Sulfate Formulation Research Articles

Effect of oxidation state and chelating agent on iron bio-accessibility from different commercial iron-supplements

Oral iron-supplementation represents the most common treatment for iron deficiency, a widely diffused mineral insufficiency. Seven commercial products containing different chelating agents (i.e. lipidic Fe (III)-pyrophosphate, Fe (III)-pyrophosphate, lipidic Fe (II)-sulphate, Fe (III)-saccharate and Fe (III)-EDTA) were analyzed. Infrared and thermal analyses highlighted that ferrous ions complexes were able to strictly interact with ascorbic acid thus forming stable soluble systems. Dynamic light scattering (DLS) analysis pointed out that lipidic Fe (II)-sulphate formulation showed the largest particle size (i.e. 184 nm against 120 nm found for lipidic Fe (III)-pyrophosphate based formulations) but showed the lowest PDI (0.25 against 0.30) that was not subjected to change after 7 days. Moreover, lipidic Fe (II)-sulphate formulation guaranteed a better bioavailability of iron using Caco-2 Cell model, permitting the absorption of more than 40% of administered iron against 20–30% found for formulations containing Fe (III) ions.

Electrodeposition of Zn-Cr Alloys: A Comparison with Pure Zinc

The electrodeposition of zinc coatings is one of the most common surface treatments for providing corrosion resistance to metallic components. From the thermodynamic point of view, zinc is located in a sweet spot, with its reduction potential being lower than most other common metals, while at the same time being not too susceptible to atmospheric corrosion; overall these features make zinc the ideal candidate for the electroplating of sacrificial coatings for corrosion protection. Owing it to its low cost and scalability, zinc electroplating has cemented itself as a cornerstone process in a variety of industrial sectors in the last decades. [1]While zinc coatings corrosion resistance has proved to be satisfactory in most cases, it could still be improved to operate even in more aggressive environments. For this purpose, electrodeposition of zinc alloys with transition metals from the iron group (Ni, Co, Fe) has proven to be a successful method to enhance zinc coatings corrosion resistance. In particular, zinc-nickel alloys have found the greater success among them, due to improved corrosion resistance and mechanical properties. [2]Zinc-chromium alloys also present a good opportunity to improve coatings performance, thanks to the passivating effect of Cr. In fact, electrodeposited ZnCr alloys with a Cr content up to 10.4% were found to exhibit a corrosion potential shifted by up 150 mV in the anodic direction with respect to the pure zinc counterpart. [3] This shift led to a significant decrease in the coating dissolution rate but was sufficiently small that the layers could still preserve their sacrificial nature towards the underlying steel.In this work, ZnCr coatings are deposited on low carbon steel from an acidic sulfate formulation containing Cr(III) ions at various concentrations. The properties of ZnCr coatings are explored by varying the most common parameters such as current density, composition, and pH. Furthermore, the resulting coatings are characterized through conventional surface analysis techniques such as SEM, EDS, XRD and XRF. Finally, the corrosion resistance performance of the ZnCr coatings is compared to pure Zn coatings to highlight the benefits of the alloy.Bibliography[1] R. Winand, “Electrodeposition of Zinc and Zinc Alloys,” Mod. Electroplat. Fifth Ed., pp. 285–307, Feb. 2011.[2] N. Lotfi, M. Aliofkhazraei, H. Rahmani, and G. B. Darband, “Zinc–Nickel Alloy Electrodeposition: Characterization, Properties, Multilayers and Composites,” Prot. Met. Phys. Chem. Surfaces, vol. 54, no. 6, pp. 1102–1140, Nov. 2018.[3] V. Chakarova, T. Boiadjieva-Scherzer, D. Kovacheva, H. Kronberger, and M. Monev, “Corrosion behaviour of electrodeposited Zn-Cr alloy coatings,” Corros. Sci., vol. 140, pp. 73–78, Aug. 2018.

