Lipid-based Emulsion Research Articles

Synergistic stabilization of emulsion gel by nanoparticles and surfactant enables 3D printing of lipid-rich solid oral dosage forms

Pharmaceutical formulation of oral dosage forms is continuously challenged by the low solubility of new drug candidates. Pickering emulsions, emulsions stabilized with solid particles, are a promising alternative to surfactants for developing long-term stable emulsions that can be tailored for controlled release of lipophilic drugs. In this work, a non-emulsifying lipid-based formulation (LBF) loaded with fenofibrate was formulated into an oil-in-water (O/W) emulsion synergistically stabilized by stearic acid and silica (SiO2) nanoparticles. The emulsion had a droplet size of 341 nm with SiO2 particles partially covering the oil–water interface. In vitro lipid digestion was faster for the emulsion compared to the corresponding LBF due to the larger total surface area available for digestion. Cellulose biopolymers were added to the emulsion to produce a gel for semi-solid extrusion (SSE) 3D printing into tablets. The emulsion gel showed suitable rheological attributes for SSE, with a trend of higher viscosity, yield stress, and storage modulus (G′), compared to a conventional self-emulsifying lipid-based emulsion gel. The developed emulsion gel allows for a non-emulsifying LBF to be transformed into solid dosage forms for rapid lipid digestion and drug release of a poorly water-soluble drug in the small intestine.

Lipid-based emulsion drug delivery systems - a comprehensive review.

Lipid-based emulsion system - a subcategory of emulsion technology, has emerged as an enticing option to improve the solubility of the steadily rising water-insoluble candidates. Along with enhancing solubility, additional advantages such as improvement in permeability, protection against pre-systemic metabolism, ease of manufacturing, and easy to scale-up have made lipid-based emulsion technology very popular among academicians and manufacturers. The present article provides a comprehensive review regarding various critical properties of lipid-based emulsion systems, such as microemulsion, nanoemulsion, SMEDDS (self microemulsifying drug delivery system), and SNEDDS (self nanoemulsifying drug delivery system). The present article also explains in detail the similarities and differences between them, the stabilization mechanism, methods of preparation, excipients used to prepare them, and evaluation techniques. Subtle differences between nearly related terminologies such as microemulsion and nanoemulsion, SMEDDS, and SNEDDS are also explained in detail to clarify the basic differences. The present article also gives in-depth information regarding the chemical structure of various lipidic excipients, various possible chemical modifications to modify their inherent properties, and their regulatory status for rational selection.

Production of mycosporine-like amino acid (MAA)-loaded emulsions as chemical barriers to control sunscald in fruits and vegetables.

Sunscald is a physiological disorder that occurs in many horticultural products when exposed to excessive solar radiation and high temperatures. Traditionally, sunscald is controlled using physical barriers that reflect radiation, however this practice is not always efficient. A possible alternative would be the use of chemical barriers, such as mycosporine-like amino acids (MAAs), which protect aquatic organisms against ultraviolet (UV) radiation. Thus, this study aimed to develop a lipid-based emulsion containing MAAs for using in the preharvest of horticultural products. Emulsions were developed using 10% (w/v) of corn oil (CO) and soybean oil (SO), carnauba wax (CW), and beeswax (BW) as lipid bases (LBs). The emulsion containing CW and ammonium hydroxide was the most stable, resembling commercial wax. Therefore, this formulation was used as the basis for the incorporation of the commercial product Helioguard™ 365, a source of MAA, in concentrations of 0%, 1%, 2%, and 4% (v/v). The MAA incorporation resulted in little modifications in the stability of the emulsion, providing an increase in the absorbance with peaks in the UV-B ranging from 280 to 300 nm. The lipid-base emulsion containing MAAs could be used as a chemical barrier to control sunscald in horticultural products. © 2021 Society of Chemical Industry.

