Parenteral Emulsions Research Articles

SolEmuls® Technology: A Way to Overcome the Drawback of Parenteral Administration of Insoluble Drugs

In this article, a nanosuspension of AmB was prepared and mixed with the preformed parenteral emulsion Lipofundin® and subjected to high-pressure homogenization (SolEmuls® technology). Characterization was performed by photon correlation spectroscopy (PCS), laser diffractometry (LD), and zeta potential measurements. Drug incorporation was studied by using light microscopy. The produced emulsions were further investigated by comparing them with the commercially available Fungizone® in regard to antifungal efficiency and toxicity. Results suggest that through the SolEmuls® process the AmB forms a reservoir, out of which it is released in such a manner that it is more efficient and less toxic than Fungizone®.

The Metabolism of Fatty Alcohols in Lipid Nanoparticles by Alcohol Dehydrogenase

ABSTRACTFatty alcohols are commonly used in lipid-based drug delivery systems including parenteral emulsions and solid lipid nanoparticles (NPs). The purpose of these studies was to determine whether horse liver alcohol dehydrogenase (HLADH), a NAD-dependent enzyme, could metabolize the fatty alcohols within the NPs and thus serve as a mechanism to degrade these NPs in the body. Solid nanoparticles (<100 nm) were engineered from oil-in-water microemulsion precursors using emulsifying wax NF as the oil phase and polyoxyethylene 20-stearyl ether (Brij 78) as the surfactant. Emulsifying wax contains both cetyl and stearyl alcohols. NPs were incubated with the enzyme and NAD+ at 37°C for up to 48 h, and the concentrations of fatty alcohols were quantitatively determined over time by gas chromatography (GC). The concentrations of cetyl alcohol and stearyl alcohol within the NPs decreased to only 10–20% remaining after 15–24 h of incubation. In parallel, NP size, turbidity and the fluorescence intensity of NADH all increased over time. It was concluded that horse liver alcohol dehydrogenase/NAD+ was able to metabolize the fatty alcohols within the NPs, suggesting that NPs made of fatty alcohols may be metabolized in the body via endogenous alcohol dehydrogenase enzyme systems.

Pharmacokinetics and tissue distribution of etoposide delivered in long circulating parenteral emulsion

Purpose: The aim of the study is to ascertain the influence of pegylation of parenteral emulsion (PE) on their long circulating property.Methods: Etoposide encapsulated parenteral emulsion (EPE) was prepared using soybean oil, egg lecithin and cholesterol. Etoposide encapsulated long circulating parenteral emulsion (PEG–EPE) was prepared using PEG (2000)-DSPE as a stealth agent. The effect of monovalent and divalent electrolytes on the stability of EP was assessed by measuring the fixed aqueous layer thickness (FALT) and flocculation rate. Pharmacokinetics and tissue distribution pattern of PE following i.v. (bolus) were assessed in Wistar rats and Swiss albino mice.Results: FALT of PEG–EPE was larger than that of EPE. In case of PEG–EPE, as the concentration of pegylated lipid (PEG) increased from 0.15 to 0.45% w/v the flocculation rate decreased asymptomatically in the presence of monovalent and divalent electrolytes. The increased circulation time of PEG–EPE (0.3%) after intravenous injection to rats confirms the presence of FALT around globules. PEG–EPE showed improved pharmacokinetic parameters with 5.5 times higher AUC than etoposide commercial formulation (ETP). Tissue distribution results show that etoposide levels in all tissues except in brain and heart were lower in case of PEG–EPE than ETP. The percentage of tumor growth suppression rate (%T/C) in Lewis lung carcinoma bearing mice was 63.23, 62.83 and 33.78% in EPE, PEG–EPE and ETP treated mice, respectively. The improved activity of PEG–EPE is due to enhanced permeability and retention effect (EPR).Conclusion: Encapsulation of etoposide in PEG-coated PE produced improved pharmacokinetic profile than that of EPE and ETP.