Advancements in salbutamol sulphate formulation: Spray-drying technique for the production of porous particles with enhanced properties for inhalation drug delivery

A fast, simple and cost-effective technique has been used to produce spray-drying porous particles of salbutamol sulfate (SS) for inhalation drug delivery. The particles were produced using water as solvent and ammonium bicarbonate as pore-forming agent. A full factorial experimental design (24) with a central point was used to evaluate the influence of process parameters (drying air inlet temperature, atomization air volume flowrate, feed volume flowrate and the pore-forming agent concentration) on process yield, moisture content, densities and particle size. In addition, particle morphology, in-vitro aerosolization properties, stability and cytotoxicity of selected samples were studied. Within the experimental design parameters window, it was shown that the highest inlet temperature and pore-forming agent concentration were the factors that more affected the process yield and tap density values. Particles with the lowest tap densities values exhibited porous morphology. In addition, the pore-forming agent concentration proved to be the most significant variable affecting particle size. The highest pore-forming agent concentration, the largest particle size. The porous particles exhibit remarkable aerosolization performance, surpassing the performance of previously reported SS porous particles and a commercial formulation. These powders showed a high process yield and the absence of ammonium bicarbonate in the final product, as confirmed by FT-IR. Furthermore, the powders presented good stability even over long periods of time and did not exhibit cytotoxicity on the murine alveolar macrophage cell line RAW 264.7.

Biofortification of Kidney Bean (Phaseolus vulgaris L.) Crops Applying Zinc Sulfate and Ferric Sulfate: Pilot Crop in Colombia.

Agriculture is one of the economic activities with the most potential in Colombia, given its climatic and geographical conditions. Bean cultivation is classified as climbing, which grows in a branched way, and bushy, whose growth occurs up to 70 cm. The objective of this research was to study zinc and iron sulfates in different concentrations as fertilizers capable of increasing the nutritional value of kidney beans (Phaseolus vulgaris L.), whose strategy is known as biofortification, and thus determine the most effective sulfate. The methodology details the sulfate formulations, their preparation, the application of additives, sampling and quantification methods of total iron, total zinc, °Brix, carotenoids, chlorophylls a, b, and antioxidant capacity using the DPPH (2,2-diphenyl-1-picrylhydrazyl) method in leaves and pods. As for the results, it was found that biofortification with iron sulfate and zinc sulfate is a strategy that favors the country's economy and human health, because it allows the increase of minerals, antioxidant capacity and total soluble solids.

Pharmacokinetics of a Modified-Release Dexamphetamine Sulfate Formulation Following Single and Multiple Dosing in Healthy Adults: Comparative Bioavailability with Immediate-Release Dexamphetamine Sulfate, between Strengths, Assessment of Food and Meal Composition Effects.

A modified-release dexamphetamine sulfate formulation (DEX-MR) is under development for the treatment of attention-deficit/hyperactivity disorder. We investigated the bioequivalence of once-daily DEX-MR to twice-daily immediate-release dexamphetamine sulfate (DEX-IR) after single and multiple dosing and between strengths, and effects of food and meal types. Three randomized, open-label, crossover studies in healthy males were conducted. In the single-dose study, participants received DEX-MR 20 mg, DEX-MR 10 mg (20 mg dose), and twice-daily DEX-IR 10 mg under fasted conditions and after a high-fat, high-calorie breakfast. In the breakfast study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg after a normocaloric and a high-fat, high-calorie breakfast. In the multiple-dose study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg for seven days each. In the run-in period (five days), participants consumed a normocaloric breakfast; on profile days, participants consumed a normocaloric breakfast (day 6) or a high-fat, high-calorie breakfast (day 7). Once-daily DEX-MR at a dose of 20 mg was bioequivalent to twice-daily DEX-IR 10 mg after single dosing under fasted and fed conditions and after multiple dosing under fed conditions. DEX-MR 10 mg and DEX-MR 20 mg were bioequivalent when administered as a single 20 mg dose. Food slightly reduced the rate and extent of absorption of DEX-MR and delayed the time to peak plasma concentration (tmax) by approximately two hours compared to the fasted state. Bioavailability of DEX-MR was comparable under different meal conditions (normocaloric vs. high-fat, high-calorie breakfast) both after single and multiple dosing. Bioequivalence of once-daily DEX-MR and twice-daily DEX-IR was established. 1×2 DEX-MR 10 mg was bioequivalent to 1×1 DEX-MR 20 mg. DEX-MR should be administered with/after a meal to achieve the targeted pharmacokinetic profile (delayed tmax). Bioavailability of DEX-MR is not affected by meal composition (i.e., fat and caloric content).

