Study on the Synthetic Characteristics of Biomass-Derived Isosorbide-Based Poly(arylene ether ketone)s for Sustainable Super Engineering Plastic.

Demand for the development of novel polymers derived from biomass that can replace petroleum resources has been increasing. In this study, biomass-derived isosorbide was used as a monomer in the polymerization of poly(arylene ether ketone)s, and its synthetic characteristics were investigated. As a phase-transfer catalyst, crown ether has increased the weight-average molecular weight of polymers over 100 kg/mol by improving the reaction efficiency of isosorbide and minimizing the effect of moisture. By controlling the experimental parameters such as halogen monomer, polymerization solvent, time, and temperature, the optimal conditions were found to be fluorine-type monomer, dimethyl sulfoxide, 24 h, and 155 °C, respectively. Biomass contents from isosorbide-based polymers were determined by nuclear magnetic resonance and accelerator mass spectroscopy. The synthesized polymer resulted in a high molecular weight that enabled the preparation of transparent polymer films by the solution casting method despite its weak thermal degradation stability compared to aromatic polysulfone. The melt injection molding process was enabled by the addition of plasticizer. The tensile properties were comparable or superior to those of commercial petrochemical specimens of similar molecular weight. Interestingly, the prepared specimens exhibited a significantly lower coefficient of thermal expansion at high temperatures over 150 °C compared to polysulfone.

Quantitative Investigation of Terbinafine Hydrochloride Absorption into a Living Skin Equivalent Model by MALDI-MSI.

The combination of microspotting of analytical and internal standards, matrix sublimation, and recently developed software for quantitative mass spectrometry imaging has been used to develop a high-resolution method for the determination of terbinafine hydrochloride in the epidermal region of a full thickness living skin equivalent model. A quantitative assessment of the effect of the addition of the penetration enhancer (dimethyl isosorbide (DMI)) to the delivery vehicle has also been performed, and data have been compared to those obtained from LC-MS/MS measurements of homogenates of isolated epidermal tissue. At 10% DMI, the levels of signal detected for the drug in the epidermis were 0.20 ± 0.072 mg/g tissue for QMSI and 0.28 ± 0.040 mg/g tissue for LC-MS/MS at 50% DMI 0.69 ± 0.23 mg/g tissue for QMSI and 0.66 ± 0.057 mg/g tissue for LC-MS/MS. Comparison of means and standard deviations indicates no significant difference between the values obtained by the two methods.

In vitro-in vivo correlation in skin permeation.

PURPOSE: In vitro skin permeation studies have been used extensively in the development and optimisation of delivery of actives in vivo. However, there are few reported correlations of such in vitro studies with in vivo data. The aim of this study was to investigate the skin permeation of a model active, niacinamide, both in vitro and in vivo. METHODS: Conventional diffusion cell studies were conducted in human skin to determine niacinamide permeation from a range of vehicles which included dimethyl isosorbide (DMI), propylene glycol (PG), propylene glycol monolaurate (PGML), N-methyl 2-pyrrolidone (NMP), Miglyol 812N® (MG), and mineral oil (MO). Single, binary or ternary systems were examined. The same vehicles were subsequently examined to investigate niacinamide delivery in vivo. For this proof-of-concept study one donor was used for the in vitro studies and one volunteer for the in vivo investigations to minimise biovariability. Analysis of in vitro samples was conducted using HPLC and in vivo uptake of niacinamide was evaluated using Confocal Raman spectroscopy (CRS). RESULTS: The amount of niacinamide permeated through skin in vitro was linearly proportional to the intensity of the niacinamide signal determined in the stratum corneum in vivo. A good correlation was observed between the signal intensities of selected vehicles and niacinamide signal intensity. CONCLUSIONS: The findings provide further support for the use of CRS to monitor drug delivery into and across the skin. In addition, the results highlight the critical role of the vehicle and its disposition in skin for effective dermal delivery.

Investigation on synthesis and properties of isosorbide based bis-GMA analogue.

