Pharmaceutical Considerations and Metabolic Fate of Parenteral Lipid Nanoparticle Dosage Forms.

The physical stability of parenteral dispersions for delivery of drugs to patients is of particular clinical importance, given their general overall superior bioavailability compared to other routes of administration. Although official pharmacopeial methods for lipid injectable emulsions have been established for triglyceride oil-in-water dispersions (i.e., "mini-emulsions") through USP Chapter <729>, no pharmaceopeial guidance exists for lipid nanoparticle (LNP)-based "micro-emulsions". At present, there are several LNP-based drugs approved for clinical use, including mRNA vaccines. Moreover, the increased interest in using mRNA as a platform technology for an array of potential therapeutic drug candidates increases the importance of developing appropriate methods to ensure their physical stability, safety and efficacy. For all dispersions and by various detection mechanisms (e.g., electrical, mechanical, mathematical), the fusion or growth of droplets/particles in the large-diameter tails of the particle size distribution (PSD) signals the onset of instability. Consequently, the measurement for LNP dispersions will require the use of a modified optical detection design in order to extend the lower particle detection limit into the "relative" large-diameter tail of the PSD for both light extinction and light-scattering methods based on single-particle optical sensing techniques. Fortunately, the technology is currently available and capable of providing the requisite quantitative analysis.

Omega-3 Fatty Acids as Antiarrhythmic Drugs: Upstream Target Modulators Affecting Acute and Long-Term Pathological Alterations in Cardiac Structure and Function.

OBJECTIVES: Postoperative atrial fibrillation (POAF) is a common complication in the acute care period following coronary artery bypass grafting (CABG) surgery that is associated with significant morbidity and mortality in both short-term and long-term settings. Recently, the Vaughn Williams Classification of antiarrhythmic agents, first proposed in 1975 and widely viewed as the authoritative description of their electrophysiologic actions, was updated and notably omega-3 fatty acids (Ω-3 fatty acids) have been included in class VII, described as "upstream target modulators," to mitigate pathological structural and electrophysiological remodeling changes in the aged and/or injured myocardium. DATA SOURCES: A PubMed literature search was performed. STUDY SELECTION: Studies examining the significance of complications in patients undergoing isolated CABG surgery were selected for inclusion. DATA EXTRACTION: Relevant data were qualitatively assessed and narratively summarized. DATA SYNTHESIS: POAF occurs in approximately 30% of patients, and inflammation from chronic coronary artery disease preoperatively, as well as acute atrial inflammation from surgery postoperatively are the leading causes. Inflammation underlies its pathophysiology; therefore Ω-3 fatty acids not only exhibit antiarrhythmic properties but are an effective anti-inflammatory treatment that may reduce the clinical risks of POAF. CONCLUSIONS: At present no effective prophylaxis is available to address POAF following CABG surgery. Clinical approaches that focus on the inflammatory response in this setting may optimize the response to treatment. The current literature supports the hypothesis that Ω-3 fatty acids may acutely reduce the inflammatory response via favorable alterations in the metabolism of prostaglandins and leukotrienes (eicosanoids) and specialized pro-resolving mediators.

Cytokine storm associated with severe COVID-19 infections: The potential mitigating role of omega-3 fatty acid triglycerides in the ICU.

Cytokine storm during severe COVID-19 infection increases the risk of mortality in critically ill patients in the intensive care unit. Multiple therapeutic proposals include, for example, anti-inflammatory and immunosuppressive agents, selective inhibitors of key pro-inflammatory receptors, and key enzymes necessary for viral replication. Unfortunately, safe and effective therapy remains an elusive goal. An alternative anti-inflammatory approach vis á vis omega-3 fatty acids, which yields less pro-inflammatory mediators by altering eicosanoid metabolism, has been proposed. Although theoretically promising, enteral tube delivery or oral capsules containing specific doses of omega-3 fatty acids take precious time (7 days to 6 weeks) to be incorporated in plasma cell membranes to be most effective, making this route of administration in the acute care setting an unfeasible therapeutic approach. Parenteral administration of precise doses of omega-3 fatty acid triglycerides in an injectable emulsion can greatly accelerate the incorporation and potential therapeutic effects (within hours), but at present, there is no commercially available product designed for this purpose. We describe a potential formulation that may address this deficiency, while recognizing that the high incidence of hyperlipidemia that occurs during severe COVID-19 infection must be recognized as a complicating factor, and, therefore, caution is advised.