Real-time monitoring of polymyxin B-sodium deoxycholate sulfate binding with immobilized human serum albumin by surface plasmon resonance

Polymyxin B (PMB) has a high protein binding capacity with human serum albumin (HSA), which is the dominant plasma protein. This study aims to evaluate the kinetic parameters to understand the binding of PMB and PMB-based sodium deoxycholate sulfate (SDCS) formulations with HSA by surface plasmon resonance. The kinetics of PMB presented the best fit with a two-state reaction model, wherein the conformational change occurred after binding. PMB interacted with HSA in a temperature and formulation-dependent manner. PMB-SDCS formulations provided lower HSA binding than PMB in all experiments. Circular dichroism spectra confirmed the secondary structure of HSA changes in a decreased α-helical content in PMB formulations. UV–visible spectra revealed the microenvironment of tryptophan-214 changes after incubation with PMB formulations. Also, three-dimensional fluorescence demonstrated that the maximum intensity of tryptophan-214 decreased and shifted. The vibrational frequency of Fourier-transform infrared spectroscopy confirmed the conformational changes in the secondary structure of HSA. Therefore, PMB formulated with SDCS affected the PMB binding to HSA. A lower protein binding with HSA from PMB-SDCS formulations was a result of shielding the positive charge of PMB by SDCS therefore higher unbound PMB is available at the target sites. From this work, the modification PMB binding with HSA would help in PMB formulation design and perhaps dose adjustment of PMB for suitable drug availability in clinical setting.

Abstract 11900: Quinidine as Salvage Therapy in Recurrent Monomorphic Ventricular Tachycardia

Introduction: Quinidine is an effective therapy for a subset of polymorphic ventricular tachycardias and ventricular fibrillation (VF), however the efficacy of quinidine on scar related monomorphic ventricular tachycardia (MMVT) is unclear. Hypothesis: We sought to assess the efficacy and adverse effects of quinidine in scar related MMVT. Methods: All patients with MMVT treated with quinidine from 2009-2020 at a single VT referral center were reviewed. Results: A total of 22 patients with MMVT and structural heart disease (age 66.7 ± 10.9, 20 males, 15 with ischemic cardiomyopathy, mean LVEF 22.2 ± 12.3%, 9 with left ventricular assist device (LVAD)) were treated with quinidine (14 patients on Gluconate formulation average dose 996mg±321, 8 patients on Sulfate formulation with average dose 1062mg±588). Quinidine was used in combination with other antiarrhythmics (AAD) in 18 (13 also on amiodarone). All patients previously failed >1 AAD (Amiodarone 100%, mexiletine 73%, sotalol 32%, other 32%) and 8 had prior ablations (median of 1.5). Quinidine was initiated in the setting of VT storm despite other AADs (6), inability to tolerate other AADs (4), or recurrent VT despite prior therapies (12). Ventricular arrhythmias requiring ICD or external shock occurred despite quinidine in 13 (59%) patients at a median of 26 (4-240) days after quinidine initiation. In patients with recurrent MMVT, VT cycle length increased from 359ms to 434ms (p=0.02). Treatment with quinidine was associated with an increase in QTc from 527ms (413-619) to 554ms (425-725) (p=0.004). Only 6 patients remained on quinidine at 1 year with recurrence of ventricular arrhythmias in all. Of the 6 patients on long term quinidine therapy, 3 patients had no shocks but did receive successful ATP within the first year. The following adverse effects were seen: GI side effects (6), QT prolongation (2), rash (1), thrombocytopenia (1), neurologic side effects (1). One patient discontinued due to cost. Conclusions: Quinidine therapy has limited tolerability and efficacy when used in the management of amiodarone-refractory scar related MMVT. When possible, more effective therapies should be offered in patients with VT refractory to standard pharmacologic therapies.

Effects of varying sources of Cu, Zn, and Mn on mineral status and preferential intake of salt-based supplements by beef cows and calves and rainfall-induced metal loss.

