Stability Of Lipid Emulsions Research Articles

Antiemetic Drugs Compatibility Evaluation with Paediatric Parenteral Nutrition Admixtures.

Chemotherapy-induced nausea and vomiting are defined as the most common of side effects of treatment and, at the same time, are very difficult to accept for patients', frequently causing changes in the therapy regimen, significantly reducing its effectiveness. Thus, an antiemetic prophylactic is essential to the provision of such a therapy for the patient. Pharmacotherapy often includes various drugs, including antiemetics, with the administration of such drugs by injection through two separate catheters being the preferred method. However, the co-administration of drugs and parenteral nutrition admixtures (PNAs) requires the consideration of compatibility, stability and potential negative interactions. To meet the purposes of clinical pharmacy, a compatibility test of ondansetron, dexamethasone and hydrocortisone with paediatric PNAs was conducted. PNAs differ in the composition of amino acid source (Primene® or Aminoplasmal Paed® 10%) and the type of injectable lipid emulsion (Lipidem® 200 mg/mL, Clinoleic® 20%, SMOFlipid® 200 mg/mL, Intralipid® 20%). An in vitro evaluation was performed in a static way as a simulated co-administration through a Y-site. The drug PNA ratios were determined based on the extreme infusion rates contained in the characteristics of medicinal products. All calculations were performed for a hypothetical patient aged 7 years weighing 24 kg. As a result of this study, it can be concluded that all tested PNAs showed the required stability in the range of parameters such as pH, osmolality, turbidity, zeta potential, MDD and homogeneity. The co-administration of antiemetic drugs does not adversely affect lipid emulsion stability. This combination was consistently compatible during the evaluation period.

Replacing synthetic antioxidants in food emulsions with microparticles from green acerola (Malpighia emarginata)

Among natural extracts with antioxidant potential, acerola fruit is an important source of bioactive compounds. The goal of this work was to evaluate the antioxidant capacity of microencapsulated and lyophilized extracts of unripe acerola fruits produced under environmentally friendly conditions. In vitro antioxidant activity was determined, and products were applied in oil-in-water emulsions. Lipid oxidation products were measured by the absorptivity at 232 nm and hydroperoxide content. Sensory characteristics resulting from the addition of acerola microparticles to emulsions were also investigated. The aqueous extracts of acerola fruits showed a high concentration of ascorbic acid (32.52 to 41.11 mg.100 mg−1) and reducing power; the retention of ascorbic acid was 88% after spray drying. Oxidation inhibition was observed upon emulsion addition of acerola products: the hydroperoxide content after 9 days under accelerated conditions in the control samples was 14.03 mmol. L−1 and from 3.02 to 3.60 mmol. L−1 in samples with TBHQ or acerola microparticles (100-200 mg.kg−1). In addition, the microparticles did not show sensory effects compared to synthetic antioxidants. Acerola microparticles obtained after simple water extraction from green fruits were effective and are a potential new ingredient for the oxidative stability of lipid emulsions.

Stability of lipid emulsion in total parenteral nutrition: An overview of literature.

Total parenteral nutrition (TPN) is an extremely complex mixture. The multitude of chemical compounds involved can give rise to numerous reactions that condition its stability. We set out to review the existing literature on different issues related to stability, and which are still of concern in the hospital environment; such as the stability of the lipid emulsion. In addition, we analyse other related factors and parameters that allow us to predict the stability of TPN based on the composition. we searched PubMed and Google Scholar, over the date range 1995-2019 for relevant studies about TPN stability. We included experimental studies where the physical stability of the lipid emulsion in TPN had been analysed. We applied specific exclusion criteria. we included 20 papers in this review of TPN stability. The studies combined different analytical techniques to assess the stability. In all the studies, the mean droplet diameter (MDD) is measured and the stability analysis is completed with other measurements. Temperature and components concentration are also considered. studies on the stability of TPN used differing components with different chemical characteristics and their results can be difficult to extrapolate. There is no clear consensus about the composition of the mixtures and there is also great variety in the analytical techniques that were used to analyse stability. It is necessary to conduct new studies to update information on TPN stability.

Evaluation of physical stability of all in one parenteral admixtures for pediatric home care with high electrolytes concentrations.