The Effect of Parenteral Fish Oil Emulsion (Omegaven®) On Wound Healing in Rats Under the Dexamethasone Treatment

The Effect of Parenteral Fish Oil Emulsion (Omegaven®) On Wound Healing in Rats Under the Dexamethasone Treatment

Pharmacokinetics and Tissue Distribution of Etoposide Delivered in Parenteral Emulsion

Etoposide was incorporated in an injectable parenteral emulsion, in an attempt to alter its pharmacokinetics and improve anticancer activity. Parenteral emulsion of etoposide (EPE), which remained stable over 6 months' storage, was prepared (under optimal experimental conditions) using soybean oil and phosphatidylcholine as emulsifier. The particle size distribution and zeta potential were measured using photon correlation spectroscopy. The pharmacokinetics and tissue distribution of EPE and commercial etoposide injectable solution (ETP) were studied in Swiss albino mice. The antitumor activity was performed on BDF1 mice bearing Lewis lung carcinoma. The particle size distribution with polydispersity indices, zeta potential, entrapment efficacy, and assay of EPE were found to be 218.7 ± 4.7 (0.14 ± 0.0) nm, −53.5 ± 0.2 mV, 75 ± 2.1%, and 0.85 ± 0.1 mg/mL, respectively. The EPE was stable for >6 months and drug leaching was 5.8 ± 1.5%. The pharmacokinetics and tissue distribution of EPE was significantly different than that of ETP. The EPE showed high AUC0–α, MRT (mean residence time), and lower clearance than that of ETP. It was found that etoposide concentration was higher in liver, spleen, and lung after ETP administration when compared with EPE; however, in heart and brain, etoposide was more after EPE than that of ETP. The EPE showed lower reticuloendothelial system (liver and spleen) tissue uptake. The anticancer activity of EPE was higher in Lewis lung carcinoma–bearing mice. On the fifteenth day of transplantation, the percentage of tumor growth suppression rate was 63.23% in EPE-treated mice and 33.78% in ETP-treated mice.

More efficient preparation of parenteral emulsions or how to improve a pharmaceutical recipe by formulation engineering

Parenteral emulsions are special O/W emulsions used to feed patients whose medical condition makes them unable to eat normally. Therefore, parenteral emulsions must comply with several specifications. One is that the maximum droplet size must be below 5 μ m in order to avoid the risk of a pulmonary embolism. In this work, we describe the step-by-step procedure followed to simplify a current industrial recipe by applying recently developed principles under the name of formulation engineering. Both hydrodynamic and physicochemical formulation parameters were manipulated to reduce energy input and equipment requirements. The current process consists of two heating steps, three mixing stages and filtering to eliminate droplets larger than 5 μ m . The mixing stages require first an agitated tank for the making of a coarse dispersion, then a high-speed mixer and last a two-stage homogenizer. Despite the intensive mixing the emulsion does not comply with droplet size specifications and filtering is necessary. Our procedure requires heating once and then two mixing stages, the first to produce a coarse dispersion and the second to refine droplet size in a conventional agitated tank. Further, no filtering is necessary since no droplets larger than 3 μ m are produced in the mixing tank. The parenteral emulsions resulting of this simplified and less energy intensive process complies with droplet size requirements and are stable over several months.

Partition of antimicrobial additives in an intravenous emulsion and their effect on emulsion physical stability

A number of antimicrobial agents are potentially applicable to the preservation of small-volume parenteral emulsions. However, the physical stability of these emulsions is of paramount importance in ensuring their safety, and it is possible that antimicrobial additives could reduce the emulsion stability by a number of mechanisms. We have studied the effects of several antimicrobial agents on the physical stability of Diprivan ®, an intravenous anaesthetic emulsion. A particular problem is that many antimicrobial additives require an acidic pH in order to be effective (e.g. sodium benzoate, sodium metabisulphite) and the emulsion surface potential is insufficient to stabilize the emulsion to coalescence under these conditions. In addition several antimicrobial agents (e.g. methyl paraben and benzoic acid) partition into the oil phase of the emulsion, requiring the use of increased concentrations to remain effective. We describe an assay technique to quantify the oil partition, liposomal partition, and droplet surface adsorption of the additives. This illustrates that significantly more additive is partitioned out of the water phase than might be predicted from simple oil/water partition experiments.