The aim of this work was to synthesize and investigate properties of a novel dimethacrylic monomer based on bioderived alicyclic diol--isosorbide. Its potential as a possible substitute of 2,2-bis[4-(2-hydroxy-3-methacryloyloxypropoxy)phenyl]propane (BISGMA), widely used in dental restorative materials and suspected for toxicity was assessed. The novel monomer was obtained in a three-step synthesis. First, isosorbide was etherified by a Williamson nucleophilic substitution and subsequently oxidized to isosorbide diglycidyl ether (ISDGE). A triphenyl phosphine catalyzed addition of methacrylic acid to ISDGE resulted in 2,5-bis(2-hydroxy-3-methacryloyloxypropoxy)- 1,4:3,6-dianhydro-sorbitol (ISDGMA). The monomer obtained was photopolymerized using camphorquinone/2-(dimethylamino)ethyl methacrylate initiating system. Next, compositions with triethylene glycol dimethacrylate (TEGDMA) were prepared and polymerized. Double bond conversion, polymerization shrinkage and water sorption of resulting polymers were determined. Selected mechanical (flexular strength and modulus, Brinell hardness) and thermomechanical (DMA analysis) properties were also investigated. BISGMA based materials were prepared as reference for comparison of particular properties.

Prevention of contrast-induced nephropathy by adequate hydration combined with isosorbide dinitrate for patients with renal insufficiency and congestive heart failure.

BACKGROUND: Adequate hydration remains the mainstay of contrast-induced nephropathy prevention, and nitrates could reduce cardiac preload. HYPOTHESIS: This study aimed to explore the adequate hydration with nitrates for patients with chronic kidney disease (CKD) and congestive heart failure (CHF) to reduce the risk of contrast-induced nephropathy (CIN) and at the same time avoid the acute heart failure. METHODS: Three hundred and ninty-four consecutive patients with CKD and CHF undergoing coronary procedures were randomized to either adequate hydration with nitrates (n = 196) or to routine hydration (control group; n = 198). The adequate hydration group received continuous intravenous infusion of isosorbide dinitrate combined with intravenous infusion of isotonic saline at a rate of 1.5 mL/kg/h during perioperative period. The definition of CIN was a 25% or 0.5 mg/dL rise in serum creatinine over baseline. This trial is registered with www.clinicaltrials.gov, number NCT02718521. RESULTS: Baseline characteristics were well-matched between the two groups. CIN occurred less frequently in adequate hydration group than the control group (12.8% vs 21.2%; P = 0.018). The incidence of acute heart failure did not differ between the two groups (8 [4.08%] vs 6[3.03%]; P = 0.599). Cumulative major adverse events (death, myocardial infarction, stoke, hospitalization for acute heart failure) during the 90-day follow-up were lower in the adequate hydration with nitrates group (P = 0.002). CONCLUSIONS: Adequate hydration with nitrates can safely and effectively reduce the risk of CIN in patients with CKD and CHF.

Computer-based formulation design and optimization using Hansen solubility parameters to enhance the delivery of ibuprofen through the skin.

Trial-and-error approach to formulation development is long and costly. With growing time and cost pressures in the pharmaceutical industry, the need for computer-based formulation design is greater than ever. In this project, emulgels were designed and optimized using Formulating for Efficacy™ (FFE) for the topical delivery of ibuprofen. FFE helped select penetration enhancers, design and optimize emulgels and simulate skin penetration studies. pH, viscosity, spreadability, droplet size and stability of emulgels were evaluated. Franz cell studies were performed to test in vitro drug release on regenerated cellulose membrane, drug permeation in vitro on Strat-M® membrane and ex vivo on porcine ear skin, a marketed ibuprofen gel served as control. Emulgels had skin compatible pH, viscosity and spreadability comparable to a marketed emulgel, were opaque and stable at 25 °C for 6 months. Oleyl alcohol (OA), combined with either dimethyl isosorbide (DMI) or diethylene glycol monoethyl ether (DGME) provided the highest permeation in 24 h in vitro, which was significantly higher than the marketed product (p < 0.01). OA + DGME significantly outperformed OA ex vivo (p < 0.05). The computer predictions, in vitro and ex vivo penetration results correlated well. FFE was a fast, valuable and reliable tool for aiding in topical product design for ibuprofen.

Physicochemical characterisation of a novel thermogelling formulation for percutaneous penetration of 5-aminolevulinic acid.

The present contribution was dedicated to the development and characterisation of a semisolid formulation of 5-aminolevulinic acid (5-ALA), appropriate for the diagnosis and treatment of actinic keratosis in photodynamic therapy. To achieve sufficiently high concentrations of the polar substance within the living epithelium after topical application, the semisolid base was enriched with penetration enhancers. A semisolid liquid crystalline system for drug delivering was the formulation of choice. It was composed of isopropyl alcohol, dimethyl isosorbide, medium chain triglycerides, water, and Pluronic F 127 as a polyoxyethylene-polyoxypropylene surface-active block copolymer. Rheometrical investigations were performed in the oscillatory mode and showed a thermo reversible gelification behaviour of the formulation, which therefore was denoted Thermogel. Permeation studies through human stratum corneum revealed higher permeation coefficients for 5-ALA from the Thermogel than from different German Pharmacopoeia creams. For example a 7.5-fold increase in comparison with Basiscreme DAC, and a 19.5-fold increase compared to water containing hydrophilic ointment. With respect to Dolgit(R) Mikrogel, the permeation coefficient from the Thermogel was 6.4-fold higher. These results were in accordance with those of differential scanning calorimetry measurements. Thermogel disclosed the strongest interactions with stratum corneum lipids.

