genotoxicity of C60(OH)n for normal cells. We concluded that one of the important mechanisms of BA-C60(OH)n-GBP-TPGS-NPs inhibiting MHCC97H cells is achieved by up-regulating the expression of Caspase-3, Caspase-8 and Caspase-9.

Improving tumor hypoxia and radiotherapy resistance via in situ nitric oxide release strategy.

Radiation therapy remains one of the main treatments for cancer. However, conventional radiotherapy not only manifests a low radiation accumulation in the tumor site, but also displays numerous negative effects. The most serious clinical problem is the radiotherapy resistance leading to cancer deterioration. As an important gaseous signal molecule, nitric oxide (NO) has been widely studied for its role in regulating angiogenesis, improving hypoxia, and inhibiting tumor growth. However, due to the unstable characteristic, the application of NO in cancer therapy is still limited. Here, we designed a micellar system formed by a NO donor, D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS)-NO, for enabling sustained NO release to efficiently deliver NO into the tumor area. TPGS-NO could accumulate in the tumor site for extended circulation, thereby releasing NO to exert antitumor effects and enhance radiotherapy effects under low-oxygen conditions. It demonstrated the increased sensitivity of radiotherapy through enhancing tumor angiogenesis appropriately reducing tumor area hypoxia, which significantly induced tumor cell apoptosis and inhibited its repair during radiation. This work may show great potential in synergistic radiotherapy against cancer by facile NO donor administration.

Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano) for Ocular Delivery of Cyclosporine-A.

The physiological protective mechanisms of the eye reduce the bioavailability of topically administered drugs above all for those with high molecular weight and /or lipophilic characteristics, such as Cyclosporine A (CyA). The combined strategy based on the association of nanomicelles and mucoadhesive polymer seems promising since a limited number of commercial products containing CyA have been recently approved. The scope of this investigation was the design of Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano), based on a binary system of two surfactants in combination with hyaluronic acid, and their biopharmaceutical evaluation. The optimisation of the ASMP-Nano in term of the amount of surfactants, CyA-loading and size determined the selection of the clear and stable Nano1HAB-CyA formulation containing 0.105% w/w CyA loaded-nanomicelles with a size of 14.41 nm. The nanostructured system had a protective effect towards epithelial corneal cells with a cell viability of more than 80%. It interacted with cellular barriers favouring the uptake and the accumulation of CyA into the cells as evidenced by fluorescent probe distribution, by hindering CyA permeation through reconstituted corneal epithelial tissue. In pharmacokinetics study on rabbits, the nanomicellar carrier prolonged the CyA retention time in the precorneal area mainly in presence of hyaluronic acid (HA), a mucoadhesive polymer.