Tocol emulsions for drug solubilization and parenteral delivery

Tocols represent a family of tocopherols, tocotrienols, and their derivatives, and are fundamentally derived from the simplest tocopherol, 6-hydroxy-2-methyl-2-phytylchroman, which is referred to as “tocol”. The most common tocol is d-α-tocopherol, also known as vitamin E. Tocols can be excellent solvents for water insoluble drugs and are compatible with other cosolvents, oils and surfactants. This review highlights the major developments in the use of tocols in parenteral emulsions for drug delivery, with a focus on drug solubilization, physicochemical properties, and biopharmaceutical applications. Tocol emulsions offer an appealing alternative for the parenteral administration of poorly soluble drugs, including major chemotherapeutics such as paclitaxel. Data will be presented on solubilization of paclitaxel, a key chemotherapeutic agent, and its corresponding formulation development, toxicity, efficacy and pharmacokinetic studies in animal models and humans. The breadth of the utility of tocol-based emulsions will be discussed and examples of specific therapeutic drugs and applications will be provided. As these formulations progress further in the clinic, the therapeutic utility of tocol emulsions is anticipated to expand.

SolEmuls ®—novel technology for the formulation of i.v. emulsions with poorly soluble drugs

Intravenously injectable o/w emulsions of drugs being poorly soluble in water and simultaneously in oils need to be produced by locating the drug in the interfacial lecithin layer, e.g. amphotericin B. For achieving this, up to now organic solvents were required. The objective was to develop a solvent-free production method for such emulsions. Drug and the pre-formed parenteral emulsion Lipofundin ® were mixed and subjected to high pressure homogenisation. Drug powder and emulsions were characterised regarding size and physical stability by photon correlation spectroscopy (PCS), laser diffractometry (LD) and zeta potential measurements. Drug incorporation was studied using light microscopy, electron microscopy (EM) and a centrifugation test to separate non-dissolved drug. Amphotericin B and carbamazepine were used as model drugs. The high streaming velocities lead to accelerated drug dissolution and partitioning into the interfacial layer (so-called “solubilisation by emulsification”, SolEmuls ® Technology). The interfacial layer could incorporate (solubilise) a certain amount of drug, revealed by EM pictures. Exceeding this concentration, hybrid dispersions were formed consisting of drug-loaded oil droplets and drug nanocrystals of similar size (approximately 200 nm). Both dispersion types are i.v. injectable opening the opportunity to deliver the drug in a concentrated form at desired low injection volume, e.g. 10 mg/ml.

Modification of the droplet size and distribution of parenteral emulsions by tangential microfiltration

In this work we studied the modification of the droplet size and distribution of stable parenteral emulsions (PEs) by microfiltration. The intravenous nutrition through PE needs to be conducted using very fine emulsified fat droplets, which have to be for health reasons at a mean diameter under 1 μm. In this work we used membrane microfiltration to decrease the fat particles mean diameter and distribution. The PE filtration was possible without coalescence, because of the high stability of the PE prepared by using an emulsification method never applied before to this type of emulsion. The membrane filtration process was carried out by using ceramic membranes with different pore sizes (0.8, 1.2 and 1.4 μm of mean pore radius). The results obtained showed that the shearing forces and trans-membrane pressure had a fundamental influence on the emulsion droplet size distribution and that depending on the membrane type or operating conditions used, the mean droplet size and distribution could be effectively decreased.

Evaluation of childhood exposure to di(2-ethylhexyl) phthalate from perfusion kits during long-term parenteral nutrition