Abstract 1853: Lipiodol-based emulsion to disrupt oxygenation and lipid homeostasis of liver tumors

Abstract Trans-arterial embolic therapies for liver tumors are used routinely in patients with hepatocellular carcinoma (HCC) and patients with liver dominant metastatic disease. Lipiodol® (Ethiodized oil; ethyl esters of iodized fatty acids of poppy seed oil) has been historically used as a vehicle for delivering chemotherapeutic agents as part of chemoembolization (cTACE) of liver tumors. Lipiodol's role in cTACE is to visualize the delivery of the mixture under fluoroscopy, emulsification and delivery of the chemotherapeutic agent, and as a microembolic agent itself. Contrary to previous studies that showed better outcome in patients with HCC treated with cTACE compared to bland embolization (TAE), more recent studies demonstrated no significant difference between drug-eluting chemoembolization and bland embolization (TAE), negating the added benefit of chemotherapy as a required agent when performing liver embolization of HCC. Therefore, we hypothesized that the added benefit of cTACE over TAE stems from the Lipiodol-based emulsion and not chemotherapy. We performed embolization of liver tumors using Lipiodol-Isovue emulsion and bland particles (TALE) but replacing chemotherapy with Isovue-300® (Iopamidol, a non-ionic iodinated contrast agent). Our preliminary data of 5 patients with non-resectable HCC (1 to 14.9 cm) treated with TALE without systemic therapy were followed for at least 5 months and response was evaluated using RECIST and mRECIST. By mRECIST, 3 patients had complete response (CR), one had a partial response (PR) and one could not be evaluated since the biopsy-proven HCC was hypovascular. Using RECIST 1.1 criteria, two patients had a stable disease (SD), and 3 had PR, including Interestingly CR of one of 2 tumors. We also treated 5 patients with metastatic renal cell carcinoma (RCC) using TALE with tumors ranging from 2.2 to 4.3 cm; using RECIST, three patients had PR, one SD, and one PD (progressive disease). Based on these results, we investigated the cytotoxic effects of Lipiodol in HCC and RCC cell lines Huh7 and A498. Lipiodol-Isovue emulsions were cytotoxic to these cells while viability of a normal/primary cell line HEK293 was not affected. Additionally, Lipiodol alone showed similar cytotoxic effects as the emulsions. Furthermore, Lipiodol was taken up by cells as seen by staining with Nile Red, a fluorescent dye that stains neutral lipids in lipid droplets using confocal microscopy. Our in vitro data indicate that RCC and HCC cells are more vulnerable to Lipiodol-induced lipotoxicity than non-cancerous primary kidney epithelial cells. There might be a synergistic effect between causing hypoxia as a result of blocking blood flow to the tumors during liver embolization and disrupting lipid homeostasis with the use of a Lipid-based emulsion. Our studies unravel a potential metabolic vulnerability that can be exploited therapeutically with liver-directed therapies. Citation Format: Smitha R. Pillai, Pravin Phadatare, Antonio Ortiz, Elie Barakat, Ghassan El-Haddad. Lipiodol-based emulsion to disrupt oxygenation and lipid homeostasis of liver tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1853.

Transdermal effectiveness of a lipid-based antimicrobial emulsion

Transdermal effectiveness of a lipid-based antimicrobial emulsion

In vivo study of hepatic oxidative stress and mitochondrial function in rabbits with severe hypotension after propofol prolonged infusion.

In humans, prolonged sedations with propofol or using high doses have been associated with propofol infusion syndrome. The main objective of this study was to evaluate the effects of prolonged high-dose administration of a specific propofol emulsion (Propofol Lipuro) and an improved lipid formulation (SMOFlipid) in liver mitochondrial bioenergetics and oxidative stress of rabbits, comparatively to a saline control. Twenty-one male New Zealand white rabbits were randomly allocated in three groups that were continuously treated for 20 h. Each group of seven animals received separately: NaCl 0.9 % (saline), SMOFlipid (lipid-based emulsion without propofol) and Lipuro 2 % (propofol lipid emulsion). An intravenous propofol bolus of 20 mg kg−1 was given to the propofol Lipuro group to allow blind orotracheal intubation and mechanical ventilation. Anesthesia was maintained using infusion rates of: 20, 30, 40, 50 and 60 mg kg−1 h−1, according to the clinical scale of anesthetic depth and the index of consciousness values. The SMOFlipid and saline groups received the same infusion rate as the propofol Lipuro group, which were infused during 20 consecutive hours. At the end, the animals were euthanized, livers collected and mitochondria isolated by standard differential centrifugation. Mitochondrial respiration, membrane potential, swelling and oxidative stress were evaluated. Data were processed using one-way ANOVA (p < 0.05). The animals revealed a significant decrease in cardiovascular parameters showing bradycardia and severe hypotension. No statistical differences were observed when using pyruvate as substrate, however, when using succinate as respiratory substrate, significant decrease in ADP-stimulated respiration rate was observed for SMOFlipid group (p = 0.002). Lipid peroxides (p < 0.01) and protein carbonyls (p = 0.01) showed a statistically significant difference between propofol Lipuro and the SMOFlipid groups. These results suggest that lipid-based emulsions can be involved in the regulation of different pathways that ultimately lead to a decrease of state 3 mitochondrial respiration rate. The infusion of propofol Lipuro during prolonged periods, in addition to marked hypotension and hypoperfusion, also showed to have higher anti-oxidant activity and lower impairment of the mitochondrial function comparatively to the improved lipid formulation, SMOFlipid, using the rabbit as animal model.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2970-2) contains supplementary material, which is available to authorized users.