The aim of the study was to evaluate stability of 48 total parenteral admixtures for pediatric patients who require home parenteral nutrition. Admixtures contain high amounts of electrolytes. In a clinical practice electrolytes-enrichment of the parenteral nutrition admixtures is a usual demand, especially on the neonatal/pediatric wards. The supplementation of parenteral nutrition with high concentration of electrolytes is a living problem due to decreased stability of lipid emulsions in nutrition admixtures caused by bivalent cations. Preliminary admixtures were prepared in two-chamber ethylene vinyl acetate bags: amino acids, glucose and electrolytes were combined in one chamber and 20% (w/w) lipid emulsions (SMOFlipid®, Intralipid ® or ClinOleic®) were placed separately in the second chamber. Organic salts of calcium and phosphates were used. Pre-admixtures were stored at +4ºC for up to 21 days after preparation. Each composition of admixtures was prepared twice, because contents of the two chambers were combined at t=0 or after 21 days of storage at +4ºC. Visual observations, globule size distribution (using optical microscopy, laser diffraction and photon correlation spectroscopy methods), pH analyses, zeta potential and surface tension were performed after combining all components together with vitamins. Among 48 of investigated admixtures only two were problematic and other may be stored for at least 21 days at 4°C and completed admixtures demonstrated stability for at least 24 h at room temperature. It was possible to obtain stable admixtures despite of the high concentration of electrolytes.

Prostaglandin E1-containing nanoparticles improve walking activity in an experimental rat model of intermittent claudication

Due to the low stability of lipid emulsions, a lipid emulsion of prostaglandin E1 (Lipo-PGE1 ) necessitates daily intravenous drip infusions. To overcome this issue, we developed nanoparticles containing PGE1 (Nano-PGE1 ). Nano-PGE1 showed a good sustained-release profile of PGE1 from the nanoparticles in vitro, which may permit a longer-lasting therapeutic effect to be achieved. We here examined the pharmacological activity of Nano-PGE1 in a rat experimental model of intermittent claudication induced by femoral artery ligation. The walking activity of the rat was tested on a rodent treadmill. Tissue levels of PGE1 were determined by enzyme immunoassay, and skeletal muscle angiogenesis (capillary growth) was monitored by immunohistochemical analysis. PGE1 could be detected in the lesion site one day after the intravenous administration of Nano-PGE1 but not of Lipo-PGE1 . An increased accumulation of Nano-PGE1 in the lesion site compared with control (unlesioned) site was also observed. The ligation procedure reduced the walking activity, which in turn was improved by a single administration of Nano-PGE1 but not of Lipo-PGE1 . The single administration of Nano-PGE1 also stimulated angiogenesis in the skeletal muscle around the ligated artery. The findings of this study suggest that Nano-PGE1 improves the walking activity of femoral artery-ligated rats through the accumulation and sustained release of PGE1 .

TCH-041 Stability of Total Parenteral Nutrition Admixtures For Paediatric Home Care in the Presence of High Concentrations of Electrolytes

BackgroundIn clinical practise electrolyte enrichment of the parenteral nutrition admixtures is a typical request, especially on the neonatal/paediatric wards. The supplementation of parenteral nutrition with high concentrations of electrolytes is...

GRP-138 Pharmaceutical Interventions in the Setting of Lipids in Paediatric Parenteral Nutrition

BackgroundThe preparation of paediatric parenteral nutrition (PPN) is subject to a great deal of variability in clinical practise. Standardization in the process is indispensable to ensure stability and improve patient...

Compatibility of Intravenous Medications With Parenteral Nutrition

Hospitalized patients requiring parenteral nutrition (PN) often need to receive intravenous (IV) medications as well. Y-site administration is occasionally necessary, but physicochemical incompatibilities can occur between the medications and PN. The aim of the present study was to assess the physical compatibility between 25 frequently coadministered IV medications and a commercially available ready-to-use total PN. PN (NuTRIflex Lipid Special; B. Braun Medical AG, Sempach, Switzerland) and medications were mixed in 1:1 (v/v) proportions, and the stability was assessed at the time of mixing and after 1 and 4 hours. The stability of lipid emulsion was observed by microscopic investigation, visual inspection, dynamic laser light scattering, and laser light obscuration. The binary admixtures of PN (without lipid emulsion) and medications were used to detect discoloration, visibly detectable precipitates, and subvisual particles. Two of 25 medications were incompatible with the lipid emulsion (serum albumin 20% and tropisetron), 2 showed signs of degradation (discoloration) over time (esomeprazole and pantoprazole), and 1 precipitated at high concentrations (5-fluorouracil). The other 20 medications were considered compatible when administered by Y-site. The present study validated the compatibility of 1 commercially available PN and 20 medications. These results offer new solutions to support the implementation of complex therapeutic schemes in practice, when coadministration via Y-site cannot be avoided.