Leachability of the plasticizer di(2-ethylhexyl) phthalate (DEHP) from administration sets into intravenous parenteral emulsions containing fat was investigated. DEHP is added to polyvinyl chloride (PVC) to impart flexibility. However, DEHP is a lipid-soluble suspected carcinogen that is hepatotoxic and teratogenic in rodents, and has been shown to leach from PVC products containing lipophilic mixtures. Consequently, total parenteral nutrition (TPN) mixtures containing fat emulsions should be stored in ethylvinyl acetate (EVA) bags rather than PVC packs. However, while TPN bags are made of EVA, they contain PVC-DEHP residues and the lines used between TPN bags and venous catheters are made of PVC-DEHP. The present study quantified the amount of DEHP leached from bags and tubing that could potentially contaminate patients during home TPN. Four types of emulsions containing fat were studied. Levels of DEHP in the bag and at the outlet tubing were measured by high-performance liquid chromatography (HPLC). This was measured during simulated TPN at different times after starting perfusion, 1 day after reconstitution of solutions in the bags, and 1 week later after storage at 4 °C. Detectable and stable amounts of DEHP were found to leach from bags (0.2±0.008 mg to 0.7±0.02 mg) and DEHP content increased in the outlet tubing (0.8±0.09 mg to 2±0.07 mg) during simulated infusions. The same phenomenon was observed after 1 week of storage at 4 °C. DEHP extraction by TPN depends on the lipid content of each TPN preparation and the flow rate. These results suggest that children treated with prolonged TPN are regularly exposed to significant amounts of DEHP.

Intravenous itraconazole emulsions produced by SolEmuls technology

Itraconazole is a drug which is poorly soluble in both the water and oil phases of emulsions. Incorporation in parenteral emulsions was performed applying the SolEmuls ® Technology, i.e. localising the drug in the interfacial lecithin layer of the emulsions by homogenising a hybrid dispersion of oil droplets and drug nanocrystals in water. The maximum loading capacity of the emulsion system was found to be 10 mg/ml; at 20 mg/ml the loading capacity was exceeded leading to remaining drug nanocrystals in the emulsion. Incorporation of itraconazole into the lecithin layer led to an enhanced dispersion effect, i.e. with increasing drug concentration the droplet size of the emulsions decreased. Physical long-term stability of the optimum emulsion with 10 mg/ml could be shown over a period of 3 months at room temperature.

Amphotericin B/Emulsion Admixture Interactions: An Approach Concerning the Reduction of Amphotericin B Toxicity

Mixing Fungizone™ with a fat emulsion used for nutritional purpose (Intralipid™ or Lipofundin™) was reported to decrease Amphotericin B (AmB) toxicity in clinical use. In an effort to understand the reason for this phenomenon, spectral and morphological analyses were done for the Fungizone™ and Fungizone™/Lipofundin™ admixture (FLmix). The absorption spectra analyses showed that not only Fungizone™ but also FLmix presented spectra that were concentration dependent. Moreover, the spectra of FLmix remained stable until the concentration of 5 × 10−7 M, and only at 5 × 10−8 M did they become similar in shape to the Fungizone™ spectra. Morphological studies revealed that even though emulsion droplets with or without Fungizone™ presented the same particle size, the former was less electron dense compared with Lipofundin™ alone. These results suggest a kind of association between Fungizone™ and Lipofundin™ that remains over the whole range of concentrations. This hypothesis was confirmed by in vitro studies in which FLmix presented an important selectivity against human and fungal cells compared with Fungizone™. These findings suggest that parenteral emulsions should be able to reduce the AmB toxicity probably by changing the AmB self‐association state by binding it with emulsion droplets. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2354–2366, 2002

Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid.

Solid lipid nanoparticles (SLNs) have gained attention as a colloidal drug carrier, particularly for drugs with limited solubility. The poor aqueous solubility of all-trans retinoic acid (ATRA) has been a limiting factor in its clinical use. This study was undertaken to overcome the solubility limitation of ATRA by loading in SLNs. The physicochemical characteristics of ATRA-loaded SLNs were investigated by particle size analysis, zeta potential measurement, thermal analysis and HPLC determination of ATRA content. The mean particle size of ATRA-loaded SLNs could be reduced (1) by mixing EggPC and Tween 80 as a surfactant and (2) by increasing the total surfactant amount. The smallest mean particle size of SLNs was obtained with 50 mg/g surfactant mixture composed of 54:46% (w/w) EggPC:Tween 80 (154.9 nm). The zeta potential of SLNs could be increased by mixing EggPC, Tween 80 and DSPE-PEG in the surfactant mixture. The zeta potential of SLNs prepared with 50 mg/g surfactant mixture composed of 48:6:46% (w/w) of EggPC:DSPE-PEG:Tween 80 was -38.18 mV. ATRA could be loaded at 2.4% (percentage of lipid matrix) on these SLNs without impairing their physical stability. After freeze-drying, the mean particle size and polydispersity index of ATRA-loaded SLNs were only slightly increased (181.8 vs. 265.2 nm, 0.173 vs. 0.200). Furthermore, no significant change was observed in the SLN-loaded concentration of ATRA and the zeta potential of SLNs after freeze-drying. Taken together, SLN formulation of ATRA with similar characteristics to those of parenteral emulsions could be obtained even after freeze-drying.