Lipid-free Fluoropolymer-based Propofol Emulsions and Lipid Reversal of Propofol Anesthesia in Rats.

Propofol, as a lipid-based emulsion, is effective at inducing anesthesia. It does, however, suffer from several drawbacks, including microbial growth, hyperlipidemia, and pain on injection. In this study, the authors examined the ability of four lipid-free propofol nanoemulsions to induce anesthesia in rats and tested whether a subsequent lipid bolus would accelerate emergence from anesthesia. The authors administered five formulations of propofol intravenously to six rats, delivering five different doses five times each, in a repeated-measures randomized crossover design and measured time to loss and recovery of righting reflex. The formulations included (1) Diprivan (AstraZeneca, United Kingdom); (2) L3, incorporating a semifluorinated surfactant plus egg lecithin; (3) B8, incorporating a semifluorinated surfactant only; (4) F8, incorporating a semifluorinated surfactant plus perfluorooctyl bromide; and (5) L80, incorporating egg lecithin only. In a second phase of the study, the authors administered a lipid bolus immediately after a dose of B8 or Diprivan. All formulations except L80 impaired the righting reflex without apparent toxic effects. The authors estimated the threshold dose for induction by determining the x-intercept of the linear regression between time to recovery versus log dose. Threshold doses ranged from 5.8 (95% CI, 5.5 to 6.2) to 8.6 (95% CI, 7.2 to 10.2) mg/kg. A 15 ml/kg lipid bolus resulted in an accelerated clearance. Three of the four novel lipid-free fluoropolymer-based formulations showed efficacy in producing anesthesia, which was comparable to that of Diprivan, and a lipid bolus hastened recovery. These novel propofol formulations have the potential to avoid complications seen with the existing lipid-based formulation.

Lipid-Based Delivery System for Topical Phenytoin

Soluble Curcumin: A Promising Oral Supplement For Health ManagementPuneet Gandhi, Zeba Khan, Nivedita Chakraverty

Effects of propofol in lipid-based emulsion and in microemulsion on the incidence of endothelial lesion in rabbits

To compare the incidence of endothelial injury after single-dose or continuous propofol infusion in conventional lipid-based emulsion (LE) versus microemulsion (ME). Forty-two rabbits (2.5-4.5 Kg) were randomly allocated into seven groups of six animals each: SHAM- surgical treatment alone; Bolus Control Group - 3 mL-intravenous (IV) bolus of saline; Continuous Infusion Control Group - 3 mL- IV bolus of saline followed by a continuous infusion of 0.2 ml/kg/min for 60 min; Bolus LE Propofol Group - IV bolus of LE propofol (3 mg/kg); Bolus ME Propofol Group - IV ME propofol bolus (3 mg/kg); Continuous LE Propofol Group - IV LE propofol bolus (3 mg/kg) followed by a continuous infusion of 0.2 ml/kg/min for 60 min; Continuous ME Propofol Group - IV ME propofol bolus (3 mg/kg) followed by a continuous infusion of 0.2 ml/kg/min for 60 min. There were no statistically significant differences between the studied groups in blood pressure, in central venous pressure and in the biochemical profile. No significant differences were found in inflammatory mediators and in tissue analysis between the two emulsions. Microemulsion and lipid-based emulsion propofol had similar inflammatory, biochemical and microscopy profiles. Thus, microemulsion propofol can be used as an alternative to lipid-based emulsion propofol.