Effect of penetration modifiers on the dermal and transdermal delivery of drugs and cosmetic active ingredients.

In this study the effect of 2 penetration modifiers, dimethyl isosorbide (DMI) and diethylene glycol monoethyl ether (DGME) on the skin delivery of hydroquinone (HQ), salicylic acid (SA) and octadecenedioic acid (DIOIC) was investigated. Ten percent DMI and DGME were separately formulated into oil-in-water emulsions containing 1.8% HQ, SA and DIOIC, respectively. Skin delivery and the flux across split-thickness human skin of the active ingredients were determined using Franz diffusion cells. An emulsion with 10% water incorporated instead of the water-soluble penetration modifiers served as a control. The study showed that neither 10% DMI nor 10% DGME significantly enhanced the skin permeation of the various lipophilic active ingredients or the uptake into the skin. It was hypothesized that the addition of the penetration modifiers to the emulsions not only enhanced the solubility of the various active ingredients in the skin but also in the formulation, resulting in a reduced thermodynamic activity and hence a weaker driving force for penetration. Therefore, the effect of DMI and DGME on the solubility of the active ingredients in the skin was counteracted by a simultaneous reduction in the thermodynamic activity in the formulation.

One-Pot Preparation of Dimethyl Isosorbide from d-Sorbitol via Dimethyl Carbonate Chemistry.

Direct synthesis of dimethyl isosorbide (DMI) from d-sorbitol via dimethyl carbonate (DMC) chemistry is herein first reported. High yield of DMI was achieved using the nitrogen superbase 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as catalyst and performing the reaction in a stainless steel autoclave by increasing the temperature from 90 to 200 °C. In this procedure, DMC features its full capacity acting in the different steps of the process as carboxymethylating, leaving-group (cyclization), and methylating agent; DMC is also employed as the reaction media.

Synthesis of 2-[(18)F]Fluoro-2-deoxyisosorbide 5-mononitrate and Assessment of Its in vivo Biodistribution as Determined by Dynamic Positron Emission Tomography (PET).

Herein we disclose the synthesis of 2-fluoro-2-deoxyisosorbide 5-mononitrate (2F-IS-5MN), a fluorinated analogue of the commonly prescribed vasodilator isosorbide 5-mononitrate (IS-5MN). X-ray structural data for IS-5MN and its C2-epimeric congener IM-5MN are presented together with structural data for 2F-IS-5MN. Radioisotope labeling of 2F-IS-5MN has, for the first time, allowed observation of the in vivo biodistribution of this organic nitrate by means of dynamic positron emission tomography (PET) in wild-type mice.

Optimization of bioavailability of topical steroids: penetration enhancers under occlusion.

The occluded vasoconstrictor assay was used to assess the effect of penetration enhancers on the topical bioavailability of a representative steroid, betamethasone 17-benzoate, with dimethylisosorbide (DMI) as a reference solvent. In the initial test, only N-methyl-2-pyrrolidone (NMP) increased the steroid bioavailability; acetone, dimethylformamide (DMF), 2-pyrrolidone (2-P), and 1-ethyl-2-pyrrolidone (EP) were equal to DMI, while propylene glycol (PG) and N,N-diethyl-m-toluamide (DEET) were poorer. Reocclusion showed that NMP and acetone established superior stratum corneum reservoirs; DMF, 2-P, EP, and PG were as effective as DMI but DEET was less effective. It was concluded that occlusive hydration and lack of thermodynamic control may have obscured the enhancing abilities of the solvents, 2-P, NMP, EP, DMF, and DEET induced erythema in some volunteers, although this was usually short-lived.

Codiffusion of propylene glycol and dimethyl isosorbide in hairless mouse skin.