Proinflammatory mediators in lipid emulsions and parenteral nutrition-associated liver disease: Review of leading factors.

Lipid injectable emulsions have been in clinical use for over 60 years. The first product launched was Intralipid, which consisted of an emulsion of soybean oil in water for intravenous administration. It was a key source of essential fatty acids and an alternative source of energy for patients with gastrointestinal dysfunction requiring long-term parenteral nutrition. With clinical experience, a condition known as parenteral nutrition-associated liver disease (PNALD), or intestinal failure-associated liver disease (IFALD), was observed, with a focus on carbohydrate and fat energy. Modifying the daily doses and infusion rates had some salutary effects, but PNALD persisted. Subsequently, on closer inspection of the fatty acids profile and phytosterol concentrations, degradation products arising from chemical and physical stability issues of the available lipid injectable emulsions were implicated. Recently, the US Food and Drug Administration convened an online workshop entitled "The Role of Phytosterols in PNALD/IFALD," with an emphasis on (1) the multifactorial pathophysiology of PNALD/IFALD, (2) risk associated with phytosterols, and (3) regulatory history. The scope of this review includes the multifactorial pathophysiology of PNALD/IFALD as it relates to the pharmaceutical aspects of the various lipid injectable emulsions on the market, with respect to potential proinflammatory components, as well as physical and chemical stability issues that may also affect products' safe intravenous administration to patients.

Potentially Important Therapeutic Interactions between Antibiotics, and a Specially Engineered Emulsion Drug Vehicle Containing Krill-Oil-Based Phospholipids and Omega-3 Fatty Acids.

The incidence of antimicrobial resistance (AMR) worldwide is increasing as the pipeline for the development of new chemotherapeutic entities is decreasing. Clearly, overexposure to antibiotics, including excessive dosing, is a key factor that fuels AMR. In fact, most of the new antibacterial agents under development are derivatives of existing classes of antibiotics. Novel approaches involving unique antimicrobial combinations, targets, and/or delivery systems are under intense investigation. An innovative combination of active pharmaceutical ingredients (APIs) consisting of antimicrobial drug(s), krill-oil-based phospholipids, and omega-3 fatty acid triglycerides, that may extend the therapeutic viability of currently effective antibiotics, at least until new chemical entities are introduced, is described.

Pharmaceutical and Clinical Aspects of Lipid Injectable Emulsions.

The first clinically successful lipid injectable emulsion was marketed in 1961, consisting of soybean oil triglycerides in sterile water for injection. Since that time, numerous products have entered the market, with the main difference being changes in the oil composition with triglycerides of plant and marine oil origin. With this change, the fatty acid profiles are unique, coming from medium- and long-chain triglycerides. The fatty acids can be saturated or unsaturated, having different pharmaceutical and metabolic activities that affect the safety and efficacy of these unique pharmaceutical dosage forms.

Commercial lipid emulsions and all-in-one mixtures for intravenous infusion - composition and physicochemical properties.

In the 20th century, the potential clinical application of lipid emulsions (LEs) for intravenous application was extensively studied, and this goal was eventually accomplished. The first safe LE for clinical use that was based on soybean oil was introduced in 1961. In the 1980s, LEs based on mixtures of soybean oil and medium-chain triglycerides (MCTs) were introduced. More recently, LEs combining various oils (soybean, MCT, fish and olive oils) have become available for safe clinical use in both acute care and long-term settings. This article focuses on the following essential aspects of the current formulations: (1) the basic physicochemical properties; (2) the relevant pharmacopoeial standards; and (3) important clinical issues to ensure their safe use in patients. LEs with a variety of chemical compositions are commercially available. They adhere to standards laid down in relevant pharmacopoeias, and they are safe to use. Different compositions may result in different functional properties.

Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities.

OBJECTIVE: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities. STUDY DESIGN: This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities. RESULTS: Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late-onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1). CONCLUSION: Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis.