Three studies were completed to evaluate the effects of Cu, Zn, and Mn source on preferential intake, trace mineral status, and rainfall-induced metal loss of salt-based mineral supplements. Mineral supplements were formulated to contain 2,500, 5,500, and 4,000 mg/kg of Cu, Zn, and Mn, respectively. Supplements differed only by source of Cu, Zn, and Mn, which were hydroxychloride, organic, or sulfate sources. In Exp. 1, the three formulations were offered simultaneously for 18 wk to preweaned beef calves (four pastures; 17 calves per pasture) within separate containers inside covered cow-exclusion areas. Consumption averaged 21 ± 2.4 g/calf daily (sum of all three sources), with a greater (P < 0.001) percentage of the total intake coming from the hydroxychloride vs. organic or sulfate sources of Cu, Zn, and Mn. In Exp. 2, the same sulfate and hydroxychloride formulations were randomly assigned to pastures (n = 4 pastures per treatment) containing 18 to 20 cow–calf pairs/pasture. Treatments were offered for 20 wk within covered areas designed to assess cow and calf intake separately. At weaning, liver biopsies were collected from four cow–calf pairs/pasture (n = 16 cows and calves per treatment). Source of Cu, Zn, and Mn had no effect on voluntary mineral intake among calves (P = 0.44) and cows (P = 0.14). Calves consuming mineral containing hydroxychloride sources of Cu, Zn, and Mn tended (P = 0.06) to have greater average daily gain over the 20-wk period compared with calves consuming sulfate sources of the same elements (1.09 vs. 1.06 kg/d; SEM = 0.013). Mineral status of cows and calves was not affected (P ≥ 0.17) by source of Cu, Zn, and Mn. In Exp. 3, each of the mineral formulations from Exp. 1 was exposed to a 10.2-cm precipitation event delivered in three equal 3.4-cm applications within a week. To accomplish this, 750 g of mineral was placed into Buchner funnels (177 cm2) on 20- to 25-µm pore filter paper. Deionized water (pH adjusted to 5.6) was poured over the mineral. Total leaching losses of Cu, Zn, and Mn were less (P < 0.001) for formulations containing hydroxychloride vs. organic and sulfate sources. These results imply that, when offered a choice, calves preferentially consume mineral supplements formulated with hydroxychloride vs. sulfate or organic sources of Cu, Zn, and Mn. In addition, hydroxychloride sources of Cu, Zn, and Mn are less susceptible to rainfall-induced leaching losses compared with sulfate and organic sources.

Pyrite-Scale Removal Using Glutamic Diacetic Acid: A Theoretical and Experimental Investigation

SummaryIron sulfide scale causes major losses in both upstream and downstream sectors of the hydrocarbon industry. Pyrite is one of the most-difficult forms of iron sulfide scale from a removal point of view. Inorganic acids such as hydrochloric acid (HCl) are not recommended for removing pyrite scales because they have many drawbacks, including low pyrite solubility, high corrosivity to the tubular system, and generation of toxic hydrogen sulfide (H2S). In this work, pyrite-scale dissolution is studied using an ecofriendly formulation of glutamic diacetic acid [L-glutamic acid, N, N-diacetic acid (GLDA)] as an alternative to HCl. Although GLDA has shown potential for removing iron sulfide in general and pyrite scale in particular, still GLDA/pyrite kinetics have not been well-understood. Both experimental and theoretical techniques have been used. The reaction kinetics has been investigated in a rotating-disk apparatus (RDA) at typical reservoir conditions of 150°C and 1,000 psi (Conway et al. 1999). Characterization techniques, including X-ray photoelectron spectroscopy (XPS) and scanning electron microscope (SEM), have been used to study the surface chemistry before and after treatment with GLDA, and the results support pyrite removal. Furthermore, density-functional-theory (DFT) calculations have been performed to understand the ability of GLDA to dissolve iron sulfide scale at the atomistic level. From the laboratory results, the reaction rate using 20-wt% GLDA (pH of 3.8) was 5.378×10−8 mol/cm2·s. The measured rate outperformed other proposed formulations according to the tetrakis(hydroxymethyl)phosphonium sulfate (THPS) formulation by 15 times. In addition, GLDA surpassed the most recent results on diethylenetriamine penta-acetic acid (DTPA) by nearly an order of magnitude. Moreover, pyrite dissolution in GLDA increases as the disk rotational speed increased, which indicates mass-transfer control with a diffusion coefficient of 1.338×10−7 cm2/s. Furthermore, from molecular modeling using DFT, the binding energy between GLDA and Fe2+ is calculated as –105.97 kcal/mol. The negative value observed correlates with the stability constant and indicates the strong binding affinity to Fe2+. Finally, GLDA could be recommended for pyrite-scale removal because it is biodegradable, less corrosive, free of H2S, and achieved solubility that outperformed THPS- and DTPA-basedformulations.