Intravenous Dosing Conditions May Affect Systemic Clearance for Highly Lipophilic Drugs: Implications for Lymphatic Transport and Absolute Bioavailability Studies

The clearance (Cl) and volume of distribution (V(ss)) of a lipophilic, lymphatically transported drug, halofantrine (Hf) have been evaluated after intravenous delivery to the systemic circulation in ex vivo lymph and plasma, and compared with the data obtained after administration of a lipid-based emulsion and a lipid-free cosolvent formulation. Systemic Cl and V(ss) were significantly lower (approximately twofold) after delivery of Hf in lymph or the emulsion when compared with the administration in plasma or the cosolvent formulation. Preadministration of drug-free lymph, immediately before administration of drug in plasma, however, resulted in plasma profiles consistent with that obtained after administration of drug in lymph/emulsion. Where drug and lipid entered the systemic circulation coincidentally, systemic Cl of Hf, therefore, appeared to be relatively unaffected by the route of entry to the systemic circulation (i.e. via the lymph or the blood), but more significantly altered by total plasma lipid levels. Because temporal changes to plasma lipid levels occur as a result of the absorption of formulation or food-derived lipids and the infusion of intravenous lipid emulsions, the current data suggest that a mismatch in plasma lipid levels after intravenous and oral administrations may lead to differences in drug Cl and errors in bioavailability assessment.

Development of ligustrazine-loaded lipid emulsion: Formulation optimization, characterization and biodistribution

Ligustrazine is a traditional Chinese medicine used to treat various cardiovascular and neurovascular complications. However, this compound exhibits rapid first-pass metabolism, a short biological half-life, low stability and potential vascular irritation that restrict its use for long-term therapy. The use of a lipid emulsion as a carrier for intravenous administration of ligustrazine might provide sustained and prolonged release, thereby reducing the frequency of administration and improving patient compliance. The main purpose of our study was to develop a highly stable and sterile optimal formulation of a ligustrazine lipid emulsion (LLE) and to evaluate its pharmacokinetic behavior and tissue distribution in rats. The final optimal formulation consisted of soybean oil (12.0%), oleic acid (0.6%), lecithin (1.0%), poloxamer 188 (0.6%) and glycerol (2.25%). The average particle size, polydispersity index (PDI), zeta-potential and pH of the final product were 215.0±2.5 nm, 0.076±0.033, -40.4±5.3 mV and 7.25±0.05, respectively. The LLE was stable for at least three months at room temperature. In vitro drug release studies of the LLE suggested a sustained release profile, which was further confirmed by in vivo pharmacokinetic studies in rats. The area under the drug concentration-time curve from 0 h to 10 h (AUC(0-10h)) for LLE was increased by 1.6-fold compared with that of the commercially available ligustrazine injection (LI), suggesting enhanced bioavailability from the lipid-based emulsion. Furthermore, a tissue distribution study showed significant improvement in the distribution pattern of ligustrazine with a higher AUC(0-180 min) observed in all tissues for LLE than for LI. In conclusion, LLE, with excellent stability, improved pharmacokinetics and tissue distribution, demonstrates great potential for the delivery of ligustrazine for clinical applications.

A novel ascorbic acid-resistant nitroxide in fat emulsion is an efficient brain imaging probe for in vivo EPR imaging of mouse

The loss of paramagnetism of nitroxide radicals due to reductant reactions in biological systems, places a fundamental time constraint on their application as an imaging probe in in vivo EPR imaging studies. However, in vitro studies of the newly synthesized tetraethyl-substituted piperidine nitroxide radical demonstrated high resistivity to paramagnetic reduction when exposed to ascorbic acid, a common reduction agent in biological systems. In this work we investigated the use of these nitroxides as an imaging probe in EPR imaging of small rodents. 2,2,6,6-Tetraethyl-piperidine nitroxide (TEEPONE) is not highly soluble in aqueous media, thus a lipid-based emulsion system of lecithin was used to solubilize TEEPONE. The obtained solution was homogenous and with low viscosity, allowing smooth intravenous injection into mice tail vein. Acquired three dimensional (3D) EPR images of mouse head clearly showed TEEPONE distributed in all tissues including brain tissues, with an average measurable signal half-life of more than 80 min, thus demonstrating high resistivity to reduction due to ascorbic acid in in vivo animal studies, and the potential for use of this compound in in vivo studies of animal model systems.