Parenteral emulsions stabilized with a mixture of phospholipids and PEG-660-12-hydroxy-stearate: evaluation of accelerated and long-term stability

Different emulsion formulations were prepared using phospholipids (Lipoid S57) and PEG-660-12-hydroxy-stearate (Solutol HS15) as single emulsifiers or in mixtures. The accelerated stability after autoclaving, freezing and centrifugation was investigated. The long-term stability was also studied at different temperatures (4, 20, and 37 °C) for 8 months. Emulsion stabilized with phospholipids displayed a stable behavior after the autoclaving and centrifugation, but it broke down after the freezing process. In mixture with Solutol HS15, however, the emulsion showed appropriate shelf stability at different temperatures for 8 months. A change in the particle size of the emulsion prepared only with Solutol HS15 was observed after centrifugation (slight) and after autoclaving (marked). In contrast to phospholipid emulsion, this emulsion (with only Solutol HS15) was less prone to breaking down after the freezing, as no complete phase separation was observed. The results obtained using an emulsifier mixture revealed that a combination of an anionic surfactant (phospholipids) and non-ionic surfactant (PEG-660-12-hydroxy-stearate) improves the emulsion's stability, compared to the emulsion's stability prepared using only a single emulsifier. However, no direct correlation could be found between the accelerated and the long-term stability data.

Intralipid 10%: physicochemical characterization

OBJECTIVES: Parenteral fat emulsions contain two populations of particles: artificial chylomicrons rich in triacylglycerols (TAG), and liposomes (bilayer of phospholipids [PL] enveloping an aqueous phase). Centrifugation permits isolating the liposomes in the infranatant called mesophase. The aim of the present work was to better characterize this mesophase chemically and to view the particles it contains by electron microscopy. METHODS: Electron microscopy (Philips 410) was performed after cryofracture on native 10% Intralipid, mesophase (centrifugation for 1 h at 27 000 g), and a liposome-enriched fraction (ring of density 1.010–1.030 g/l obtained after centrifuging mesophase in a KBr density gradient at 100 000 g for 24 h). The TAG and protein content of the mesophase was analyzed and the proteins partially characterized by immunodetection (Western-blot). RESULTS: This electron microscope study of 10% Intralipid gives evidence for the coexistence of artificial chylomicrons (mean diameter, 260 nm) and liposomes (43 nm), the latter being smaller than expected and containing 8% w/w TAG after purification. The solubilization of TAG in PL bilayers (reported to be ≤3.1% w/w) might have been increased in parenteral emulsions by the manufacturing process or/and the high TAG/PL ratio. Minute amounts of proteins have also been detected and partially characterized using a specific antibody raised against the human 7 kDa Anionic Polypeptide Factor (APF), known to strongly interact with PL in bile. CONCLUSIONS: This work has shown that the size (mean diameter, 43 nm) of the liposomes present in 10% Intralipid is smaller than that usually assumed. Traces of hydrophobic proteins in the emulsion may account for certain allergic reactions sometimes observed in infused patients.

Use of ultrasound to prepare lipid emulsions of lorazepam for intravenous injection

Lipid emulsions can be used as a vehicle for the production of low-volume injectable preparations with minimally water-soluble active ingredients. First, we focus on the galenic and technological conditions established by ultrasound techniques. A 2 5 factorial design was used to optimize the carrier emulsion. The study then deals with the development of a parenteral emulsion formulation for lorazepam (1 mg/ml), which is compared with the highest concentration (0.05 mg/ml) achieved in the optimal aqueous diluent for lorazepam (dextrose 5% in water). The physical and chemical stability of lorazepam in the emulsion was examined for 7 months.