Development of collagen-poly(caprolactone)-based core-shell scaffolds supplemented with proteoglycans and glycosaminoglycans for ligament repair

Core-shell scaffolds offer a promising regenerative solution to debilitating injuries to anterior cruciate ligament (ACL) thanks to a unique biphasic structure. Nevertheless, current core-shell designs are impaired by an imbalance between permeability, biochemical and mechanical cues. This study aimed to address this issue by creating a porous core-shell construct which favors cell infiltration and matrix production, while providing mechanical stability at the site of injury. The developed core-shell scaffold combines an outer shell of electrospun poly(caprolactone) fibers with a freeze-dried core of type I collagen doped with proteoglycans (biglycan, decorin) or glycosaminoglycans (chondroitin sulphate, dermatan sulphate). The aligned fibrous shell achieved an elastic modulus akin of the human ACL, while the porous collagen core is permeable to human mesenchymal stem cell (hMSC). Doping of the core with the aforementioned biomolecules led to structural and mechanical changes in the pore network. Assessment of cellular metabolic activity and scaffold contraction shows that hMSCs actively remodel the matrix at different degrees, depending on the core's doping formulation. Additionally, immunohistochemical staining and mRNA transcript levels show that the collagen-chondroitin sulphate formulation has the highest matrix production activity, while the collagen-decorin formulation featured a matrix production profile more characteristic of the undamaged tissue. Together, this demonstrates that scaffold doping with target biomolecules leads to distinct levels of cell-mediated matrix remodeling. Overall, this work resulted in the development of a versatile and robust platform with a combination of mechanical and biochemical features that have a significant potential in promoting the repair process of ACL tissue.

Investigation of covers and chemical treatment for the suppression of cyanobacteria in water treatment systems

AbstractAlgal growth in water treatment plants can lead to the introduction of toxin and odour compounds from cyanobacteria and causes filter fouling. Here, we investigate the use of woven polypropylene covers and a proprietary copper sulfate formulation (EarthTec) to prevent algal growth within mesocosms designed to simulate settling basins. Chlorophyll a, soluble nutrients, weather patterns and cyanobacterial gene abundance were measured. The covers suppressed algal and cyanobacterial growth in mesocosms, likely due to a combination of light blockage and prevention of insects from entering the mesocosms. In contrast, mesocosms amended with EarthTec exhibited little difference from the control mesocosms in terms of algal growth. qPCR analysis revealed that only a small fraction of cyanobacteria in the system contained genes necessary for the production of the microcystin toxin. Despite differences between mesocosms and full‐scale settling basins, the data here suggest that woven covers can suppress algal growth while minimising evaporative water losses.

Sugar Surfactant‐Based Shampoos

AbstractNaturally derived surfactants in hair care products are a trend in cosmetic technology. This study aimed to formulate and fully characterize the performance of shampoos with sugar‐derived surfactants, namely, the alkyl polyglucosides decyl glucoside and coco‐glucoside. In addition, different thickeners and conditioning ingredients were added to improve the formulation properties. A sodium laureth sulfate (SLES) formulation was used as control. Rheology, pH, foaming, contact angles on a keratin surface, and surface tensions were determined. The safety of the formulations was evaluated by in vitro cytotoxicity studies using the human keratinocyte HaCaT cell line and human retinal pigment epithelial cells ARPE‐19. The efficacies were studied by in vitro hair combing force assays and in vivo sensorial analysis. The formulated sugar surfactant‐based shampoos showed the following properties: (i) pH values higher than those of SLES (which were posteriorly lowered with lactic acid); (ii) higher foamability than SLES, and high wettability; (iii) Newtonian behavior and predominance of liquid state with a suitable viscosity; (iv) low cytotoxicity in both human keratinocytes and retinal cell lines (in contrast to SLES); (v) easier hair combing than SLES, when Polyquaternium‐7 was used as conditioner; (vi) efficient and gentle hair washing; and (vii) favorable sensorial analysis confirming the previous washing properties. In conclusion, the sugar surfactants had a considerable impact in the properties of the shampoo formulations, in terms of both hair cleansing properties and efficacy, as demonstrated here. These favorable outcomes clearly support the use of these ingredients in shampoo formulation design.