Long-term physico-chemical stability of standard parenteral nutritions for neonates

Two ready-to-use parenteral nutritions (PN) have been developed, for the first days of life of the premature newborn, along with syringes of lipid emulsion with or without vitamins. Long-term physico-chemical stability for storage in wards was assessed. Physico-chemical stability of PN: visual inspection, particle size, pH, osmolarity measurement, amino acids, glucose, and electrolytes dosages. Physico-chemical stability of lipid emulsion: visual inspection, globule size, peroxide level and vitamins A, E, and C dosages. Stability was studied for 12 weeks on refrigerated (2-8 °C) and room temperature (30 ± 2 °C) samples. No precipitation was detected in any PN. A brown coloration was observed in PN stored for four weeks at room temperature but not in the refrigerator. Concentrations of all the nutrients remained constant over the 12 week-study period. Phase separation of the lipid emulsion occurred after three weeks, but particle size complied with the USP limits for 12 weeks. Peroxide content increased only in the samples without vitamins at room temperature. Vitamins remained stable for one week under refrigeration. The PN did not present a detectable change of the tested properties when refrigerated for 12 weeks. The lipid emulsion with vitamins is stable for one week when refrigerated.

Influence of the calcium concentration in the presence of organic phosphorus on the physicochemical compatibility and stability of all-in-one admixtures for neonatal use.

BackgroundPreterm infants need high amounts of calcium and phosphorus for bone mineralization, which is difficult to obtain with parenteral feeding due to the low solubility of these salts. The objective of this study was to evaluate the physicochemical compatibility of high concentrations of calcium associated with organic phosphate and its influence on the stability of AIO admixtures for neonatal use.MethodsThree TPN admixture formulas were prepared in multilayered bags. The calcium content of the admixtures was adjusted to 0, 46.5 or 93 mg/100 ml in the presence of a fixed organic phosphate concentration as well as lipids, amino acids, inorganic salts, glucose, vitamins and oligoelements at pH 5.5. Each admixture was stored at 4°C, 25°C or 37°C and evaluated over a period of 7 days. The physicochemical stability parameters evaluated were visual aspect, pH, sterility, osmolality, peroxide formation, precipitation, and the size of lipid globules.ResultsColor alterations occurred from the first day on, and reversible lipid film formation from the third day of study for the admixtures stored at 25°C and 37°C. According to the parameters evaluated, the admixtures were stable at 4°C; and none of them presented precipitated particles due to calcium/phosphate incompatibility or lipid globules larger than 5 μm, which is the main parameter currently used to evaluate lipid emulsion stability. The admixtures maintained low peroxide levels and osmolarity was appropriate for parenteral administration.ConclusionThe total calcium and calcium/phosphorus ratios studied appeared not to influence the physicochemical compatibility and stability of AIO admixtures.

Pharmaceutical quality evaluation of lipid emulsions containing PGE 1: Alteration in the number of large particles in infusion solutions

There are two generics of a parenteral lipid emulsion of prostaglandin E1 (PGE 1) (Lipo-PGE 1) in addition to two innovators. It was reported the change from innovator to generic in clinical practice caused the slowing of drip rate and formation of aggregates in the infusion line. Thus, we investigated the difference of pharmaceutical quality in these Lipo-PGE 1 formulations. After mixing with some infusion solutions, the mean diameter and number of large particles were determined. Although the mean diameter did not change in any infusion solutions, the number of large particles (diameter >1.0 μm) dramatically increased in generics with Hartmann's solution pH 8 or Lactec ® injection with 7% sodium bicarbonate. Next, we investigated the effect of these infusion solutions on the retention rate of PGE 1 in lipid particles. The retention rate of PGE 1 in these two infusion solutions decreased more quickly than that in normal saline. Nevertheless, there were no significant differences among the formulations tested. Our results suggest that there is no difference between innovators and generics except in mixing with these infusion solutions. Furthermore, that monitoring the number of large particles can be an effective means of evaluating pharmaceutical interactions and/or the stability of lipid emulsions.