Stability of MCT/LCT-based total nutrient admixtures for neonatal use over 30 hours at room temperature: applying pharmacopeial standards.

BACKGROUND: United States Pharmacopeial Chapter <729> places a limit on the percentage of large fat globules >5 microm, expressed as a PFAT5 of <0.05% for all native lipid emulsions. Some adult total nutrient admixtures (TNAs) have also remained below this limit for up to 48 hours. In 2003, medium-chain/long-chain triglyceride (MCT/LCT)-based neonatal TNAs with between 2% and 3% amino acid (AA) concentrations were shown to be similarly stable by the PFAT5 parameter. Stability assessment of neonatal TNAs with AA <2% or > or =3% were tested. METHODS: Eight neonatal TNAs with various combinations of AA (1%, 1.5%, 3%, and 4%), glucose (G; 5% and 10%), and MCT/LCT (ML; 2% and 4%) and standard concentrations of additives were tested in triplicate (n = 24) over 30 hours (immediately after mixing, then at 6, 24, and 30 hours) at 25 degrees C +/- 2 degrees C. PFAT5 determinations for all 24 formulations were made in duplicate, immediately after mixing, and then at 6, 24, and 30 hours later. Mean droplet size (MDS) and pH were assessed at the outset and end of the study. RESULTS: The differences in the PFAT5 levels were significant (P < .001) by a 2-way analysis of variance based on formula and time as the independent variables. The TNAs with 1% and 1.5% AA with all Gs and MLs (group 1, n = 12) had PFAT5 levels >0.05% (up to 0.50%) in most samples (68 of 96 samples, or 71% of cases) in the study, whereas in the same TNAs, but made with 3% and 4% AA (group 2, n = 12), 100% of samples (all 96 cases) had PFAT5 levels <0.05% (up to 0.04%), and this difference was significant (P < .001). Pairwise comparisons between groups based on overall values of PFAT5, MDS, and pH showed significant differences between groups for all variables. CONCLUSIONS: For neonatal TNAs, AA level is the most sensitive determinant of stability, and the PFAT5 parameter is the most sensitive indicator of stability.

Calcium and phosphate compatibility in low-osmolarity parenteral nutrition admixtures intended for peripheral vein administration.

BACKGROUND: Precipitation of calcium (Ca) and phosphate (P) salts can lead to potentially lethal outcomes, especially in low-osmolarity parenteral nutrition (LO-PN) formulations. Three concentrations of amino acids (AA) and 2 concentrations of calcium gluconate and sodium phosphate injections on the compatibility of Ca and P in LO-PN admixtures were studied. METHODS: Final AA concentrations of 1%, 2%, or 3% (n = 3) and 5% glucose (G) were prepared with either 2.5 or 5 mmol/L (5 or 10 mEq) of Ca (n = 2) and 15 or 30 mmol/L of P (n = 2) for a total of 12 base (3 x 2 x 2) formulations. Triplicate bags of each were analyzed for subvisible micro-precipitates using the light obscuration (or extinction) method for particle counts per milliliter (PC) in the size range of 1.8-50 mum at 7 time intervals over 48 hours stored at 30 degrees C +/- 0.2 degrees C. Visual evaluation was performed using a high-intensity lamp against a black background for detection of macro-precipitates. The pH of all 36 admixtures was measured at 0 and 48 hours. Any precipitated material was isolated and characterized by polarized light microscopy and infrared spectroscopy. RESULTS: Of the 12 base LO-PN formulations tested, those containing 1% and 2% AA with 5 mmol/L of Ca and 30 mmol/L of P showed significant increases in PC, and some resulted in visible dibasic calcium phosphate precipitation. Analyses of variance based on concentrations of AA, Ca, P, and time were highly significant independent variables for increases in the PC of potentially embolic particles, that is, sizes >5 mum (P < .0001). The lowest concentrations of Ca and P, 2.5 and 15 mmol/L, respectively, had significantly lower PC (P < .05) for all sizes compared with the other Ca and P combinations. CONCLUSIONS: LO-PN admixtures (AA

Pharmacopeial compliance of fish oil-containing parenteral lipid emulsion mixtures: Globule size distribution (GSD) and fatty acid analyses.