Pharmacokinetics of AR19, an Immediate-Release Amphetamine Sulfate Formulation Designed to Deter Manipulation for Administration Via Nonoral Routes: Bioequivalence to Reference Racemic Amphetamine Sulfate, Dose Proportionality, and Food Effect

Objectives: We evaluated the pharmacokinetics (PK) of an investigational immediate-release amphetamine (AMP) sulfate formulation (AR19) designed to deter nonoral administration versus reference racemic amphetamine sulfate (RA-AMPH). We investigated AMP bioavailability from AR19, the effect of taking AR19 with food or sprinkling the capsules on food, and dose proportionality. Methods: Participants received AR19 (20 mg) or reference RA-AMPH (20 mg) (bioequivalence study) or AR19 5 or 30 mg (dose comparison study). Food effect study participants received AR19 (20 mg) as intact capsule while fasted or after high-fat/-calorie meal, or as pellets sprinkled on applesauce or yogurt (≥6-day washout). Blood samples were analyzed for dextroamphetamine (d-AMP) and levoamphetamine (l-AMP) PK: Cmax, AUClast, AUCinf, λz, T½, and Tmax. Safety was assessed. Results: Bioequivalence, dose comparison, and food effect studies included 36, 24, and 36 participants. The 90% confidence intervals (CIs) of Cmax, AUClast, and AUCinf for AR19 20 mg versus reference RA-AMPH or AR19 with intact capsule and meal or sprinkled AR19 pellets on food versus fasted were between 80% and 125%. Dose-normalized Cmax/D, AUClast/D, and AUCinf/D for AR19 5 versus 30 mg had CIs within 80%-125%. Mean ± standard deviation (SD) Tmax was comparable for AMP (d-AMP; l-AMP) following AR19 20 mg (2.84 ± 1.05; 3.05 ± 1.22) versus reference RA-AMPH (2.52 ± 0.75; 2.75 ± 1.00), and AR19 5 mg (2.48 ± 0.57; 2.65 ± 0.65) versus AR19 30 mg (2.55 ± 0.56; 2.72 ± 0.65). Mean ± SD Tmax for AMP (d-AMP; l-AMP) was higher with intact capsule and meal (5.59 ± 1.57; 5.59 ± 1.59) versus fasted (2.85 ± 0.76; 2.97 ± 0.79). No serious adverse events were reported. Conclusion: AR19 was bioequivalent to reference RA-AMPH. Bioavailability was similar at doses between 5 and 30 mg and was not impacted by meal consumption or sprinkling on food. AR19 at tested doses was well tolerated.

硫酸バリウム製剤に入れ歯安定剤が及ぼす粘度変化と その対策における定量的・視覚的評価

硫酸バリウム製剤に入れ歯安定剤が及ぼす粘度変化と その対策における定量的・視覚的評価

Identification and structural characterization of four novel degradation products and a process impurity of isavuconazonium sulfate for injection formulation bulk by LC-ESI-QTOF-MS/MS.

Isavuconazonium sulfate is a highly water-soluble pro-drug of active triazole isavuconazole. The degradation profile of isavuconazonium sulfate for injection formulation bulk under acid hydrolysis, alkaline hydrolysis, oxidation, heat, and light conditions was studied using LC-PDA/MS technique. Four degradation products (DP1 to DP4) and one process impurity (PI1) were identified in isavuconazonium sulfate formulation bulk and characterized the identified impurities by liquid chromatography-electron spray ionization-quadruple-time of flight tandem mass spectrometry. Isavuconazole (DP1) was found to be one of the major degradation products of isavuconazonium sulfate.

