Establishing a Stability Window for Medium- and Long-chain-triglyceride Lip
Abstract and Introduction
Purpose: The stability window of medium-chain triglyceride (MCT) and long-chain-triglyceride (LCT) lipid-based total nutrient admixtures (TNAs) was studied.
Methods: Sixteen different admixtures were selected for study. Of these, eight base macronutrient concentrations representing low and high concentrations were selected, along with low and high concentrations of electrolytes. All TNAs studied contained 2 mg of elemental iron as part of the trace-element formulation, an amount previously shown to produce unstable TNAs with pure LCT-based lipid injectable emulsions. All admixtures were prepared in triplicate and analyzed over five time intervals: time 1 (immediately after preparation), time 2 (after four days of storage at 6 ± 2 °C), and times 3, 4, and 5, corresponding to 6, 24, and 30 hours of storage at 25 ± 2 °C, respectively, after time 2. Stability was measured by comparing results with USP standards for fat globule size in lipid injectable emulsions.
Results: A total of 48 admixtures were studied. Samples at each time interval showed an inconsistent but general increase in the number of globules with a diameter of >1.8 μm over time. All admixtures met both the proposed pharmacopeial criteria for stability with respect to mean droplet size and volume-weighted proportion of fat globules with a diameter of >5 μm.
Conclusion: A wide range of macronutrients and micronutrients were tested in a series of MCT-LCT-based TNAs and found to be stable. The use of MCTs and LCTs in lipid injectable emulsions confers greater stability to TNAs than has been achieved with pure LCT-based formulations.
Lipid injectable emulsions are thermodynamically unstable systems with a shelf life of 18-24 months from the date of manufacture. During commercial production of lipid injectable emulsions, the formulations typically undergo homogenization during which a concentrated mixture of oil, water, and emulsifier is forced through a small orifice at high pressures, ultimately yielding a submicronsized dispersion of lipid droplets in water. The subsequent nanosized droplets are stabilized by a lecithin emulsifier containing surface-active egg phospholipids that adsorb along the oil-water interface of each droplet. Acting as an amphipathic surfactant, the phospholipid is composed of a hydrophilic "head" and a lyophilic "tail" (Figure 1). The hydrophilic head group (R3 position of the triglyceride) extends outward into the continuous aqueous phase, with the polar phosphate group becoming ionized. The expected pH range is 6.0-9.0 for lipid injectable emulsions, as proposed in the United States Pharmacopeia (USP). The lyophilic tail groups (R1 and R2 positions of the triglyceride) are long-chain fatty acids, similar to those found in the long-chain triselected, along with low and high concenglycerides (LCTs) contained in the oil phase, where they are more or less miscible with the lipid droplets along the oil-water interface, forming a thin protective coating. The final dispersion is ionically stabilized via the net negative charge imparted by the emulsifier to each droplet, thereby conferring electrostatic repulsion. The resulting zeta potential associated with the droplet surface charge can be measured. In freshly manufactured lipid injectable emulsions with a pH of 6.0-9.0, the zeta potential is generally -30 to -50 mV. This common electrostatic repulsion prevents droplet aggregation that would otherwise occur in the absence of an effective surfactant due to the overwhelming Van der Waals attractive forces that normally exist between the nonpolar lipid droplets. The emulsion is therefore temporarily stabilized throughout its shelf life, thus forestalling the inevitable separation of the internal oil phase from the external aqueous phase. In stable lipid injectable emulsions, the goal of the pharmaceutical manufacturer is to minimize the population of largediameter fat globules found in the extreme (outlier) tail of the globule size distribution (GSD). Recently, the United States Pharmacopeial Convention proposed globule size limits on both the mean droplet diameter (MDD) and the population of largediameter fat globules.
General structure of the phospholipid emulsifier and functional groups in egg lecithin. R1 and R2 are long-chain fatty acids (palmitic acid [16:0] and linoleic acid [18:2n-6], respectively). R3 is an alcohol (e.g., choline [C5H14NO]).
Instability of the emulsion system is manifested as an increase in the number of large-diameter fat globules whenever the egg phospholipid surfactant fails to maintain an effective surface charge and associated zeta potential. During destabilization of the emulsion, the once-predominant population of submicron droplets becomes progressively replaced by very large (>5 μm) fat globules through coalescence (i.e., fusion of droplets). Coalescence can be accelerated before the manufacturer-assigned expiration date is reached (e.g., as a result of exposure to temperature extremes [<4 °C or >30 °C] or excessive concentrations of electrolytes during the compounding of total nutrient admixtures [TNAs]). Recent evidence has demonstrated that conventional LCTs (e.g., soybean oil-in-water emulsion) are less stable as TNAs than triglycerides prepared from lipid injectable emulsions containing mixtures of both LCTs and medium-chain triglycerides (MCTs) in high osmolality (centralvein infusion) and low osmolality (peripheral-vein infusion) formulations. In addition, MCT-LCT emulsions have been used to produce stable TNAs indicated for the neonatal and pediatric populations in whom pure LCTs have failed. The stabilizing influence of lipid injectable emulsions containing MCTs is most likely due to the favorable interfacial location of MCTs at the droplet surfaces in these mixed emulsions.
The purpose of this study was to investigate the stability window of these MCT-LCT emulsions by testing clinically relevant extremes in the concentrations of macronutrients and electrolytes. In addition, we added a trace-element preparation containing elemental iron in a concentration previously shown to be the most significant factor causing destabilization in a large study of pure LCTs.