Recently, the United States Pharmacopeia (USP) has established Chapter 729 with GSD limits for all lipid emulsions where the mean droplet size (MDS) must be <500 nm and the percent of fat larger than 5 microm (PFAT(5)) must be <0.05%, irrespective of the final lipid concentration. As well, the European Pharmacopeia (EP) Monograph no. 1352 specifies n3-fatty acid (FA) limits (EPA+DHA> or =45%; total n3 or T-n3> or =60%) for fish oil. We assessed compliance with USP physical and EP chemical limits of two fish oil-containing lipid emulsion mixtures. All lipid emulsions passed USP 729 limits. No samples tested had an MDS >302 nm or a PFAT(5) value >0.011%. Only one product met EP limits while the other failed. All emulsions tested were extremely fine dispersions and easily met USP 729 GSD limits. The n3-FAs profiles were lower in one, despite being labeled to contain 50% more fish oil than the other product. This latter finding suggests the n3-FA content of the fish oil source and/or the applied manufacturing processes in these products is different.

Lipid globule size in total nutrient admixtures prepared in three-chamber plastic bags.

PURPOSE: The stability of injectable lipid emulsions in three-chamber plastic (3CP) bags, applying the globule-size limits established by United States Pharmacopeia ( USP ) chapter 729, was studied. METHODS: A total of five premixed total nutrient admixture (TNA) products packaged in 3CP bags from two different lipid manufacturers containing either 20% soybean oil or a mixture of soybean oil and medium-chain-triglyceride oil as injectable lipid emulsions were tested. Two low-osmolarity 3CP bags and three high-osmolarity 3CP bags were studied. All products were tested with the addition of trace elements and multivitamins. All additive conditions (with and without electrolytes) were tested in triplicate at time 0 (immediately after mixing) and at 6, 24, 30, and 48 hours after mixing; the bags were stored at 24-26 degrees C. All additives were equally distributed in each bag for comparative testing, applying both globule sizing methods outlined in USP chapter 729. RESULTS: Of the bags tested, all bags from one manufacturer were coarse emulsions, showing signs of significant growth in the large-diameter tail when mixed as a TNA formulation and failing the limits set by method II of USP chapter 729 from the outset and throughout the study, while the bags from the other manufacturer were fine emulsions and met these limits. Of the bags that failed, significant instability was noted in one series containing additional electrolytes. CONCLUSION: Injectable lipid emulsions provided in 3CP bags that did not meet the globule-size limits of USP chapter 729 produced coarser TNA formulations than emulsions that met the USP limits.

Hepatic indicators of oxidative stress and tissue damage accompanied by systemic inflammation in rats following a 24-hour infusion of an unstable lipid emulsion admixture.

BACKGROUND: Use of lipid emulsions in parenteral nutrition therapy is an important source of daily energy in substitution of potentially harmful glucose calories when given in excess in the intensive care unit. When added to parenteral nutrition (PN) admixtures as a total nutrient admixture (TNA), the stability and safety of the emulsion may be compromised. Development of a rat model of a stable vs unstable lipid infusion would enable a study of the potential risk. DESIGN: Prospective, randomized, controlled study. METHODS: Surgical placement of a jugular venous catheter for the administration of TNAs was performed. Two groups were studied: a stable or s-TNA (n = 16) and an unstable or u-TNA (n = 17) as a 24-hour continuous infusion. Stability of TNAs was determined immediately before and after infusion using a laser-based method approved by the United States Pharmacopeia. RESULTS: Blood levels of aspartate aminotransferase, glutathione-S-transferase, and C-reactive protein were significantly elevated in u-TNA vs s-TNA (P < .05). Also, liver tissue concentrations of malondialdehyde were significantly higher in the u-TNA group (P < .05), and triglyceride tissue levels were also higher in u-TNA and approached statistical significance (P = .077). CONCLUSIONS: Unstable lipid infusions over 24 hours produce evidence of hepatic accumulation of fat associated with oxidative stress, liver injury, and a low-level systemic inflammatory response.