Cold isostatic pressing of hydrating calcium sulfate as a means to produce parenteral slow-release drug formulations

In the present study, cold isostatic pressing of hydrating biocompatible inorganic materials was used to encapsulate active substance in a highly dense microstructure of bioresorable/biodegradable material. This forms the basis in the NanoZolid® technology. It was shown that such microstructures can be used to produce slow-release parenteral formulations for long-term drug release.The described novel principle to produce slow-release depot powder formulations was explored to manufacture a water-solvable calcium sulfate formulation encapsulating the anti-androgen substance 2-hydroxyflutamide (2-HOF) in a microstructurally designed calcium sulfate matrix. The microstructure of the solidified depot consisted of a composite of porous and dense material providing a combination of faster and slower release features. By mixing the drug loaded powder, consisting of densified and non-densified granular components, with an aqueous sodium carboxymethyl cellulose solution, an injectable suspension was formulated, which is injectable and which solidifies in vivo as a result of the ability of calcium sulfate to solidify by hydration.The NanoZolid powder was characterised regarding pharmaceutical process parameters and the microstructure of the solidified formulation was evaluated with scanning electron microscopy and elemental mapping. The in vitro drug release was evaluated with a specially designed dissolution method with convection only at sampling occasions.

Effects of Adjuvants on HIV-1 Envelope Glycoprotein SOSIP Trimers In Vitro.

ABSTRACTNative-like, soluble, recombinant SOSIP trimers of various designs and based on several env genes of human immunodeficiency virus type 1 (HIV-1) are being tested as immunogens in different animal models. These experiments almost always involve coformulating the trimers with an adjuvant to boost the magnitude of the immune responses. One factor relevant to the choice of an adjuvant is that it should not physically damage the immunogen or impede its ability to present relevant epitopes. As examples, an adjuvant formulation that includes harsh detergents could disrupt the structural integrity of a trimer, and any charged compounds in the formulation could bind to countercharged regions of the trimer and physically occlude nearby epitopes. While a few adjuvants have been tested for their potential effects on SOSIP trimers in vitro, there has been no systematic study. Here, we have assessed how nine different adjuvants of various compositions affect SOSIP trimers of the BG505 and B41 genotypes. We used negative-stain electron microscopy, thermal denaturation, and gel electrophoresis to evaluate effects on trimer integrity and immunoassays to measure effects on the presentation of various epitopes. We conclude that most of the tested adjuvants are benign from these perspectives, but some raise grounds for concern. An acidified alum formulation is highly disruptive to trimer integrity, and a DNA-based polyanionic CpG oligodeoxynucleotide adjuvant binds to trimers and occludes the trimer apex epitope for the PGT145 neutralizing antibody. The methods described here should be generalizable to protein subunit vaccines targeting various pathogens.IMPORTANCE Adjuvant formulations increase the magnitude of immune responses to vaccine antigens. They are critically important for formulation of HIV-1 envelope glycoprotein (Env) vaccines intended to induce antibody production, as Env proteins are otherwise only very weakly immunogenic. The HIV-1 vaccine field now uses the well-defined structures of trimeric Env glycoproteins, like SOSIPs, to present multiple known epitopes for broad and potent neutralizing human antibodies in a native-like conformation. Successful adjuvant formulations must not disrupt how the trimers are folded, as that could adversely affect their performance as immunogens. We studied whether the various adjuvants most commonly used in animal experiments affect the integrity of two different SOSIP trimers in vitro. Most adjuvant classes are not problematic, but an aluminum sulfate formulation is highly damaging, as it exposes trimers to acidic pH and a nucleic acid-based adjuvant can bind to the trimer and block access to a key neutralizing epitope.

Influence of Absorbable Calcium Sulfate-Based Bone Substitute Materials on Human Haemostasis-In Vitro Biological Behavior of Antibiotic Loaded Implants.

Calcium sulfate (CS) formulations are frequently implanted as antibiotically impregnated bone substitutes in orthopedic and trauma surgery to prevent or treat bone infections. Calcium ions have been discussed as candidates to accelerate blood coagulation. The goal of this study is to evaluate substance-specific influences of CS formulations on blood coagulation. Specific ELISAs were conducted to determine markers of activated blood coagulation after incubation of human blood with CS beads. Additionally, wettability with freshly drawn human blood was measured. Three different types of CS bone substitute beads were compared (CS dihydrate with tripalmitin, containing Gentamicin (Herafill®-G: Group A) or Vancomycin (CaSO4-V: Group B); and a CS hemihydrate with Tobramycin (Osteoset®: Group C)). Examinations were performed by ELISA assays for F1+2, FXIIa and C3a. Our results prove that none of the CS preparations accelerated single specific assays for activated coagulation markers. This allows the conclusion that neither Herafill®-G (CaSO4-G) nor CaSO4-V alter haemostasis negatively. Blood samples incubated with Osteoset® display an elevated F1+2-activity. The addition of tripalmitin in Herafill®-G shifts the original into a significantly hydrophobic formulation. This was additionally proven by contact angle examination of the three substances with freshly drawn human blood, showing that acceleration of plasmatic coagulation is hindered by lipids and induced by surface effects caused by presence of rapidly soluble calcium ions in the Osteoset® preparation.