Lipid-based emulsion system as non-viral gene carriers

The genetic materials for systemic administration meet a number of hurdles before they reach the nucleus of the target cells, such as enzymatic degradation in the bloodstream, extravascularization around the target tissue, endocytosis by the target cells, and endosomal escape of the genes. Therefore, there have been tremendous needs of effective gene carriers that can deliver the genetic materials to the target site. Of numerous approaches, recent studies have demonstrated that the lipid-based emulsion systems have the high potential as non-viral gene carriers: 1 lipid emulsions are biocompatible because their major constituents are composed of the non-toxic oils and amphiphilic lipids; 2 the cationic lipid emulsions can form nano-sized complexes with negatively charged DNAs, through which the genetic materials can be protected from the enzymatic degradation in the body fluids; 3 The emulsion/DNA complexes are shown to be stable in the bloodstream since their surfaces are rarely recognized by the immune-related cells and serum proteins; and 4 the surfaces of the emulsion complexes are readily modified by varying the lipid composition. In this review, highlighted are the recent advances in the emulsion-based gene carriers.

In vivo time-dependent gene expression of cationic lipid-based emulsion as a stable and biocompatible non-viral gene carrier

To make stable and biocompatible non-viral gene carriers for therapeutic gene therapy, we developed a cationic lipid-based emulsion (CLE) prepared by an oil-in-water (O/W) emulsion method, wherein squalene oil was used as an oil core and the cationic lipid, 1,2-dioleoyl- sn-glycero-3-trimethylammonium-propane (DOTAP), was employed as an emulsifier. To evaluate in vivo characteristics such as toxicity and time-dependent gene expression, a bioluminescence reporter gene in pCMV- luc plasmid DNA was simply mixed with CLE in aqueous condition, resulting in a CLE/DNA complex. The CLE/DNA complex was optimized to form a compact and stable nano-sized particle by adding different amounts of plasmid DNA, and an optimal cationic lipid-to-DNA (C/D) weight ratio of 4 was identified. Freshly prepared CLE/DNA complex, with a C/D of 4, showed a high transfection efficiency and minimal cytotoxicity in vitro, compared to controls of a liposome (DOTAP)/DNA complex and a branched poly(ethyleneimine) (Mw = 25 kDa) (bPEI)/DNA complex, respectively. The in vivo characteristics of the CLE/DNA complex were evaluated after intravenous injection into Balb/c mice. Time-dependent gene expression data in vivo were obtained using a non-invasive, whole animal bioluminescence imaging system. These data showed that the CLE/DNA complex offered prolonged high-level gene expression for 1 week, particularly in the liver and spleen. On the other hand, the controls of DOTAP/DNA complex and bPEI/DNA complex showed a relatively lower gene expression, because of the unstable and toxic properties of the control carriers. Our in vivo gene expression data demonstrate the potential of the CLE/DNA complex as a non-viral gene carrier for in vivo gene delivery.

Low toxicity of cationic lipid-based emulsion for gene transfer

Cationic liposome has been studied as one of the most promising non-viral gene delivery systems. However, it has major drawbacks such as the formation of large aggregates at higher concentrations and the instability in the serum due to cationic lipid. As an alternative gene delivery system, cationic emulsion was formulated and transfection efficiency was evaluated in vitro and in vivo, in comparison with cationic liposome. Cationic emulsion was prepared with varying compositions of 3 β [ N-( N′, N′-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol), dioleoylphosphatidyl ethanolamine (DOPE), caster oil and Tween 80. Cationic liposome was prepared with DC-Chol and DOPE. The particle size of all the DNA/lipid complexes varied from 150 to 230 nm. The in vitro transfection efficiency of plasmid DNA was assessed by the expression of green fluorescent protein as a reporter. Of various formulations, cationic emulsion E2 (DC-Chol/DOPE/Castor Oil/Tween 80=0.3:0.3:0.3:0.15) and cationic liposome L3 (DC-Chol/DOPE=0.6:0.3) showed improved transfection. DNA/E2 complexes exhibited higher transfection efficiencies (17.39±0.58%) in comparison with DNA/L3 complexes (11.47±0.59%). DNA/E2 complexes also showed a better physical stability and a stronger serum resistance than DNA/L3 complexes. Moreover, the cytotoxicity of DNA/E2 complexes was comparable to that of DNA/L3 complexes. When DNA/lipid complexes were intravenously administered, DNA/E2 complexes showed a prolonged circulation in blood and mRNA expression in various tissues compared with DNA/L3 complexes. These results suggest that cationic emulsion E2 could be a potential gene delivery system in clinical approaches because of enhanced in vivo gene transfer with low toxicity.