Effects of temperature and handling conditions on lipid emulsion stability in veterinary parenteral nutrition admixtures during simulated intravenous administration

To determine whether lipid particle coalescence develops in veterinary parenteral nutrition (PN) admixture preparations that are kept at room temperature (23 degrees C) for > 48 hours and whether that coalescence is prevented by admixture filtration, refrigeration, or agitation. 15 bags of veterinary PN solutions. Bags of a PN admixture preparation containing a lipid emulsion were suspended and maintained under different experimental conditions (3 bags/group) for 96 hours while admixtures were dispensed to simulate IV fluid administration (rate, 16 mL/h). Bags were kept static at 4 degrees C (refrigeration); kept at 23 degrees C (room temperature) and continuously agitated; kept at room temperature and agitated for 5 minutes every 4 hours; kept static at room temperature and filtered during delivery; or kept static at room temperature (control conditions). Admixture samples were collected at 0, 24, 48, 72, and 96 hours and examined via transmission electron microscopy to determine lipid particle diameters. At 96 hours, 2 samples were collected at a location distal to the filter from each bag in that group for bacterial culture. Distribution of lipid particle size in the control preparations and experimentally treated preparations did not differ significantly. A visible oil layer developed in continuously agitated preparations by 72 hours. Bacterial cultures of filtered samples yielded no growth. Data indicated that the veterinary PN admixtures kept static at 23 degrees C are suitable for use for at least 48 hours. Manipulations of PN admixtures appear unnecessary to prolong lipid particle stability, and continuous agitation may hasten lipid breakdown.

Safety and Stability of Lipid Emulsions

Safety and Stability of Lipid Emulsions

Safety and Stability of Lipid Emulsions—Response

Safety and Stability of Lipid Emulsions—Response

Stability of drug-carrier emulsions containing phosphatidylcholine mixtures

Lipid emulsion particles containing 10% of medium chain triglycerides were prepared using 2% w/w of a mixture 1:1 w/w of purified soya phosphatidylcholine and 2-hexanoyl phosphatidylcholine as emulsifier mixture, for use as drug carriers. The mean droplet sizes of emulsions, prepared using an Ultra Turrax or a high-pressure homogenizer, were about 288 and 158 nm, respectively, compared with 380 and 268 nm for emulsions containing lecithin, or 325 and 240 nm for those containing 6-phosphatidylcholine. The stability of the emulsions, determined by monitoring the decrease of a lipophilic marker at a specified level within the emulsion, and observing coalescence over time, was also greatly increased using the emulsifier mixture. The emulsion stability did not notably change in the presence of a model destabilizing drug, indomethacin. The use of a second hydrophilic surfactant to adjust the packing properties of the lecithin at the oil–water interface provided an increase in the stability of lipid emulsions, and this may be of importance in the formulation of drug delivery systems.

Stability and plasma apolipoprotein binding of lipid emulsions

The stability of lipid emulsions was studied during the ultracentrifugation flotation and freeze–thawing processes. The relationship between the droplets’ coalescence and the average spontaneous curvature of surface phospholipid monolayers was discussed on the basis of the coalescence transition state theory recently developed by Kabalnov et al. In addition, the effects of maltose on the emulsion coalescence in the frozen state were briefly discussed. The maximum binding amounts of apolipoprotein C-2 (apoC-2) and apolipoprotein E (apoE) to egg-phosphatidylcholine/triglyceride-emulsions were about 10 times larger than those to egg-phosphatidylcholine-vesicles (liposomes) in plasma. Accordingly, plasma-clearance of emulsions through apoE receptors was more rapid than vesicles in rat. The maximum binding amount of the isolated apolipoprotein A-1 (apoA-1) was also much larger for emulsions than vesicles. The different binding capacities between emulsions and vesicles were explained by the interaction of surface phosphatidylcholine and core triglyceride. Although binding of apolipoproteins to surface monolayers led to the packing stress (positive curvature), the interaction between core triglyceride and the surface egg PC monolayers releases the stress and increases the maximum binding amount (binding capacity).

Physicochemical assessments of parenteral lipid emulsions: light obscuration versus laser diffraction

The United States Pharmacopeia (USP) has proposed a new Chapter 〈729〉 entitled ‘Globule Size Distribution in Intravenous Emulsions’ that is intended to identify methods for analyzing the stability of lipid emulsions. We studied the differences between particle-sizing instruments when analyzing the physicochemical stability of a parenteral nutrition mixture compounded with intravenous lipid emulsion, known as an all-in-one mixture. As the growth of lipid droplets, i.e. coalescence, signals an irreversible change in emulsion stability, we focused our investigation on the large diameter tail (>5 μm) of the globule size distribution. Of the four proposed methods, droplet size was studied over a range of mixture stabilities using a low osmolality parenteral nutrition formula employing both light scattering and light obscuration techniques. In addition, the same mixtures were also freshly prepared, and then spiked with a known amount of 5 μm latex spheres. The response obtained from the light obscuration technique was linear and detected both unstable and latex-spiked mixtures in every case for droplets or particles >5 μm. The results of the laser diffraction method were non-linear and overestimated, was less sensitive or missed entirely, globules or particles in the large diameter tail of the dispersion. The results demonstrate that light obscuration is superior to laser diffraction in identifying unstable intravenous fat emulsions.