The in vitro percutaneous fluxes of propylene glycol (PG), cis-oleic acid (OA) and dimethyl isosorbide (DI) were determined and their effect on nifedipine (N) flux and lag time evaluated. PG, OA and DI flux through hairless mouse (HM) skin was measured in vitro by beta-scintigraphy and N permeation was measured by HPLC under finite and infinite dose conditions. Evaluation of each of the solvents separately showed that pure DI possessed the inherent ability to traverse the skin (12% in 24 h). For the tested formulation after 24 h, 57% of the PG and 40% of the DI had permeated across the skin with nearly linear permeation between 4 and 18 h and the relative order of permeation was PG > DI > N. DI permeation was further aided in the presence of PG and OA. N flux was dependent on concomitant solvent permeation. Over a 24-h test period a dose dependent response was observed for N, with 4.9-15.6 mg of N delivered from the lowest and highest doses, respectively, and the highest dose yielding zero-order flux of 146 (g/h per cm2).

Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate.

Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 degrees C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 degrees C over the pH range 1.03-9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing alpha-chymotrypsin [EC 3.1.1.1] (t(1/2)=200.9 min), carboxyl esterase [EC 3.1.1.1] (t(1/2)=31.5 min), human serum albumin (t(1/2)=603 min), purified human serum butyrylcholinesterase [EC 3.1.1.8] (80 micro g/ml; t(1/2)=9.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 micro g/ml; t(1/2)=1.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 micro M). The results indicate that a specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate.

Single oral dose study of two isosorbide-based aspirin prodrugs in the dog.

The objective of this study was to compare two aspirin prodrugs, isosorbide diaspirinate (ISDA) and a nitroaspirin (ISMNA), with aspirin in terms of effects on dog platelet function after administration of a single oral dose. Groups of six dogs were administered ISDA (2mg kg(-1)), ISMNA (4 mg kg(-1)) or aspirin (2mg kg(-1)). Blood was sampled at 1, 2, 4, 8, 12 and 24 h post-dosing and evaluated for capacity to generate post-clotting thromboxane (TX)B2. The aggregation response to arachidonic acid (AA) (100 microM), ADP (30 microM) or collagen (10 microg mL(-1)) was estimated at each time-point using the whole blood impedance method. Plasma ISMN following oral administration of ISMNA was also measured and compared with plasma ISMN following administration of a physical mixture of ISMN and aspirin. ISDA administration (2 mg kg(-1)) was associated with a significant reduction (P < 0.05) in serum TXB2 at 12 and 24 h (>90%) post-dosing and persistent inhibition of AA-induced platelet aggregation. ISDA administration caused a more marked depression of post-clotting TXB2 levels than aspirin in this study, although its ability to inhibit platelet aggregation was less consistent than that of aspirin. The nitroaspirin ISMNA was least effective at inhibiting platelet aggregation response or TXB2 production. The ISMN AUC(0-24 h) for the ISMNA-treated dogs was 77% of that for the physical mix-treated dogs and the tmax was delayed. This study indicates that the two aspirin esters cause aspirin-like effects on platelet function, probably through aspirin release, when administered orally to dogs.

Treatment of aphthous stomatitis with saturated potassium nitrate/dimethyl isosorbide.

Concentrated potassium nitrate has been used to lessen the pain caused by aphthous stomatitis. The problem with this approach is that it can have difficulty penetrating into the deeper layers of mucosae or skin, and for this reason, its beneficial affects are not routinely predictable. When dimethyl isosorbide is added to potassium nitrate in an aqueous hydroxyethyl cellulose gel, it enhances the capacity of potassium nitrate to more completely permeate these tissues and predictably promote rapid pain control and aphthae healing.

Potentiating potassium nitrate's desensitization with dimethyl isosorbide.

Desensitization of hypersensitive teeth by the combination of dimethyl isosorbide (DMI) and potassium nitrate (KNO3) is more effective than when KNO3 is used alone. KNO3/DMI work together to desensitize hypersensitive teeth at a higher, quicker, and more profound and lasting level.

Preparation of polymeric particles in CO(2) medium using non-toxic solvents: formulation and comparisons with a phase separation method.

The aim of this work was to elaborate formulation strategies to encapsulate a protein into biodegradable polymeric particles for sustained release purpose. In this paper, two encapsulation methods will be presented, one dealing with a phase separation phenomenon while the other involving an emulsification/extraction process in CO(2) medium. In those methods, only non-volatile injectable solvents such as glycofurol or isosorbide dimethyl ether were used to dissolve the polymer. Moreover, experimental designs were built up to help us to go further in the understanding of the processes and to better predict output responses in design space. Spherical particles were successfully generated with a satisfactory encapsulation yield. Further characterization steps such as in vitro, in vivo releases will be carried out to validate the interest of our encapsulation methods in the development of drug delivery systems.