Development of a Novel Parenteral Formulation for Tetrazepam Using a Lipid Emulsion

A novel parenteral formulation for tetrazepam (10 mg/ml) was developed using lipid emulsions. This formulation utilized a new lipid emulsion formulation, which was developed by changing the polarity of the oil phase. It was found that increasing the polarity of the oil phase resulted in enhanced solubility of tetrazepam. Tetrazepam showed higher solubility in a mixture of castor oil and middle-chain triglycerides (MCTs) (1:1) than in any other oil investigated. This mixture resulted in low interfacial tension and moderate viscosity, which seemed to be the optimum oil phase. In addition, to increase the concentration of tetrazepam, an emulsion formulation containing 30% oil phase was produced and optimized. The drug-free emulsion formulation showed fine particle sizes with an imperceptible change in physicochemical properties after more than 2 years on the shelf. As a result, it was possible to produce a parenteral emulsion formulation containing 10 mg/ml tetrazepam. No change in the physicochemical properties of the emulsion was observed after the addition of tetrazepam. The tetrazepam emulsion showed stable behavior during the autoclaving process and good shelf stability for at least 10 months as well. Tetrazepam itself also displayed good stability during the autoclaving process and also showed good shelf stability in this emulsion formulation.

Formulation development and antitumor activity of a filter-sterilizable emulsion of paclitaxel.

Paclitaxel is currently administered i.v. as a slow infusion of a solution of the drug in an ethanol:surfactant:saline admixture. However, poor solubilization and toxicity are associated with this drug therapy. Alternative drug delivery systems, including parenteral emulsions, are under development in recent years to reduce drug toxicity, improve efficacy and eliminate premedication. Paclitaxel emulsions were prepared by high-shear homogenization. The particle size of the emulsions was measured by dynamic light scattering. Drug concentration was quantified by HPLC and in vitro drug release was monitored by membrane dialysis. The physical stability of emulsions was monitored by particle size changes in both the mean droplet diameter and 99% cumulative distribution. Paclitaxel potency and changes in the concentration of known degradants were used as chemical stability indicators. Single dose acute toxicity studies were conducted in healthy mice and efficacy studies in B 16 melanoma tumor-bearing mice. QW8184, a physically and chemically stable sub-micron oil-in-water (o/w) emulsion of paclitaxel, can be prepared at high drug loading (8-10 mg/mL) having a mean droplet diameter of <100 nm and 99% cumulative particle size distribution of <200 nm. In vitro release studies demonstrated low and sustained drug release both in the presence and absence of human serum albumin. Based on single dose acute toxicity studies, QW8184 is well tolerated both in mice and rats with about a 3-fold increase in the maximum-tolerated-dose (MTD) over the current marketed drug formulation. Using the B16 mouse melanoma model, a significant improvement in drug efficacy was observed with QW8184 over Taxol. QW8184, a stable sub-micron o/w emulsion of paclitaxel has been developed that can be filter-sterilized and administered i.v. as a bolus dose. When compared to Taxol, this emulsion exhibited reduced toxicity and improved efficacy most likely due to the composition and dependent physicochemical characteristics of the emulsion.

In vitro investigation of the effect of various isotonic substances in parenteral emulsions on human erythrocytes

The hemolytic behaviour of human erythrocytes in parenteral emulsions containing various isotonizing substances (xylitol, sorbitol and glycerol) was studied. It was found that complete hemolysis of human erythrocytes occurred in parenteral emulsions with isotonic or isosmotic concentration of glycerol after 5 min, whereas emulsions which contained an isotonic concentration of xylitol or sorbitol did not show any hemolysis after 40 min. Conversely, formulations with different concentrations of glycerol in an isotonic solution of sorbitol did not show any hemolytic behaviour after 40 min. It appeared that all the hemolytic phenomena encountered in glycerol were of an isotonic character since hemolysis was totally prevented by the inclusion of an isotonic concentration of sorbitol. According to these in vitro results it seems that glycerol, a commonly used substance in commercial parenteral emulsions, may not be the best isotonizing substance.