Copper-catalyzed oxidation of a structured lipid-based emulsion containing alpha-tocopherol and citric acid: influence of pH and NaCl.

The effects of salt and pH on copper-catalyzed lipid oxidation in structured lipid-based emulsions were evaluated. Ten percent oil-in-water emulsions were formulated with a canola oil/caprylic acid structured lipid and stabilized with 0.5% whey protein isolate. alpha-Tocopherol and citric acid were added to the emulsions to determine how changes in pH or the addition of NaCl affected their antioxidant activity. The peroxide values and anisidine values of emulsions stored at 50 degrees C were measured over an 8-day period. Increased lipid oxidation occurred in the pH 7.0 emulsions and when 0.5 M NaCl was added to the pH 3.0 samples. Adding alpha-tocopherol, citric acid, or a combination of the two compounds slowed the formation of hydroperoxides and their subsequent decomposition products in pH 3.0 emulsions.

The association of propofol usage with postoperative wound infection rate in clean wounds: a retrospective study.

To determine if the use of propofol influences the postoperative infection rate of clean surgical wounds in dogs and cats. Retrospective study. 863 dogs and cats undergoing clean surgical procedures. Medical and anesthetic records of surgical cases used as part of a previously described epidemiologic study on postoperative wound infection rates were reviewed. The records of all animals with clean surgical wounds were reviewed to determine if propofol had been used for anesthetic induction or maintenance during the procedure. To determine the effect of propofol use on wound infection rate, data were analyzed using Fisher's exact test, followed by multiple logistic regression to adjust for various factors, including surgery time, time from clipping to surgery, antibiotic usage, coexisting distant infection, endocrine disease, and the use of immunosuppressive drugs in the perioperative period. Of 863 dogs and cats with clean surgical wounds, 46 received propofol as part of the anesthetic protocol. A total of 6 of 46 animals (13%) receiving propofol developed postoperative wound infections, compared with 33 of 817 animals (4%) not receiving propofol (P = .014; % difference = 9%; 95% CI = 0.5% to 24%). Adjusting for all other factors evaluated, animals receiving propofol were 3.8 times more likely to develop postoperative wound infections compared to animals not given propofol (95% CI = 1.5-9.9). Propofol is a lipid-based emulsion capable of supporting microbial growth. Administration of a potentially contaminated solution may contribute to surgical wound infection or other patient morbidity or mortality. Strict aseptic technique in the preparation of the solution and prompt disposal of unused drug are imperative to curtail the potential for extrinsic contamination.

Commentary: Liposomes or Lipid Science?

The Journal of Liposome Research is a misleading name. It implies that our chief concern should be liposomes, which most people understand to be single or multilamellar vesicles. Such a single-minded focus would not only be boring, it would fail to describe the breadth of the field or the preoccupations of most of the practitioners. A more accurate title for what most readers expect from this journal might be Journal of Lipid-Based Delivery Systems, which would also cover, for example, lipid systems for delivering DNA into cells, polymer-lipid delivery vehicles, lipid-based emulsion systems, etc. Although this title might be more accurate, I, for one, would find it disappointing because it implies that our sole concern is how lipids could be used as delivery systems in the pharmaceutical industry. My preferred title–though I doubt that the Editor would stand for it– would be the Journal of Lipid-Based Delivery Systems and All the Other Research Related to Lipids That Any Scientist with a Healthy Curiosity Ought to Find Interesting. A bit awkward perhaps, but at least it conveys a sense, not of where we are, but where many us feel we should be.