Rheological characterization and permeation behavior of poloxamer 407-based systems containing 5-aminolevulinic acid for potential application in photodynamic therapy.

Topical application of 5-aminolevulinic acid (ALA) in photodynamic therapy is of great interest because of avoiding systemic side effects with such an easy way of application. However, due to ALA's high polarity its dermal bioavailability is rather limited and thus, permeation enhancement of this active is of major interest in research. In a previous study, a semisolid poloxamer 407-based (POX), five-component system ("thermogel") was developed for permeation enhancement of ALA across isolated human stratum corneum. In the present study, five-component systems of systematically varied compositions were investigated both rheologically and in terms of permeation enhancement. The five-component systems contained water, a fixed combination of 1:1 of isopropyl alcohol (IPA) and dimethyl isosorbide (DMIS) and a fixed ratio of 4:1 of POX to propylene glycol dicaprylocaprate (MIG). Rheological characterization showed that complex viscosity depended on IPA/DMIS and POX/MIG content. The gelation temperature (GT) was strongly influenced by interactions between MIG, IPA and DMIS. Regarding permeation behavior, several systems showing better permeation fluxes than the original "thermogel" were identified. Surprisingly, permeation flux did not inversely correlate with the complex viscosity, showing that permeation behavior may depend on a variety of further physicochemical characteristics including individual composition and microstructure of the respective formulation.

Formulation optimization, skin irritation, and efficacy characterization of a novel skin-lightening agent.

BACKGROUND: Skin-lightening preparations are used by people all over the world for a diverse range of dermatologic indications. The gold standard treatment for skin lightening is with hydroquinone but has been controversial because of the presence of several side effects. Therefore, there has been a constant search for developing new treatment alternatives. Furthermore, the new amendments and bans on animal testing by ECVAM have made the three-dimensional models like EpiDerm(™) and MelanoDerm(™) increasingly popular. OBJECTIVE: This work aims at the formulation development for a new skin-lightening agent, SMA-012, followed by testing for skin irritation and efficacy. METHODS: Formulation parameters such as concentration of SMA-012, amount of ethanol, effect of permeation enhancers and pH were first optimized using Franz cell experiments. Tape stripping and underlying skin assays were performed to analyze the amounts of SMA-012 in different layers of skin. The irritation potential and efficacy of the screened formulation were evaluated using Epiderm(™) and Melanoderm(™) models. RESULTS: Skin permeation experiments suggested that concentrations of 0.1% SMA-012, 35% ethanol, and pH of 8.5 to be the best formulation characteristics. This particular formulation was found to be nonirritant for short-term exposure, when tested in Epiderm(™) model and also significantly effective in decreasing the amount of melanin in pigmented skin equivalent models. CONCLUSION: SMA-012 shows a good promise as a skin-lightening agent for cosmetic and therapeutic applications. Additionally, our study demonstrates the application of skin equivalent models as alternatives to animal testing in studying the regulation of skin pigmentation.

Differential inhibition of tumour cell-induced platelet aggregation by the nicotinate aspirin prodrug (ST0702) and aspirin.

BACKGROUND AND PURPOSE: Tumour cell-induced platelet aggregation (TCIPA) facilitates cancer cell invasion, angiogenesis and the formation of metastatic foci. TCIPA can be modulated by pharmacological inhibitors of MMP-2 and ADP; however, the COX inhibitor aspirin did not prevent TCIPA. In this study, we have tested the pharmacological effects of a new group of isosorbide-based aspirin prodrugs on TCIPA. EXPERIMENTAL APPROACH: TCIPA was induced in human platelets by mixing with human adenocarcinoma or fibrosarcoma cells under no flow and flow conditions. The release of gelatinases and P-selectin expression during TCIPA were studied by zymography and flow cytometry respectively. KEY RESULTS: Tumour cells caused platelet aggregation. This aggregation resulted in the release of MMP-2 and a significant up-regulation of P-selectin on platelets, indicative of platelet activation. Pharmacological modulation of TCIPA revealed that ST0702, one of the aspirin prodrugs, down-regulated TCIPA while aspirin was ineffective. The deacetylated metabolite of ST0702, 5-nicotinate salicylate (ST0702 salicylate), down-regulated both ADP-stimulated platelet aggregation and TCIPA. CONCLUSIONS AND IMPLICATIONS: Our results show that ST0702 was an effective inhibitor of TCIPA in vitro. Its deacetylated metabolite may contribute to the effects of ST0702 by inhibiting ADP-mediated TCIPA.