FORMULATION DEVELOPMENT AND EVALUATION OF GASTRO-RETENTIVE DOSAGE FORM OF ATAZANAVIR SULPHATE

Objective: To improve dissolution properties of atazanavir sulphate by preparing gastro-retentive granules by solid dispersion method and development of RP-HPLC method for estimation of this drug.Methods: Estimation of atazanavir sulphate was done using high performance liquid chromatography (HPLC) on inertsil column (5 µm, 250x4, 6 mm) with a mobile phase consists of methanol: water (91:9 v/v), at 0.5 ml/min flow rate and 249 nm UV detection. The method was validated as per ICH guidelines. Selection of the carrier for gastro-retentive formulation was based on phase solubility study of the drug. Solid dispersions of gastro-retentive granules of different composition of drug and carrier, were prepared by the kneading, heating and solvent evaporation. A 32factorial design was applied to optimize the gastro-retentive formulation. The amounts of polyethylene glycol 6000 (PEG 6000) (X1) and hydroxypropyl methyl cellulose (HPMC) (X2) were selected as independent variables and in vitro-release at 5, 9 h and total floating time was selected as dependent variables. Results: HPLC method was found to be linear in a concentration range of 10-60 μg/ml of the drug (r2= 0.999). The low value of % RSD in precision study indicates reproducibility of the method. The low value of LOD and LOQ suggests the sensitivity of the method. The solubility enhancement study of drug with various carriers followed descending order of solubility [Gelucire 44/14&gt;PEG 6000&gt;polyvinyl pyrrilidone (PVP)]. Highest % cumulative release was observed for the heating method at drug polymer (PEG 6000) ratio 1:5. Hence, this ratio has been selected for preparation of solid dispersion. From comparison of dissolution profile of formulated batches, formulation F4 [containing PEG6000 (1.6 g) and HPMC (200 mg)] showed promising dissolution parameters with desired floating properties.Conclusion: Results obtained by validation studies suggested that the developed HPLC method is simple, accurate, precise and can be used for routine analysis of atazanavir sulphate formulation. Results of evaluation of prepared batches indicate that batch F4 is a promising formulation for gastro-retentive dosage form of drug.

40P - Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel

Background: Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Its effectiveness in clinical practice is associated with a variety of acute and long term side effects. To reduce the systemic side effects, a local slow-release depot formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed. Methods: Two formulations with a twofold difference in docetaxel drug load (corresponding to 12.5 and 25.0 mg/kg body weight) were manufactured with the calcium sulfate based NanoZolid™ technology. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two local depot formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The slow-release depots were compared to systemic intraperitoneal injections of docetaxel (25.0 mg/kg) and a calcium sulfate placebo formulation. Tumor volumes were measured and systemic side effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations. In addition, a histological evaluation was performed. Results: Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral depot formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts. The extracellular deposits of calcium sulfate, observed in all groups with intra-tumoral injections, did not lead to significant inflammatory changes. Conclusions: It was shown that intra-tumoral slow-release depots of calcium sulfate with docetaxel were well tolerated and released docetaxel at amounts sufficient for satisfactory local antitumor effect and for a low level plasma detection. The use of such depots can be an alternative to intravenous injection as an efficient antitumoral treatment with reduced systemic toxicity. Legal entity responsible for the study: Uppsala University, Department of Immunology, Genetics and Pathology, Marie Jeansson Funding: This study was supported by an IGP Young Investigator grant (MJ), the Swedish Research Council (521-2012-865, MJ), Åke Wiberg Foundation (738866289, MJ), Magnus Bergvalls Foundation (24942-1-2013, 2014-00055, MJ), and Ture Stenholms Foundation for Surgical Research (MS) Disclosure: S. Grudén: Consultant for LIDDS AB. N. Axén: Consultant for LIDDS AB and have equity interests in LIDDS AB. All other authors have declared no conflicts of interest.