Influence of the non-ionic surfactant PEG-660-12-hydroxy stearate on the surface properties of phospholipid monolayers and their effect on lipid emulsion stability

The effect of the interaction between phospholipid monolayers and PEG-660-12-hydroxy stearate as a non-ionic surfactant on lipid emulsion stability in dynamic and static conditions was studied. The presence of PEG-660-12-hydroxy stearate molecules with phospholipid monolayers (static state) leads to a remarkable increase in the surface pressure (from 5 to 30 mN/m in the initial molecular area), whereas in the dynamic state, when the two emulsifiers are separated and each dissolved in one phase of the two emulsion phases, a sudden decrease in the surface pressures is observed. This indicates that PEG-660-12-hydroxy stearate molecules are intercalated between the phospholipid monolayers forming a molecular mixed film. At the same time, a part of the phospholipid monolayers interacts with the surfactant monomers to form a soluble or partially soluble association complex. This interpretation was also supported by interfacial tension measurements, where the interfacial tension in the dynamic state was lower than that in the static one. This indicates that in static conditions the phospholipids partially interact with PEG-660-12-hydroxy stearate resulting in a non-active association complex. Subsequently there is insufficient utilization of the available surfactants during the emulsification process. In contrast, in dynamic conditions both emulsifiers are available at the free surface from the beginning. This behaviour was substantiated by investigating the stability of emulsions which were prepared either by the static condition or the dynamic one during the autoclaving process.

Effect of surface charge on the stability of oil/water emulsions during steam sterilization

Intravenous lipid emulsions are used for total parenteral nutrition and as carriers for lipophilic drugs. Exposure to the high temperature (121 °C) required for steam sterilization may cause coalescence and an increase in droplet size. The purpose of this study was to investigate whether an increase in the electrostatic repulsive force between oil droplets produced by formulation modification improves the thermal stability of lipid emulsions during autoclaving. The addition of a small amount, 0.66 or 1.32 mmol/kg (mm), of purified anionic phospholipid fractions (phosphatidic acid, phosphatidylglycerol, or phosphatidylinositol) to the standard formula increased the Z potential from its normal value of –11 mV to –39 mV. Emulsions with the larger negative Z; potential did not exhibit any change in oil droplet size or distribution during steam sterilization at 121 °C for 15 min. The autoclaved emulsions having the larger negative Z potential did not exhibit any evidence of coalescence when samples were stored for 1 month at 4 °C, room temperature, or 40 °C. Reduction of the negative surface charge of the oil droplets by the addition of stearylamine confirmed that the surface charge was an important factor, as emulsions having a reduced negative surface charge separated into two phases during autoclaving.

Pharmacologic Levels of Heparin Do Not Destabilize Neonatal Parenteral Nutrition

Calcium and heparin are known to destabilize the lipid emulsion of total parenteral nutrition (TPN). However, these observations were made over long periods of time, using 5 to 10 times the amount of heparin used in a neonatal intensive care unit. We investigated the effects of lower heparin concentrations with lipid-to-nutrient ratios normally administered to premature infants. Lipid emulsion stability was assessed over 30 minutes by measuring viscosity at 10 mmol/L calcium after the addition of 0, 0.5, 1, and 5 IU heparin/mL. This was done at a range of lipid-to-nutrient ratios in clinical use. The effect of varying calcium concentration and different multivitamin preparations on emulsion stability also was observed. Heparin caused an immediate increase in viscosity of pure Intralipid 20% (Intralipid; Kabi Pharmacia AB, Stockholm, Sweden), which eventually separated into two phases. Although changes in viscosity were observed at 1:1 lipid-to-nutrient ratios, no effect was seen at a 1:9 ratio. With the 1:1 ratio, the multivitamin preparations, MVI Pediatric (Rhone-Poulec Rorer, Montreal, Canada) and Vitlipid (Kabi Pharmacia AB), reduced the increase in viscosity. Heparin and calcium destabilize Intralipid. This is unlikely to cause problems for most infants receiving TPN, provided low heparin concentrations are used. In all cases, especially where the lipid ratio is high, the risk of the lipid phase separating out can be further minimized by (1) the addition of multivitamin preparations containing detergent or an emulsifying agent and (2) by having the shortest possible delivery tube between the point of mixing the lipid and amino acid solutions of TPN and entry into the infant.